Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders: A review.

PubMed

Yan, Yishu; Ji, Yang; Su, Nan; Mei, Xiang; Wang, Yi; Du, Shanshan; Zhu, Wenming; Zhang, Chong; Lu, Yuan; Xing, Xin-Hui

2017-03-15

Low molecular weight heparins (LMWHs) are produced by chemical or enzymatic depolymerization of unfractionated heparin (UFH). Besides their well-known anticoagulant effects, LMWHs have also been reported to exhibit numerous anti-inflammatory properties. Previous studies have, however, shown that different production processes result in unique structural characteristics of LMWHs. The structural variations may help explain the different therapeutic spectrums in disease treatment for non-anticoagulant effects. In the present review, we summarize major advances in understanding and exploiting the anti-inflammatory disorder activities of LMWHs, based on mechanistic studies, preclinical experiments and clinical trials. We highlight differences in these activities of commercially available LMWHs produced using different manufacturing processes. We stress the importance of structure-activity relationship (SAR) studies on the non-anticoagulant effects of LMWHs and discuss strategies for exploring new clinical indications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis.

PubMed

Murphy, Sabina A; Gibson, Charles Michael; Morrow, David A; Van de Werf, Frans; Menown, Ian B; Goodman, Shaun G; Mahaffey, Kenneth W; Cohen, Marc; McCabe, Carolyn H; Antman, Elliott M; Braunwald, Eugene

2007-09-01

To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint. We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97). When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.

Anticoagulation management in the ambulatory surgical setting.

PubMed

Eisenstein, Diana Hill

2012-04-01

Many people receiving maintenance anticoagulation therapy require surgery each year in ambulatory surgery centers. National safety organizations focus attention toward improving anticoagulation management, and the American College of Chest Physicians has established guidelines for appropriate anticoagulation management to balance the risk of thromboembolism when warfarin is discontinued with the risk of bleeding when anticoagulation therapy is maintained. The guidelines recommend that patients at high or moderate risk for thromboembolism should be bridged with subcutaneous low-molecular-weight heparin or IV unfractionated heparin with the interruption of warfarin, and low-risk patients may require subcutaneous low-molecular-weight heparin or no bridging with the interruption of warfarin. The guidelines recommend the continuation of warfarin for patients who are undergoing minor dermatologic or dental procedures or cataract removal. The literature reveals, however, that there is not adequate adherence to these recommendations and guidelines. Management of anticoagulation therapy by a nurse practitioner may improve compliance and safety in ambulatory surgery centers. Copyright © 2012 AORN, Inc. Published by Elsevier Inc. All rights reserved.

VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy

PubMed Central

Greer, Ian A.; Middeldorp, Saskia; Veenstra, David L.; Prabulos, Anne-Marie; Vandvik, Per Olav

2012-01-01

Background: The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy. Methods: The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B). Conclusions: Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population. PMID:22315276

Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism.

PubMed

van der Heijden, J F; Hutten, B A; Büller, H R; Prins, M H

2002-01-01

People with venous thromboembolism are generally treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin followed by three months of vitamin K antagonists treatment. Treatment with vitamin K antagonists requires regular laboratory measurements and some patients have contraindications for treatment. To evaluate the efficacy and safety of long-term treatment of venous thromboembolism with low-molecular-weight heparins compared to vitamin K antagonists. Searches of MEDLINE, EMBASE and ISI Web of Science, the Specialised Trials Register of the Cochrane Peripheral Vascular Disease Group and the Cochrane Controlled Trials Register were made and relevant journals were hand-searched. Additional trials were sought through communication with colleagues and pharmaceutical companies. Two reviewers evaluated studies independently for methodological quality. Two reviewers extracted data independently. Primary analysis concerned all trial participants during the period of randomized treatment. Separate analyses were performed for category I and category II studies; i.e. studies using similar treatments initially in both study arms, and those that did not; and the different periods of follow-up. All seven studies fulfilling our criteria combined, a statistically non-significant reduction in the risk of recurrent venous thromboembolism favoring low-molecular-weight heparin treatment (OR 0.70; 95% CI [0.42, 1.16]) was found. Analysis of pooled data for category I studies showed a non-significant reduction in the risk of recurrent venous thromboembolism favoring low-molecular-weight heparin treatment (OR 0.75; 95% CI [0.40, 1.39]). Omitting a potentially-confounded study, a statistically non-significant reduction in the risk of recurrent venous thromboembolism favoring vitamin K antagonist treatment remained (OR 1.95; 95% CI [0.74, 5.19]). All studies combined, the difference in bleeding significantly favored treatment with low-molecular-weight heparin (OR 0.38; 95% CI [0.15, 0.94]), however, considering only category I studies a non-significant trend favoring low-molecular-weight heparin remained (OR 0.80; 95% CI [0.21, 3.00]). No difference was observed in mortality (OR 1.13; 95% CI [0.47, 2.69]). Low-molecular-weight heparins are possibly as effective as vitamin K antagonists in preventing symptomatic venous thromboembolism after an episode of symptomatic deep venous thrombosis, but are much more expensive. Treatment with low-molecular-weight heparin is significantly safer than treatment with vitamin K antagonists and is possibly a safe alternative in some patients; especially those in geographically inaccessible places, reluctant to visit the thrombosis service regularly, or with contraindications to vitamin K antagonists. However, treatment with vitamin K antagonists remains the treatment of choice for the majority of patients.

Heparin in acute ischemic stroke revisited.

PubMed

Chamorro, A

2008-10-01

The evidence gathered in clinical trials of low molecular weight heparins (LMWHs) or with unfractionated heparin (UH) given subcutaneously at low or medium doses to patients with acute stroke cannot be extrapolated to the insufficiently tested effects of intravenous, weight-adjusted UH. Recent small studies have provided encouraging results but are potentially confounded and deserve confirmation in larger randomized controlled trials. In accordance with the current understanding of the biology of acute ischemic stroke and the pharmacology of UH, the new randomized controlled trials on heparin should give appropriate credit to the importance of a short therapeutic window, adequate dose adjustment of the drug, intravenous administration, and close monitoring of biological effects. UH is an orphan drug and only an academic driven trial would be able to face such an enterprise. Meanwhile, recommendations against the value of "early" anticoagulation with full dose of weight adjusted UH in the setting of acute ischemic stroke are not based on direct evidence but on extrapolations.

Spontaneous heparin-induced thrombocytopenia presenting as bilateral adrenal hemorrhages and pulmonary embolism after total knee arthroplasty.

PubMed

Elshoury, Amro; Khedr, Maha; Abousayed, Mostafa M; Mehdi, Syed

2015-09-01

Heparin-induced thrombocytopenia syndrome is an acquired potentially life-threatening prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 bound to heparin or heparin-like molecules. It typically occurs after exposure to unfractionated heparin, to a lesser extent after exposure to low-molecular-weight heparins, and rarely after exposure to fondaparinux. Herein, we report the case of a 48-year-old woman who developed severe thrombocytopenia, bilateral pulmonary embolism, and bilateral adrenal hemorrhages after total knee arthroplasty without evidence of heparin exposure. Antibodies to the heparin-platelet factor 4 complex and serotonin-release assay were positive. Spontaneous heparin-induced thrombocytopenia syndrome should be considered in patients with unexplained thrombocytopenia after knee replacement surgery even without heparin exposure, and a high index of suspicion for adrenal hemorrhage is needed in patients with fever, abdominal pain, and shock.

Electrophoresis for the analysis of heparin purity and quality.

PubMed

Volpi, Nicola; Maccari, Francesca; Suwan, Jiraporn; Linhardt, Robert J

2012-06-01

The adulteration of raw heparin with oversulfated chondroitin sulfate (OSCS) in 2007-2008 produced a global crisis resulting in extensive revisions to the pharmacopeia monographs and prompting the FDA to recommend the development of additional methods for the analysis of heparin purity. As a consequence, a wide variety of innovative analytical approaches have been developed for the quality assurance and purity of unfractionated and low-molecular-weight heparins. This review discusses recent developments in electrophoresis techniques available for the sensitive separation, detection, and partial structural characterization of heparin contaminants. In particular, this review summarizes recent publications on heparin quality and related impurity analysis using electrophoretic separations such as capillary electrophoresis (CE) of intact polysaccharides and hexosamines derived from their acidic hydrolysis, and polyacrylamide gel electrophoresis (PAGE) for the separation of heparin samples without and in the presence of its relatively specific depolymerization process with nitrous acid treatment. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Electrophoresis for the analysis of heparin purity and quality

PubMed Central

Volpi, Nicola; Maccari, Francesca; Suwan, Jiraporn; Linhardt, Robert J.

2012-01-01

The adulteration of raw heparin with oversulfated chondroitin sulfate (OSCS) in 2007–2008 produced a global crisis resulting in extensive revisions to the pharmacopeia monographs and prompting the FDA to recommend the development of additional methods for the analysis of heparin purity. As a consequence, a wide variety of innovative analytical approaches have been developed for the quality assurance and purity of unfractionated and low-molecular-weight heparins. This review discusses recent developments in electrophoresis techniques available for the sensitive separation, detection, and partial structural characterization of heparin contaminants. In particular, this review summarizes recent publications on heparin quality and related impurity analysis using electrophoretic separations such as capillary electrophoresis (CE) of intact polysaccharides and hexosamines derived from their acidic hydrolysis, and polyacrylamide gel electrophoresis (PAGE) for the separation of heparin samples without and in the presence of its relatively specific depolymerization process with nitrous acid treatment. PMID:22736353

[Neutralization of anticoagulant activity of heparin by N-[(2-hydroxy-3-trimethylammonium) propyl] chloride derivatives of chitosan].

PubMed

Shagdarova, B Ts; Drozd, N N; Il'ina, A V; Logviniva, Yu S; Varlamov, V P

2016-01-01

Alkylated derivatives of low molecular weight chitosan with different substitution degrees of 98, 40, and 9% (I, II, and III respectively) have been synthesized. The structure of the obtained derivatives was defined by spectral assays (IR-spectroscopy and proton magnetic resonance). Chitosan derivatives were characterized with positive zeta-potential (33–51 mV) and solubility from 2 to 100 mg/mL in pH 7.4 and 25°C. It was shown that, at a concentration of 0.0014–0.0029 mg/mL, derivative I, as well as protamine sulfate, could be used to neutralize the anticoagulant activity of unfractionated or low molecular weight heparin. At a concentration of 0.0029–0.58 mg/mL, derivative I enhanced platelet aggregation, which would be necessary when hemostatic compounds or materials were used. Derivatives II and III enhanced platelet aggregation to a lesser extent.

An international survey of current practice in the laboratory assessment of anticoagulant therapy with heparin.

PubMed

Favaloro, Emmanuel J; Bonar, Roslyn; Sioufi, John; Wheeler, Michael; Low, Joyce; Aboud, Margaret; Lloyd, John; Street, Alison; Marsden, Katherine

2005-06-01

We conducted a survey of laboratory practice for assessment of heparin anticoagulant therapy by participants of the Royal College of Pathologists of Australasia Quality Assurance Program (RCPA QAP). A questionnaire was sent to 646 laboratories enrolled in the Haematology component of the QAP, requesting details of tests used for monitoring heparin therapy. Seventy laboratories (10.8%) returned results that indicated that they performed laboratory monitoring of heparin therapy. Most laboratories (69/70 = 98.6%) use the activated partial thromboplastin time (APTT) to monitor unfractionated heparin, with eight (11.4%) also using the APTT for monitoring low molecular weight (LMW) heparin. Five (7.1%) laboratories use the thrombin time (TT) test to help monitor heparin therapy and 37 (52.9%) laboratories use an anti-Xa assay to monitor heparin (either LMW or unfractionated). Normal reference ranges (NRR) for APTT differed considerably between laboratories, even those using the same reagent. Therapeutic ranges (TR) also differed considerably between laboratories, for both APTT and the anti-Xa assay. Laboratory differences in NRR and TR using the same reagents could only be partly explained by the use of different instrumentation. There is a large variation in current laboratory practice relating to monitoring of heparin anticoagulant therapy. This finding is similar to that of a similar survey conducted by the RCPA QAP almost a decade ago. This study suggests that better standardisation is still required for laboratory monitoring of heparin therapy.

Heparin and structurally related polymers attenuate eotaxin-1 (CCL11) release from human airway smooth muscle.

PubMed

Kanabar, V; Page, C P; Simcock, D E; Karner, C; Mahn, K; O'Connor, B J; Hirst, S J

2008-06-01

The glycosaminoglycan heparin has anti-inflammatory activity and is exclusively found in mast cells, which are localized within airway smooth muscle (ASM) bundles of asthmatic airways. Interleukin (IL)-13 induces the production of multiple inflammatory mediators from ASM including the eosinophil chemoattractant chemokine, eotaxin-1. Heparin and related glycosaminoglycan polymers having structurally heterogeneous polysaccharide side chains that varied in molecular weight, sulphation and anionic charge were used to identify features of the heparin molecule linked to anti-inflammatory activity. Cultured human ASM cells were stimulated with interleukin (IL)-13 in the absence or presence of heparin and related polymers. Eotaxin-1 was quantified using chemokine antibody arrays and ELISA. Unfractionated heparin attenuated IL-13-dependent eotaxin-1 production and this effect was reproduced with low molecular weight heparins (3 and 6 kDa), demonstrating a minimum activity fragment of at least 3 kDa. N-desulphated, 20% re-N-acetylated heparin (anticoagulant) was ineffective against IL-13-dependent eotaxin-1 production compared with 90% re-N-acetylated (anticoagulant) or O-desulphated (non-anticoagulant) heparin, suggesting a requirement for N-sulphation independent of anticoagulant activity. Other sulphated molecules with variable anionic charge and molecular weight exceeding 3 kDa (dextran sulphate, fucoidan, chondroitin sulphate B) inhibited IL-13-stimulated eotaxin-1 release to varying degrees. However, non-sulphated dextran had no effect. Inhibition of IL-13-dependent eotaxin-1 release by heparin involved but did not depend upon sulphation, though loss of N-sulphation reduced the attenuating activity, which could be restored by N-acetylation. This anti-inflammatory effect was also partially dependent on anionic charge, but independent of molecular size above 3 kDa and the anticoagulant action of heparin.

Hydrophilic interaction chromatography-multiple reaction monitoring mass spectrometry method for basic building block analysis of low molecular weight heparins prepared through nitrous acid depolymerization.

PubMed

Sun, Xiaojun; Guo, Zhimou; Yu, Mengqi; Lin, Chao; Sheng, Anran; Wang, Zhiyu; Linhardt, Robert J; Chi, Lianli

2017-01-06

Low molecular weight heparins (LMWHs) are important anticoagulant drugs that are prepared through depolymerization of unfractionated heparin. Based on the types of processing reactions and the structures of the products, LMWHs can be divided into different classifications. Enoxaparin is prepared by benzyl esterification and alkaline depolymerization, while dalteparin and nadroparin are prepared through nitrous acid depolymerization followed by borohydride reduction. Compositional analysis of their basic building blocks is an effective way to provide structural information on heparin and LMWHs. However, most current compositional analysis methods have been limited to heparin and enoxaparin. A sensitive and comprehensive approach is needed for detailed investigation of the structure of LMWHs prepared through nitrous acid depolymerization, especially their characteristic saturated non-reducing end (NRE) and 2,5-anhydro-d-mannitol reducing end (RE). A maltose modified hydrophilic interaction column offers improved separation of complicated mixtures of acidic disaccharides and oligosaccharides. A total of 36 basic building blocks were unambiguously identified by high-resolution tandem mass spectrometry (MS). Multiple reaction monitoring (MRM) MS/MS quantification was developed and validated in the analysis of dalteparin and nadroparin samples. Each group of building blocks revealed different aspects of the properties of LMWHs, such as functional motifs required for anticoagulant activity, the structure of heparin starting materials, cleavage sites in the depolymerization reaction, and undesired structural modifications resulting from side reactions. Copyright © 2016 Elsevier B.V. All rights reserved.

Risk factors for upper extremity venous thrombosis associated with peripherally inserted central venous catheters.

PubMed

Marnejon, Thomas; Angelo, Debra; Abu Abdou, Ahmed; Gemmel, David

2012-01-01

To identify clinically important risk factors associated with upper extremity venous thrombosis following peripherally inserted central venous catheters (PICC). A retrospective case control study of 400 consecutive patients with and without upper extremity venous thrombosis post-PICC insertion was performed. Patient data included demographics, body mass index (BMI), ethnicity, site of insertion, size and lumen of catheter, internal length, infusate, and co-morbidities, such as diabetes mellitus, congestive heart failure, and renal failure. Additional risk factors analyzed were active cancer, any history of cancer, recent trauma, smoking, a history of prior deep vein thrombosis, and recent surgery, defined as surgery within three months prior to PICC insertion. The prevalence of trauma, renal failure, and infusion with antibiotics and total parenteral nutrition (TPN) was higher among patients exhibiting upper extremity venous thrombosis (UEVT), when compared to controls. Patients developing UEVT were also more likely to have PICC line placement in a basilic vein and less likely to have brachial vein placement (P<.001). Left-sided PICC line sites also posed a greater risk (P=.026). The rate of standard DVT prophylaxis with low molecular weight heparin and unfractionated heparin and the use of warfarin was similar in both groups. Average length of hospital stay was almost double among patients developing UEVT, 19.5 days, when compared to patients undergoing PICC line insertion without thrombosis, 10.8 days (t=6.98, P<.001). In multivariate analysis, trauma, renal failure, left-sided catheters, basilic placement, TPN, and infusion with antibiotics, specifically vancomycin, were significant risk factors for UEVT associated with PICC insertion. Prophylaxis with low molecular weight heparin, unfractionated heparin or use of warfarin did not prevent the development of venous thrombosis in patients with PICCs. Length of hospital stay and cost are markedly increased in patients who develop PICC-associated upper extremity venous thrombosis.

Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer.

PubMed

Akl, Elie A; Labedi, Nawman; Terrenato, Irene; Barba, Maddalena; Sperati, Francesca; Sempos, Elena V; Muti, Paola; Cook, Deborah; Schünemann, Holger

2011-11-09

The choice of the appropriate perioperative thromboprophylaxis in patients with cancer depends on the relative benefits and harms of low molecular weight heparin (LMWH) and unfractionated heparin (UFH). To systematically review the evidence for the relative efficacy and safety of LMWH and UFH for perioperative thromboprophylaxis in patients with cancer. A comprehensive search for trials of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science. Randomized controlled trials (RCTs) that enrolled cancer patients undergoing a surgical intervention and compared the effects of LMWH to UFH on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, and thrombocytopenia. Two review authors used a standardized form to independently extract in duplicate data on risk of bias, participants, interventions and outcomes of interest. Where possible, we conducted meta-analyses using the random-effects model. Of 8187 identified citations, we included 16 RCTs with 11,847 patients in the meta-analyses, all using preoperative prophylactic anticoagulation. The overall quality of evidence was moderate. The meta-analysis did not conclusively rule out either a beneficial or harmful effect of LMWH compared to UFH for the following outcomes: mortality (RR = 0.90; 95% CI 0.73 to 1.10), symptomatic DVT (RR = 0.73; 95% CI 0.23 to 2.28), PE (RR = 0.59; 95% CI 0.25 to1.41), minor bleeding (RR = 0.88; 95% CI 0.47 to 1.66) and major bleeding (RR = 0.84; 95% CI 0.52 to 1.36). LMWH was associated with lower incidence of wound hematoma (RR = 0.60; 95% CI 0.43, 0.84) while UFH was associated with higher incidence of intra-operative transfusion (RR = 1.16; 95% CI 0.69,1.62). We found no difference between perioperative thromboprophylaxis with LMWH verus UFH in their effects on mortality and embolic outcomes in patients with cancer. Further trials are needed to more carefully evaluate the benefits and harms of different heparin thromboprophylaxis strategies in this population.

Unfractionated and Low-Molecular-Weight Heparin and the Phosphodiesterase Inhibitors, IBMX and Cilostazol, Block Ex Vivo Equid Herpesvirus Type-1-Induced Platelet Activation.

PubMed

Stokol, Tracy; Serpa, Priscila Beatriz da Silva; Zahid, Muhammad N; Brooks, Marjory B

2016-01-01

Equid herpes virus type-1 (EHV-1) is a major pathogen of horses, causing abortion storms and outbreaks of herpes virus myeloencephalopathy. These clinical syndromes are partly attributed to ischemic injury from thrombosis in placental and spinal vessels. The mechanism of thrombosis in affected horses is unknown. We have previously shown that EHV-1 activates platelets through virus-associated tissue factor-initiated thrombin generation. Activated platelets participate in thrombus formation by providing a surface to localize coagulation factor complexes that amplify and propagate thrombin generation. We hypothesized that coagulation inhibitors that suppress thrombin generation (heparins) or platelet inhibitors that impede post-receptor thrombin signaling [phosphodiesterase (PDE) antagonists] would inhibit EHV-1-induced platelet activation ex vivo . We exposed platelet-rich plasma (PRP) collected from healthy horses to the RacL11 abortigenic and Ab4 neuropathogenic strains of EHV-1 at 1 plaque-forming unit/cell in the presence or absence of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) or the PDE inhibitors, 3-isobutyl-1methylxanthine (IBMX), and cilostazol. We assessed platelet activation status in flow cytometric assays by measuring P-selectin expression. We found that all of the inhibitors blocked EHV-1- and thrombin-induced platelet activation in a dose-dependent manner. Platelet activation in PRP was maximally inhibited at concentrations of 0.05 U/mL UFH and 2.5 μg/mL LMWH. These concentrations represented 0.1-0.2 U/mL anti-factor Xa activity measured in chromogenic assays. Both IBMX and cilostazol showed maximal inhibition of platelet activation at the highest tested concentration of 50 μM, but inhibition was lower than that seen with UFH and LMWH. Our results indicate that heparin anticoagulants and strong non-selective (IBMX) or isoenzyme-3 selective (cilostazol) PDE antagonists inhibit ex vivo EHV-1-induced platelet activation. These drugs have potential as adjunctive therapy to reduce the serious complications associated with EHV-1-induced thrombosis. Treatment trials are warranted to determine whether these drugs yield clinical benefit when administered to horses infected with EHV-1.

Pentasaccharides in the prophylaxis and treatment of venous thromboembolism: a systematic review.

PubMed

Nijkeuter, M; Huisman, M V

2004-09-01

The aim of this review is to perform a critical analysis of all completed studies evaluating pentasaccharides-synthetically derived, selective inhibitors of activated factor X-in prophylaxis in major orthopedic surgery and the treatment of venous thromboembolism. Venous thromboembolism is a disorder with considerable morbidity when left untreated. New antithrombotic agents have been developed that selectively inhibit components of the coagulation system, thereby avoiding the difficulties associated with current anticoagulants. The pentasaccharides fondaparinux and idraparinux are the first of a new class of synthetic selective inhibitors of activated factor X. Fondaparinux has been extensively investigated in two areas: orthopedic surgery and venous thromboembolism. It is clear from four thromboprophylaxis studies in major orthopedic surgery that fondaparinux is 50% more effective in reducing venous thromboembolism than enoxaparin. This superior efficacy led to an overall increase in major bleeding, which was however primarily due to more fondaparinux-treated patients with bleeding indexes of 2 or greater. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two groups. In the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, fondaparinux was equally effective as low molecular weight heparins and unfractionated heparin, respectively, without a different incidence in major bleeding in fondaparinux and comparator heparin groups. Fondaparinux, one of the first of a new class of synthetic selective factor Xa inhibitors, is overall 50% more effective in reducing venous thromboembolism than enoxaparin in major orthopedic surgery, with an overall 1% increased rate of major bleeding, when compared with enoxaparin. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two treatment groups. Fondaparinux is equally effective as low molecular weight heparins and unfractionated heparin in the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, respectively. Finally, as with any new drug, fondaparinux should be used cautiously and only in patients who reflect the population of the clinical trials in which the drug was evaluated.

Anticoagulant therapy: basic principles, classic approaches and recent developments.

PubMed

Sinauridze, Elena I; Panteleev, Mikhail A; Ataullakhanov, Fazoil I

2012-09-01

The standard multipotent anticoagulants (unfractionated and low molecular weight heparins, antagonists of vitamin K) are commonly used for treatment and/or prophylaxis of different thrombotic complications, such as deep vein thrombosis, thrombophilia, pulmonary embolism, myocardial infarction, stroke and so on. Advantages and shortcomings of these anticoagulants are considered. The modern tendencies to use small selective direct inhibitors of thrombin or factor Xa are surveyed. The search of the new targets in the coagulation cascade for development of new promising anticoagulants and improvement in antithrombotic therapy is discussed.

Unfractionated heparin versus low molecular weight heparins for avoiding heparin-induced thrombocytopenia in postoperative patients.

PubMed

Junqueira, Daniela R; Zorzela, Liliane M; Perini, Edson

2017-04-21

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction presenting as a prothrombotic disorder related to antibody-mediated platelet activation. It is a paradoxical immune reaction resulting in thrombin generation in vivo, which leads to a hypercoagulable state and the potential to initiate venous or arterial thrombosis. A number of factors are thought to influence the incidence of HIT including the type and preparation of heparin (unfractionated heparin (UFH) or low molecular weight heparin (LMWH)) and the heparin-exposed patient population, with the postoperative patient population at higher risk.Although LMWH has largely replaced UFH as a front-line therapy, there is evidence supporting a lack of superiority of LMWH compared with UFH regarding prevention of deep vein thrombosis and pulmonary embolism following surgery, and similar frequencies of bleeding have been described with LMWH and UFH. The decision as to which of these two preparations of heparin to use may thus be influenced by harmful effects such as HIT. We therefore sought to determine the relative impact of UFH and LMWH on HIT in postoperative patients receiving thromboembolism prophylaxis. This is an update of a review first published in 2012. The objective of this review was to compare the incidence of heparin-induced thrombocytopenia (HIT) and HIT complicated by venous thromboembolism in postoperative patients exposed to unfractionated heparin (UFH) versus low molecular weight heparin (LMWH). For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (May 2016), CENTRAL (2016, Issue 4) and trials registries. The authors searched Lilacs (June 2016) and additional trials were sought from reference lists of relevant publications. We included randomised controlled trials (RCTs) in which participants were postoperative patients allocated to receive prophylaxis with UFH or LMWH, in a blinded or unblinded fashion. Studies were excluded if they did not use the accepted definition of HIT. This was defined as a relative reduction in the platelet count of 50% or greater from the postoperative peak (even if the platelet count at its lowest remained greater than 150 x 10 9 /L) occurring within five to 14 days after the surgery, with or without a thrombotic event occurring in this timeframe. Additionally, we required circulating antibodies associated with the syndrome to have been investigated through laboratory assays. Two review authors independently extracted data and assessed the risk of bias. Disagreements were resolved by consensus with participation of a third author. In this update, we included three trials involving 1398 postoperative participants. Participants were submitted to general surgical procedures, minor and major, and the minimum mean age was 49 years. Pooled analysis showed a significant reduction in the risk of HIT with LMWH compared with UFH (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.07 to 0.73); low-quality evidence. The number needed to treat for an additional beneficial outcome (NNTB) was 59. The risk of HIT was consistently reduced comparing participants undergoing major surgical procedures exposed to LMWH or UFH (RR 0.22, 95% CI 0.06 to 0.75); low-quality evidence. The occurrence of HIT complicated by venous thromboembolism was significantly lower in participants receiving LMWH compared with UFH (RR 0.22, 95% CI 0.06 to 0.84); low-quality evidence. The NNTB was 75. Arterial thrombosis occurred in only one participant who received UFH. There were no amputations or deaths documented. Although limited evidence is available, it appears that HIT induced by both types of heparins is common in people undergoing major surgical procedures (incidence greater than 1% and less than 10%). This updated review demonstrated low-quality evidence of a lower incidence of HIT, and HIT complicated by venous thromboembolism, in postoperative patients undergoing thromboprophylaxis with LMWH compared with UFH. Similarily, the risk of HIT in people undergoing major surgical procedures was lower when treated with LMWH compared to UFH (low-quality evidence). The quality of the evidence was downgraded due to concerns about the risk of bias in the included studies and imprecision of the study results. These findings may support current clinical use of LMWH over UFH as front-line heparin therapy. However, our conclusions are limited and there was an unexpected paucity of RCTs including HIT as an outcome. To address the scarcity of clinically-relevant information on HIT, HIT must be included as a core harmful outcome in future RCTs of heparin.

Low-molecular-weight heparin use in the obese, elderly, and in renal insufficiency.

PubMed

Clark, N P

2008-01-01

Superior bioavailability and simple weight-based dosing have made low-molecular-weight heparins (LMWH) the preferred agents for treatment and prevention of venous thromboembolism (VTE) for most indications. Despite improved pharmacokinetics, there remain populations where appropriate LMWH dose intensity and frequency are open to question. Obese patients have a lower proportion of lean body mass as a percentage of total body weight. As a result, LMWH dosing based on total body weight could cause supra-therapeutic anticoagulation. Elderly patients also have less lean body mass in addition to a higher incidence of age-related renal disease and increased risk of bleeding. Renal insufficiency presents a risk of LMWH accumulation as well as increased risk of bleeding. Among LMWH products, only dalteparin labeling recommends a maximum dose. Prospective data call into question the validity of this dose limitation. Additionally, because obese patients are already at higher risk of VTE recurrence, they may be particularly sensitive to subtherapeutic anticoagulation. Prospective data evaluating LMWH use in elderly patients have been limited to in-patient treatment. Few recommendations can be made in this population other than close monitoring. Renal insufficiency is a risk for bleeding during LMWH use. Available evidence supports the potential for enoxaparin accumulation, but not tinzaparin. Enoxaparin dose adjustment, either empiric or based on anti-Xa monitoring, has insufficient data to support widespread implementation. Unfractionated heparin is not reliant on renal elimination and is a sensible option for VTE treatment in patients with a creatinine clearance<30 ml/min.

Non-Vitamin K Oral Anticoagulants (NOACs) A Review of Clinical Management and Laboratory Issues.

PubMed

Blann, Andrew

2016-01-01

The non-vitamin K oral anticoagulants (NOACs) are set to replace vitamin K antagonists (principally warfarin), unfractionated heparin and low molecular weight heparin as the leading antithrombotic prophylaxis in several medical and surgical settings. As a group, NOACs have a better safety profile and at least an equivalent (and sometimes superior) efficacy profile than their comparator. The objective of this review is to provide the practitioner with a comprehensive, balanced and contemporary view of these drugs and their applications. More specifically, it focuses on the evidence base for their licences, use in clinical practice (such as in renal dysfunction, orthopaedic surgery, atrial fibrillation, and venous thromboembolism, and the effects of co-medications), responses to actual or perceived haemorrhage, and the role of the laboratory.

An antithrombotic fucoidan, unlike heparin, does not prolong bleeding time in a murine arterial thrombosis model: a comparative study of Undaria pinnatifida sporophylls and Fucus vesiculosus.

PubMed

Min, Soon-Ki; Kwon, Oh-Choon; Lee, Sub; Park, Ki-Hyuk; Kim, Jong-Ki

2012-05-01

The antithrombotic activities and bleeding effects of selected fucoidans (source from either Undaria pinnatifida sporophylls or from Fucus vesiculosus) have been compared with heparin in the ferric chloride-induced arterial thrombus mouse model. Thrombosis was induced by applying 5% ferric chloride for 3 min on the carotid artery region of Balb/c mouse. Five minutes prior to thrombus induction, mice were infused through the tail vein with either saline (control) or polysaccharides. Either fucoidan or heparin was dosed at 0.1, 1.25, 2.5, 5.0, 10, 25, or 50 mg/kg intravenously (i.v.) The carotid blood flow was monitored until more than 60 min post-thrombus induction. Mouse tail transection bleeding time was measured up to 60 min after making a cut in the mouse tail. Both antithrombotic and bleeding effects were observed in a dose-dependent manner for both fucoidans and heparin. Thrombus formation was totally (reflected by Doppler flow meter) inhibited at either 5 or 50 mg/kg of unfractionated Undaria fucoidan or a low-molecular-weight Undaria fucoidan fraction, respectively, without prolonging the time-to-stop bleeding compared with the control (p < 0.01). The total inhibition of thrombus formation was observed for unfractionated Fucus fucoidan at 25 mg/kg where the time-to-stop bleeding was still significantly prolonged, by as much as 8 ± 1.7 min (p < 0.02). In contrast the heparin-treated group showed total inhibition of thrombus formation even at a small dose of 0.8 mg/kg (400 IU) at which bleeding continued until 60 min. In conclusion algal fucoidans are highly antithrombotic without potential haemorrhagic effects compared with heparin in the arterial thrombus model, but this property differs from algal species to species, and from the molecular structure of fucoidans. Copyright © 2011 John Wiley & Sons, Ltd.

Low molecular weight heparin and cancer survival: clinical trials and experimental mechanisms.

PubMed

Zhang, Ning; Lou, Weihua; Ji, Fang; Qiu, Lihua; Tsang, Benjamin K; Di, Wen

2016-08-01

The relationship between cancer and thrombosis is complex, as the hemostatic system is inextricably linked to the mechanisms of cancer growth and metastasis. The coagulation system thus appears to be a site for oncogenic events and necessary for the survival and spread of malignant cells. Although several meta-analyses on the effectiveness of unfractionated heparin and low molecular weight heparin (LMWH) in the treatment of venous thromboembolism (VTE) have suggested a lower mortality risk in cancer patients receiving LMWH, this contention has not received general acceptance. In fact, there exist no sufficiently powered studies to date supporting the routine use of LMWH to improve cancer survival. Meanwhile, the molecular mechanism underlying the anti-neoplastic effect of LMWH which is independent of its anti-coagulant function is largely unexplored and is a topic of active investigation. In this communication, we aimed to review comprehensively evidences from clinical trials, meta-analysis as well as experimental molecular research and to identify future research areas of importance so as to stimulate future research on the potential anti-tumor action of LMWH. Although benefit of LMWH on cancer patients' survival is controversial depending on the tumor type, cancer stage as well as LMWH type, it appears to be associated with a reduction in VTE and increased bleeding is minor and controllable; thus, randomized controlled trials targeting the survival benefit of certain specific LWMH are needed and justified, and more in-depth experimental researches are imperative to elucidate the anti-tumor effect of anticoagulants.

Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin.

PubMed

Chan, Anthony K C; Paredes, Nethnapha; Thong, Bruce; Chindemi, Paul; Paes, Bosco; Berry, Leslie R; Monagle, Paul

2004-05-01

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are used for prophylaxis and treatment of thrombosis. However, UFH has a short plasma half-life and variable anticoagulant response in vivo due to plasma or vessel wall protein binding and LMWH has a decreased ability to inactivate thrombin, the pivotal enzyme in the coagulation cascade. Covalent linkage of antithrombin to heparin gave a complex (ATH) with superior anticoagulant activity compared to UFH and LMWH, and longer intravenous half-life compared to UFH. We found that plasma proteins bound more to UFH than ATH, and least to LMWH. Also, UFH bound significantly more to endothelial cells than ATH, with 100% of UFH and 94% of ATH binding being on the cell surface and the remainder was endocytosed. Competition studies with UFH confirmed that ATH binding was likely through its heparin moiety. These findings suggest that differences in plasma protein and endothelial cell binding may be due to available heparin chain length. Although ATH is polydisperse, the covalently-linked antithrombin may shield a portion of the heparin chain from association with plasma or endothelial cell surface proteins. This model is consistent with ATH's better bioavailability and more predictable dose response.

Thromboprophylaxis in Head and Neck Microvascular Reconstruction.

PubMed

Abraham, Manoj; Badhey, Arvind; Hu, Shirley; Kadakia, Sameep; Rasamny, J K; Moscatello, Augustine; Ducic, Yadranko

2018-06-01

Head and neck patients undergoing microvascular reconstruction are at high risk for thromboembolism. While the prevention of thromboembolism has become an essential aspect of care, within the field of microsurgery, concern for anastomotic complications have hindered the creation of an accepted regimen. The aim of this review was to evaluate the risks and benefits of prophylactic agents for thromboprophylaxis. A literature search was conducted in MEDLINE, Cochrane Library, and PubMed/NCBI databases. Articles discussing thromboprophylaxis in otolaryngology, head and neck surgery, or microvascular reconstruction were considered in the review from the past 30 years. The majority of patients undergoing microvascular surgery have multiple risk factors for thrombus formation. Several consensus guidelines exist for the prophylaxis in patients who are critically ill, undergoing surgery, or with malignancy. Significant evidence supports the routine use of mechanical means, such as early mobilization and pneumatic compression along with subcutaneous heparin. Low-molecular-weight heparin is also frequently utilized, although results are largely divided. Data on aspirin remain equivocal. Studies on microvascular failure and flap loss have demonstrated little to no association with chemoprophylaxis. The evidence for postoperative thromboprophylaxis regimens in patients undergoing head and neck free tissue transfer is variable. Multiple studies have supported the use of unfractionated heparin or low-molecular-weight heparin. There appears to be an expert consensus for the combined use of mechanical prophylactic methods and chemical prophylaxis. Prospective randomized trials are required to validate the most effective combination of chemoprophylaxis agents.

Interaction of albumins and heparinoids investigated by affinity capillary electrophoresis and free flow electrophoresis.

PubMed

Mozafari, Mona; El Deeb, Sami; Krull, Friederike; Wildgruber, Robert; Weber, Gerhard; Reiter, Christian G; Wätzig, Hermann

2018-02-01

A fast and precise affinity capillary electrophoresis (ACE) method has been applied to investigate the interactions between two serum albumins (HSA and BSA) and heparinoids. Furthermore, different free flow electrophoresis methods were developed to separate the species which appears owing to interaction of albumins with pentosan polysulfate sodium (PPS) under different experimental conditions. For ACE experiments, the normalized mobility ratios (∆R/R f ), which provided information about the binding strength and the overall charge of the protein-ligand complex, were used to evaluate the binding affinities. ACE experiments were performed at two different temperatures (23 and 37°C). Both BSA and HSA interact more strongly with PPS than with unfractionated and low molecular weight heparins. For PPS, the interactions can already be observed at low mg/L concentrations (3 mg/L), and saturation is already obtained at approximately 20 mg/L. Unfractionated heparin showed almost no interactions with BSA at 23°C, but weak interactions at 37°C at higher heparin concentrations. The additional signals also appeared at higher concentrations at 37°C. Nevertheless, in most cases the binding data were similar at both temperatures. Furthermore, HSA showed a characteristic splitting in two peaks especially after interacting with PPS, which is probably attributable to the formation of two species or conformational change of HSA after interacting with PPS. The free flow electrophoresis methods have confirmed and completed the ACE experiments. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anti-proliferative effects of O-acyl-low-molecular-weight heparin derivatives on bovine pulmonary artery smooth muscle cells.

PubMed

Garg, Hari G; Mrabat, Hicham; Yu, Lunyin; Hales, Charles A; Li, Boyangzi; Moore, Casey N; Zhang, Fuming; Linhardt, Robert J

2011-08-01

Heparin (HP) inhibits the growth of several cell types in vitro including bovine pulmonary artery (BPA) smooth muscle cells (SMCs). In initial studies we discovered that an O-hexanoylated low-molecular-weight (LMW) HP derivative having acyl groups with 6-carbon chain length was more potent inhibitor of BPA-SMCs than the starting HP. We prepared several O-acylated LMWHP derivatives having 4-, 6-, 8-, 10-, 12-, and 18- carbon acyl chain lengths to determine the optimal acyl chain length for maximum anti-proliferative properties of BPA-SMCs. The starting LMWHP was prepared from unfractionated HP by sodium periodate treatment followed by sodium borohydride reduction. The tri-n-butylammonium salt of this LMWHP was O-acylated with butanoic, hexanoic, octanoic, decanoic, dodecanoic, and stearyl anhydrides separately to give respective O-acylated LMWHP derivatives. Gradient polyacrylamide gel electrophoresis (PAGE) was used to examine the average molecular weights of those O-acylated LMWHP derivatives. NMR analysis indicated the presence of one O-acyl group per disaccharide residue. Measurement of the inhibition of BPA-SMCS as a function of O-acyl chain length shows two optima, at a carbon chain length of 6 (O-hexanoylated LMWHP) and at a carbon chain length 12-18 (O-dodecanoyl and O-stearyl LMWHPs). A solution competition SPR study was performed to test the ability of different O-acylated LMWHP derivatives to inhibit fibroblast growth factor (FGF) 1 and FGF2 binding to surface-immobilized heparin. All the LMWHP derivatives bound to FGF1 and FGF2 but each exhibited slightly different binding affinity.

Outpatient treatment of venous thromboembolism using low molecular weight heparins. An overview.

PubMed

Matsagas, M I

2004-12-01

The development of low-molecular-weight heparins (LMWHs) was a significant advance in the treatment of venous thromboembolism (VTE). Their better bioavailability and more predictable anticoagulant activity than unfractionated heparin (UFH) allow subcutaneous administration without close laboratory monitoring, and thus make outpatient treatment of deep vein thrombosis (DVT) feasible. The safety and efficacy of outpatient treatment in selected patients were established in randomized clinical trials comparing subcutaneous LMWH administered primarily at home with inpatient intravenous UFH. Furthermore, during the last few years a large number of studies have supported these findings in various clinical settings of every-day practice. It is also important that home treatment has lead to substantial cost reductions along with improvement in patients' satisfaction and quality of life. Thus, outpatient treatment of DVT provides an opportunity, rarely seen in medicine, to improve patient care while reducing the overall VTE health-care cost, and it is likely that will be the preferred regime for the majority of patients in the future. However, the implementation of a home treatment program is not simple, as the risks of insufficient or excessive anticoagulation would be considerable. A structured protocol is necessary to ensure that patient care is optimal, and the keys to a successful outpatient treatment program are patient selection, patient education, patient access to health care team, appropriate follow-up and health care team communication.

Randomized, placebo-controlled trial of low molecular weight heparin in active ulcerative colitis.

PubMed

de Bièvre, M A; Vrij, A A; Schoon, E J; Dijkstra, G; de Jong, A E; Oberndorff-Klein Woolthuis, A H; Hemker, H C; Stockbrügger, R W

2007-06-01

In several open and 1 controlled trial, unfractionated heparin was effective in the treatment of active ulcerative colitis (UC). Low molecular weight heparin (LMWH) had a similar effect in several open studies. We studied the efficacy, safety, and tolerability of LMWH in mild to moderately active UC in a randomized, double-blind, placebo-controlled trial. In all, 29 patients with a mild or moderate recurrence of UC during salicylate treatment were randomized to receive either reviparin 3,436 IU (n = 15) subcutaneously twice daily or placebo (n = 14). The study period was 8 weeks. Treatment was discontinued if there was no improvement at 4 weeks or at any disease progression. Primary outcome measure was clinical improvement at 8 weeks measured by the Colitis Activity Index (CAI) and the Clinical Symptoms Grading (CSG, based on the CAI). Endoscopic and histologic grading and quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) were secondary outcome measures. Patients were closely monitored for adverse events. Twenty of 29 patients finished the 8-week treatment period (reviparin versus placebo: 11 versus 9; P = 0.70). There was no difference in CSG, CAI, endoscopic and histologic grading, or IBDQ. Treatment was well tolerated and no serious adverse events occurred. In this study, treatment with LMWH showed no significant clinical advantage compared to placebo in mild to moderately active UC.

Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial.

PubMed

Steg, Philippe Gabriel; Jolly, Sanjit S; Mehta, Shamir R; Afzal, Rizwan; Xavier, Denis; Rupprecht, Hans-Jurgen; López-Sendón, Jose L; Budaj, Andrzej; Diaz, Rafael; Avezum, Alvaro; Widimsky, Petr; Rao, Sunil V; Chrolavicius, Susan; Meeks, Brandi; Joyner, Campbell; Pogue, Janice; Yusuf, Salim

2010-09-22

The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain. To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux. Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010. Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT). Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30. The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15). Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications. clinicaltrials.gov Identifier: NCT00790907.

[Secondary osteoporosis induced by anticoagulants?].

PubMed

Riess, H; Loew, A; Himmelreich, G

2001-07-01

Generalized osteoporosis is a result of different causes and pathogenic mechanisms, which often combine forces to become clinically relevant. Among the different exogenic factors, drugs play an important role, frequently in connection with other factors such as immobilization or pregnancy. It has been suggested that anticoagulation therapy with heparins or coumarins may induce osteoporotic changes or enhance the development of osteoporosis for other reasons. According to in vitro experiments, preclinical trials, and clinical investigations, it seems reasonable to assume that heparins induce increased bone loss in a time- and dose-related manner. Low-molecular-weight heparins most likely have less effect on bone turnover when compared to unfractionated heparin. Oral anticoagulation therapy with vitamin K-antagonists is believed to have a weak effect on induction of osteoporosis, but clinical studies are contradictory. In spite of the fact that a relevant effect of these drugs on the induction of osteoporosis is questionable, it must be taken into consideration that anticoagulant drugs may enhance the negative effects on bone density of other risk factors capable of inducing osteoporosis such as immobilization, pregnancy, or endocrinological disorders.

Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis.

PubMed

Chande, Nilesh; McDonald, John Wd; Macdonald, John K; Wang, Josh J

2010-10-06

There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis. The MEDLINE (PUBMED), and EMBASE databases, The Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on ulcerative colitis, and references from identified papers were searched up to June 2010 in an effort to identify all randomized trials studying UFH or LMWH use in patients with ulcerative colitis. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above. The Cochrane Risk of Bias tool was used to assess study quality. Studies published in abstract form only were included if the authors could be contacted for further information. A data extraction form was developed and used to extract data from included studies. At least 2 authors independently extracted data. Any disagreements were resolved by consensus. Data were analyzed on an intention-to-treat basis. The primary outcome was induction of remission, as defined by the studies. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (OR 2.73; 95% CI 1.32 to 5.67; P = 0.007), clinical improvement (OR 2.99; 95% CI 1.30 to 6.87; P = 0.01), and endoscopic improvement (OR 2.25; 95%CI 1.01 to 5.01; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.

Antithrombotic Therapy for VTE Disease

PubMed Central

Kearon, Clive; Comerota, Anthony J.; Prandoni, Paolo; Bounameaux, Henri; Goldhaber, Samuel Z.; Nelson, Michael E.; Wells, Philip S.; Gould, Michael K.; Dentali, Francesco; Crowther, Mark; Kahn, Susan R.

2012-01-01

Background: This article addresses the treatment of VTE disease. Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). Conclusion: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences. PMID:22315268

Short-term therapy with enoxaparin or unfractionated heparin for venous thromboembolism in hospitalized patients: utilization study and cost-minimization analysis.

PubMed

Argenta, Catia; Ferreira, Maria Angélica Pires; Sander, Guilherme Becker; Moreira, Leila Beltrami

2011-01-01

To evaluate the direct costs of venous thromboembolism (VTE) treatment with unfractionated heparin (UFH) and low-molecular weight heparin, from the institutional perspective. This is a real-world cohort study that included inpatients treated with UFH or enoxaparin for deep venous thromboembolism or pulmonary embolism in a tertiary public hospital. To estimate medical costs we computed the acquisition costs of drugs, supplies for administration, laboratory tests, and hospitalization cost according to the patient ward. One hundred sixty-seven patients aged 18 to 92 years were studied (50 treated with UFH and 117 with enoxaparin). The median of days in use of heparin was the same in both groups. Activated partial thromboplastin time was monitored in 98% of patients using UFH and 56.4% using enoxaparin. Nonstatistically significant differences were observed between groups in the number of bleeding events (10.0% and 9.4%; P = 1.00); blood transfusion (2.0% and 2.6%; P = 1.00); death (8.0% and 3.4%; P = 0.24); and recurrent VTE, bleeding, or death (20.0% and 14.5%; P = 0.38). Daily mean cost per patient was US$12.63 ± $4.01 for UFH and US$9.87 ± $2.44 for enoxaparin (P < 0.001). The total costs considering the mean time of use were US$88.39 and US$69.11. The treatment of VTE with enoxaparin provided cost savings in a large teaching hospital located in southern Brazil. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials

PubMed Central

Whiteley, William N; Adams, Harold P; Bath, Philip MW; Berge, Eivind; Sandset, Per Morten; Dennis, Martin; Murray, Gordon D; Wong, Ka-Sing Lawrence; Sandercock, Peter AG

2013-01-01

Summary Background Many international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke. Methods We obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome “dead or dependent” in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis. Findings Patients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59–0·67) and for haemorrhagic events was 0·60 (0·55–0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events. Interpretation There was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised. Funding MRC. PMID:23642343

Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials.

PubMed

Whiteley, William N; Adams, Harold P; Bath, Philip M W; Berge, Eivind; Sandset, Per Morten; Dennis, Martin; Murray, Gordon D; Wong, Ka-Sing Lawrence; Sandercock, Peter A G

2013-06-01

Many international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke. We obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome "dead or dependent" in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis. Patients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59-0·67) and for haemorrhagic events was 0·60 (0·55-0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events. There was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised. MRC. Copyright © 2013 Elsevier Ltd. All rights reserved.

A 1-year drug utilization evaluation of protamine in hospitalized patients to identify possible future roles of heparin and low molecular weight heparin reversal agents.

PubMed

Mahan, Charles E

2014-04-01

Despite widespread use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH), protamine sulfate remains the only reversal agent for UFH that is approved by the Food and Drug Administration within the US. Availability of new reversal agents for approved anticoagulants and those in development may improve patient safety and care. Delparantag (PMX-60056) is a novel small molecule that shows ability to neutralize the anticoagulation effects of UFH and LMWH in animals and humans. This study examined the 1-year utilization of protamine within an acute care hospital in order to determine the need for a novel reversing agent like delparantag. All patients having documented protamine administration within a 1-year period were included. Pharmacy automated dispensing machines and computerized medication management systems were queried for all doses of protamine withdrawn, billed for, or dispensed. Scanned medical records were reviewed and protamine and anticoagulant information was abstracted. Primary procedural group categorizations for protamine patients were coronary artery bypass graft, cardiac valve surgeries, abdominal aortic aneurysm and other open abdominal surgeries, fistula placement, non-cardiac vascular, cardiac catheter and electrophysiology lab, and "other." Average doses of protamine administered were 439, 423, 126, 26, 46, 36, and 35 mg in these groups, respectively. Four major bleeds and one serious adverse event occurred over the year period. Protamine is used in a wide array of procedures. Evaluating protamine's current use may be beneficial in identifying roles for future UFH and LMWH reversal agent use.

[Heparin-induced thrombocytopenia developed during the acute phase after left upper lobectomy for lung cancer].

PubMed

Mitomo, Hideki; Miyamoto, Akira; Tabata, Toshiharu; Sugawara, Takafumi; Yabuki, Hiroshi; Fujimura, Shigefumi

2014-12-01

Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin administration. This must not be rarely encountered but is not often reported in Japan compared to Western countries. A 68-year-old woman underwent left upper lobectomy for lung cancer. Low-dose unfractionated heparin was administrated to prevent thromboembolism after the operation. Two days later, sudden dyspnea appeared and ultracardiosonography showing an extensive thromboembolus from the main trunk to both main branches of pulmonary artery indicated pulmonary embolization. After the establishment of percutaneous cardiopulmonary support (PCPS) support, the embolus was removed by emergent open heart surgery. However, despite further unfractionated heparin administration following embolization surgery, other thrombus was identified in both the bi-lateral internal jagular veins and inferior vena cava by ultrasonography and contrast computed tomography( CT). Her platelet count was decreased gradually despite platelet transfusion. Plate factor 4( PF4) antibody against heparin in her blood examination was found, and HIT II was diagnosed. Discontinuation of unfractionated heparin and administration of antithrombin agent improved platelet count, and no additional embolization was identified.

Advances in the management of venous thromboembolism.

PubMed

Schulman, Sam

2012-09-01

The past decade has witnessed important advances in the diagnosis and treatment of venous thromboembolism with excellent opportunities to apply evidence-based medicine for many of the steps in the management of the disease. This review discusses the clinical prediction rules that should be used to reduce utilization of imaging diagnosis for deep vein thrombosis or pulmonary embolism and the risk stratification for thrombolytic therapy or outpatient management of pulmonary embolism. The treatment options have increased and include low-molecular-weight heparin (LMWH), intravenous or subcutaneous unfractionated heparin - the latter either monitored or not monitored, fondaparinux and rivaroxaban for the initial phase. Thereafter, vitamin K antagonists (VKAs), LMWH, oral factor Xa or thrombin inhibitors are or will soon become available. The VKAs have been subjected to many randomised trial addressing the initiation, intensity, monitoring and self-management. Extended anticoagulation and the selection for that is finally reviewed. Copyright © 2012. Published by Elsevier Ltd.

Economic impact of enoxaparin after acute ischemic stroke based on PREVAIL.

PubMed

Pineo, Graham; Lin, Jay; Stern, Lee; Subrahmanian, Tarun; Annemans, Lieven

2011-04-01

The efficacy and safety of low-molecular-weight heparins (LMWHs) versus unfractionated heparin (UFH) has been demonstrated for the prevention of venous thromboembolism (VTE) after acute ischemic stroke. Few data exist regarding the economic impact of LMWHs versus UFH in this population. A decision-analytic model was constructed using clinical information from the Prevention of VTE after Acute Ischemic stroke with LMWH Enoxaparin (PREVAIL) study, and drug costs and mean Centers for Medicare & Medicaid Services event costs. When considering the total cost of events and drugs, enoxaparin was associated with cost-savings of $895 per patient compared with UFH ($2018 vs $2913). Findings were retained within the univariate and multivariate analyses. From a payer perspective, enoxaparin was cost-effective compared with UFH in patients with acute ischemic stroke. The difference was driven by the lower clinical event rates with enoxaparin. Use of enoxaparin may help to reduce the clinical and economic burden of VTE.

Current Status of New Anticoagulants in the Management of Venous Thromboembolism

PubMed Central

Montoya, Roberto C.; Gajra, Ajeet

2012-01-01

Venous Thromboembolism, manifested as deep venous thrombosis and pulmonary embolism, is a common problem associated with significant morbidity, mortality, and resource expenditure. Unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists are the most common treatment and prophylaxis, and have demonstrated their efficacy in a vast number of previous studies. Despite their broad use, these agents have important limitations that have led to the development of new drugs in a bid to overcome the disadvantages of the old ones without decreasing their therapeutic effect. These novel medications, some approved and others in different stages of development, include direct thrombin inhibitors like dabigatran etexilate, and direct activated factor X inhibitors like rivaroxaban. The current paper will review the characteristics, clinical trial results, and current and potential therapeutic uses of these new agents with a focus on the categories of direct thrombin inhibitors and activated factor X inhibitors. PMID:22496694

Molecular weight dependence of LB morphology of poly(n-hexyl isocyanate) (PHIC).

PubMed

Morioka, Takako; Shibata, Osamu; Kawaguchi, Masami

2010-12-07

The morphologies of Langmuir-Blodgett (LB) films of two fractionated poly(n-hexyl isocyanate) (PHIC) and those of their binary mixtures were observed by AFM, together with those of an unfractionated PHIC. The low molecular weight PHIC formed random packing of bundles consisting of rigid rods, while the high molecular weight PHIC formed random packing of bundles consisting of hairy rods. Bundle interpenetration was observed only for the latter in the semidilute regime. In the bilayer region, the area occupied by the PHIC bundles in the upper layer was obviously smaller for the high molecular weight PHIC than for the low molecular weight PHIC, suggesting that the bundles of high molecular weight PHIC more easily interpenetrate than those of low molecular weight PHIC. For the blended films composed of both low and high molecular weight PHICs, the characteristic morphologies of the respective PHIC samples were no longer present. Moreover, the morphologies of the blended films appeared to resemble each other at any molar fraction owing to the ideal miscibility of the low molecular weight and high molecular weight PHICs. The morphologies of the blended films were also similar to that of the unfractionated PHIC film in the dilute regime. In the semidilute regime, the blended films became rounded owing to an increase in bundles interpenetration between PHICs as compared to that in the dilute regime, whereas the morphology of unfractionated PHIC films remained unchanged as compared to that in the dilute regime.

Heparin concentration is critical for cell culture with human platelet lysate.

PubMed

Hemeda, Hatim; Kalz, Jana; Walenda, Gudrun; Lohmann, Michael; Wagner, Wolfgang

2013-09-01

Culture media for mesenchymal stromal cells (MSCs) are generally supplemented with fetal bovine serum. Human platelet lysate (hPL) has been proven to be a very effective alternative without the risk of xenogeneic infections or immune reactions. In contrast to fetal bovine serum, hPL comprises plasma, and anticoagulants-usually unfractionated heparin (UFH)-need to be added to prevent gel formation. Cultures of MSCs in hPL media with various concentrations of UFH and enoxaparin, a low-molecular-weight heparin (LMWH), were systematically compared with regard to proliferation, fibroblastoid colony-forming unit frequency, immunophenotype and in vitro differentiation. At least 0.61 IU/mL UFH or 0.024 mg/mL LMWH was necessary for reliable prevention of coagulation of hPL pools used in this study. Higher concentrations impaired cellular proliferation in a dose-dependent manner even without benzyl alcohol, which is commonly added to heparins as a bacteriostatic agent. Colony-forming unit frequency was also reduced at higher heparin concentrations, particularly with LMWH, whereas no significant effect was observed on cellular morphology or immunophenotype. High concentrations of heparins reduced the in vitro differentiation toward adipogenic and osteogenic lineages. Heparin concentration is critical for culture of MSCs in hPL media; this is of particular relevance for cellular therapy where cell culture procedures need to be optimized and standardized. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Fragment profiling of low molecular weight heparins using reversed phase ion pair liquid chromatography-electrospray mass spectrometry.

PubMed

Xu, Xiaohui; Li, Daoyuan; Chi, Lequan; Du, Xuzhao; Bai, Xue; Chi, Lianli

2015-04-30

Low molecular weight heparins (LMWHs) are linear and highly charged carbohydrate polymers prepared by chemical or enzymatic depolymerization of heparin. Compared to unfractionated heparin (UFH), LMWHs are prevalently used as clinical anticoagulant drugs due to their lower side effects and better bioavailability. The work presented herein provides a rapid and powerful fragment mapping method for structural characterization of LMWHs. The chain fragments of two types of LMWHs, enoxaparin and nadroparin, were generated by controlled enzymatic digestion with each of heparinase I (Hep I, Enzyme Commission (EC) # 4.2.2.7), heparinase II (Hep II, no EC # assigned) and heparinase III (Hep III, EC # 4.2.2.8). Reversed phase ion pair high performance liquid chromatography (RPIP-HPLC) coupled with electrospray ion trap time-of-flight mass spectrometry (ESI-IT-TOF-MS) was used to profile the oligosaccharide chains ranging from disaccharides to decasaccharides. A database containing all theoretical structural compositions was established to assist the mass spectra interpretation. The six digests derived by three enzymes from two types of LMWHs exhibited distinguishable fingerprinting patterns. And a total of 94 enoxaparin fragments and 109 nadroparin fragments were detected and identified. Besides the common LMWH oligosaccharides, many components containing characteristic LMWH structures such as saturated L-idopyranosuronic acid, 2,5-anhydro-D-mannitol, 1,6-anhydro-D-aminopyranose, as well as odd number oligosaccharides were also revealed. Quantitative comparison of major components derived from innovator and generic nadroparin products was presented. This approach to profile LMWHs' fragments offers a highly reproducible, high resolution and information-rich tool for evaluating the quality of this category of anticoagulant drugs or comparing structural similarities among samples from various sources. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antithrombotic Treatment for Recurrent Miscarriage

PubMed Central

Zhang, Tianyi; Ye, Xiaofei; Zhu, Tiantian; XIAO, Xiang; Liu, Yuzhou; Wei, Xin; Liu, Yu; Wu, Cheng; Guan, Rui; Li, Xiao; Guo, Xiaojing; Hu, Huili; He, Jia

2015-01-01

Abstract Combined use of heparin and aspirin is frequently prescribed for treatment of recurrent miscarriage (RM) in patients with antiphospholipid syndrome (APS), or in those without apparent cause of RM other than thrombophilia; however, this strategy is largely based on expert opinion and has not been well studied. The option for the use of different antithrombotic therapies to improve live birth remains unclear. In this network meta-analysis, we incorporated direct and indirect evidence to evaluate effects of different antithrombotic treatments on prevention of pregnancy losses. We searched PubMed and Embase for randomized clinical trials comparing effects of at least 2 antithrombotic treatments on live birth in RM patients published from 1965 through the early of May 2015. Potential risk bias of eligible trials was evaluated according to the Cochrane Collaboration guidelines. Bayesian network meta-analysis was used to estimate relative effects on live birth. A total of 19 trials involving 2391 RM patients with or without thrombophilia and 543 with APS were included. No beneficial effect of antithrombotic treatment was observed either in RM patients with or without thrombophilia or in patients with APS; however, for patients with or without thrombophilia, low molecular weight heparin therapy had the greatest probability (61.48%) of being the best option in terms of live birth; for patients with APS, unfractionated heparin plus aspirin was the superior treatment for RM with the highest possibility (75.15%) of being top 2 places for reducing pregnancy losses. Aspirin was inferior in both groups. Our results do not support the use of combined low molecular weight heparin and aspirin for RM treatment, and suggested aspirin may have negative effects for lowering the risk of pregnancy loss. PMID:26559249

An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial.

PubMed

Massicotte, Patricia; Julian, Jim A; Gent, Michael; Shields, Karen; Marzinotto, Velma; Szechtman, Barbara; Andrew, Maureen

2003-01-25

Venous thromboembolic events (VTE) are serious complications in children and for which the standard of care, unfractionated heparin followed by oral anticoagulation (UFH/OA), is problematic. The objective of REVIVE was to compare the efficacy and safety of a low molecular weight heparin (reviparin-sodium) to UFH/OA for the treatment of VTE in children. This multicenter, open-label study, with blinded central outcome adjudication, randomized patients with objectively confirmed VTE to receive either reviparin-sodium or UFH/OA. Dose adjustments were made using nomograms. The efficacy outcome was based on recurrent VTE and death due to VTE during the 3-month treatment period. The safety outcomes were major bleeding, minor bleeding and death. Due to slow patient accrual, REVIVE was closed prematurely. At 3 months, with reviparin-sodium, 2/36 patients (5.6%) had recurrent VTE or death compared to 4/40 patients (10.0%) receiving UFH/OA (odds ratio=0.53; 95% CI=(0.05, 4.00); Fisher's exact test: 2P=0.677). There were 7 major bleeds, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in UFH/OA group (odds ratio=0.41; 95% confidence interval 0.04, 2.76); Fisher's exact test: P=0.435). There were 5 deaths during the study period, 1 (2.8%) in the reviparin-sodium group and 4 (10.0%) in the UFH/OA group. All five deaths were unrelated to VTE but one was due to an intracranial hemorrhage in the UFH/OA group. Although limited by small sample size, REVIVE provides valuable information on the incidence of recurrent VTE, major bleeding and problematic issues associated with therapy of VTE in children.

Thromboembolic Prophylaxis with Heparin in Patients with Blunt Solid Organ Injuries Undergoing Non-operative Treatment.

PubMed

Khatsilouskaya, Tatsiana; Haltmeier, Tobias; Cathomas, Marionna; Eberle, Barbara; Candinas, Daniel; Schnüriger, Beat

2017-05-01

Patients with blunt solid organ injuries (SOI) are at risk for venous thromboembolism (VTE), and VTE prophylaxis is crucial. However, little is known about the safety of early prophylactic administration of heparin in these patients. This is a retrospective study including adult trauma patients with SOI (liver, spleen, kidney) undergoing non-operative management (NOM) from 01/01/2009 to 31/12/2014. Three groups were distinguished: prophylactic heparin (low molecular weight heparin or low-dose unfractionated heparin) ≤72 h after admission ('early heparin group'), >72 h after admission ('late heparin group'), and no heparin ('no heparin group'). Patient and injury characteristics, transfusion requirements, and outcomes (failed NOM, VTE, and mortality) were compared between the three groups. Overall, 179 patients were included; 44.7% in the 'early heparin group,' 34.6% in the 'late heparin group,' and 20.8% in the 'no heparin group.' In the 'late heparin group,' the ISS was significantly higher than in the 'early' and 'no heparin groups' (median 29.0 vs. 17.0 vs. 19.0; p < 0.001). The overall NOM failure rate was 3.9%. Failed NOM was significantly more frequent in the 'no heparin group' compared to the 'early' and 'late heparin groups' (10.8 vs. 3.2 vs. 1.3%; p = 0.043). In the 'early heparin group' 27.5% patients suffered from a high-grade SOI; none of these patients failed NOM. Mortality did not differ significantly. Although not statistically significant, VTE were more frequent in the 'no heparin group' compared to the 'early' and 'late heparin groups' (10.8 vs. 4.8 vs. 1.3%; p = 0.066). In patients with SOI, heparin was administered early in a high percentage of patients and was not associated with an increased NOM failure rate or higher in-hospital mortality.

Long-term low-molecular-weight heparin and the post-thrombotic syndrome: a systematic review.

PubMed

Hull, Russell D; Liang, Jane; Townshend, Grace

2011-08-01

Post-thrombotic syndrome causes considerable morbidity. The Home-LITE study showed a lower incidence of post-thrombotic syndrome and venous ulcers after 3 months of treating deep vein thrombosis with the low-molecular-weight heparin tinzaparin versus oral anticoagulation. This systematic review examined whether long-term treatment of deep vein thrombosis using low-molecular-weight heparin, rather than oral anticoagulation, reduces development of post-thrombotic syndrome. We identified 9 articles comparing treatment of deep vein thrombosis using long-term low-molecular-weight heparin with any comparator, which reported outcomes relevant to the post-thrombotic syndrome assessed ≥ 3 months post-deep vein thrombosis. Pooled analysis of 2 studies yielded an 87% risk reduction with low-molecular-weight heparin in the incidence of venous ulcers at ≥ 3 months (P = .019). One study showed an overall odds ratio of 0.77 (P = .001) favoring low-molecular-weight heparin for the presence of 8 patient-reported post-thrombotic syndrome signs and symptoms. Pooled analysis of 5 studies showed a risk ratio for low-molecular-weight heparin versus oral anticoagulation of 0.66 (P < .0001) for complete recanalization of thrombosed veins. These results support the lower incidence of post-thrombotic syndrome and venous ulcers observed in Home-LITE. Long-term treatment with low-molecular-weight heparin rather than oral anticoagulation after a deep vein thrombosis may reduce or prevent development of signs and symptoms associated with post-thrombotic syndrome. Post-thrombotic syndrome and associated acute ulcers may develop more rapidly after deep vein thrombosis than previously recognized. Copyright © 2011 Elsevier Inc. All rights reserved.

Adequacy of Fixed-Dose Heparin Infusions for Venous Thromboembolism Prevention after Microsurgical Procedures.

PubMed

Bertolaccini, Corinne M; Prazak, Ann Marie B; Agarwal, Jayant; Goodwin, Isak A; Rockwell, W Bradford; Pannucci, Christopher J

2018-05-22

 In microvascular surgery, patients often receive unfractionated heparin infusions to minimize risk for microvascular thrombosis. Patients who receive intravenous (IV) heparin are believed to have adequate prophylaxis against venous thromboembolism (VTE). Whether a fixed dose of IV heparin provides detectable levels of anticoagulation, or whether the "one size fits all" approach provides adequate prophylaxis against VTE remains unknown. This study examined the pharmacodynamics of fixed-dose heparin infusions and the effects of real-time, anti-factor Xa (aFXa) level driven heparin dose adjustments.  This prospective clinical trial recruited adult microvascular surgery patients placed on a fixed-dose (500 units/h) unfractionated heparin infusion during their initial microsurgical procedure. Steady-state aFXa levels, a marker of unfractionated heparin efficacy and safety, were monitored. Patients with out-of-range aFXa levels received protocol-driven real-time dose adjustments. Outcomes of interest included aFXa levels in response to heparin 500 units/h, number of dose adjustments required to achieve goal aFXa levels, time to reach goal aFXa level, and 90-day clinically relevant bleeding and VTE.  Twenty patients were recruited prospectively. None of 20 patients had any detectable level of anticoagulation in response to heparin infusions at 500 units/h. The median number of dose adjustments required to reach goal level was five, and median weight-based dose to reach goal level was 11.8 units/kg/h. Real-time dose adjustments significantly increased the proportion of patients with in-range levels (60 vs. 0%, p  = 0.0001). The 90-day VTE rate was 5% and 90-day clinically relevant bleeding rate was 5%.  Fixed-dose heparin infusions at a rate of 500 units/h do not provide a detectable level of anticoagulation after microsurgical procedures and are insufficient for the majority of patients who require VTE prophylaxis. Weight-based heparin infusions at 10 to 12 units/kg/h deserve future study in patients undergoing microsurgical procedures to increase the proportion of patients receiving adequate VTE prophylaxis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects of heparin fractions on the prevention of skin necrosis resulting from adriamycin extravasation: an experimental study.

PubMed

Askar, Ibrahim; Erbas, M Kemal; Gurlek, Ali

2002-09-01

Extravasation of a chemotherapeutic agent is one of the most frequent complications in cancer patients. Full-thickness skin necrosis often occurs after extravasation. Alternative approaches to treatment are local wound care, elevation, and hypothermia. It was shown that heparin prevents skin necrosis. In this experimental study, the effects of heparin fractions on the prevention of skin necrosis were compared by applying an extravasation model of Adriamycin in rats. Forty Sprague-Dawley male rats weighing 250 to 300 g were used. A total of 0.3 ml doxorubicin hydrochloride was administered subcutaneously to all rats. Ten minutes later, in the control group (group I), 1 ml normal saline was administered subcutaneously. In the first experimental group (group II), 100 U per day heparin sodium was administered in a volume of 1 ml subcutaneously. In the second experimental group (group III), nadroparin calcium (5 anti-Xa U per kilogram per day) was administered. In the third and last experimental group (group IV), dalteparin sodium (5 anti-Xa U per kilogram per day) was administered. All drugs were administered for 2 weeks. Necrotic areas were measured 4 weeks later. Statistical analysis was performed using the Kruskal-Wallis analysis of variance and the Mann-Whitney test. Heparin fractions caused a decreased ulcer rate and size than controls ( < 0.05). There was no superiority among heparin fractions. The authors think that low-molecular weight heparins are preferred, considering the higher risk of bleeding with unfractionated heparin.

Analysis of heparin oligosaccharides by capillary electrophoresis-negative-ion electrospray ionization mass spectrometry.

PubMed

Lin, Lei; Liu, Xinyue; Zhang, Fuming; Chi, Lianli; Amster, I Jonathan; Leach, Franklyn E; Xia, Qiangwei; Linhardt, Robert J

2017-01-01

Most hyphenated analytical approaches that rely on liquid chromatography-MS require relatively long separation times, produce incomplete resolution of oligosaccharide mixtures, use eluents that are incompatible with electrospray ionization, or require oligosaccharide derivatization. Here we demonstrate the analysis of heparin oligosaccharides, including disaccharides, ultralow molecular weight heparin, and a low molecular weight heparin, using a novel electrokinetic pump-based CE-MS coupling eletrospray ion source. Reverse polarity CE separation and negative-mode electrospray ionization were optimized using a volatile methanolic ammonium acetate electrolyte and sheath fluid. The online CE hyphenated negative-ion electrospray ionization MS on an LTQ Orbitrap mass spectrometer was useful in disaccharide compositional analysis and bottom-up and top-down analysis of low molecular weight heparin. The application of this CE-MS method to ultralow molecular heparin suggests that a charge state distribution and the low level of sulfate group loss that is achieved make this method useful for online tandem MS analysis of heparins. Graphical abstract Most hyphenated analytical approaches that rely on liquid chromatography-MS require relatively long separation times, produce incomplete resolution of oligosaccharide mixtures, use eluents that are incompatible with electrospray ionization, or require oligosaccharide derivatization. Here we demonstrate the analysis of heparin oligosaccharides, including disaccharides, ultralow molecular weight heparin, and a low molecular weight heparin, using a novel electrokinetic pump-based CE-MS coupling eletrospray ion source. Reverse polarity CE separation and negative-mode electrospray ionization were optimized using a volatile methanolic ammonium acetate electrolyte and sheath fluid. The online CE hyphenated negative-ion electrospray ionization MS on an LTQ Orbitrap mass spectrometer was useful in disaccharide compositional analysis and bottom-up and top-down analysis of low molecular weight heparin. The application of this CE-MS method to ultralow molecular heparin suggests that a charge state distribution and the low level of sulfate group loss that is achieved make this method useful for online tandem MS analysis of heparins.

[Intensive care of children with DIC syndrome based on the use of low molecular weight heparins].

PubMed

Chuprova, A V; Shmakov, A N; Solov'ev, O N; Anokhina, T Iu; Loskutova, S A; Pinegina, Iu S

2002-01-01

The first section of this paper presents data on low-molecular-weight heparins: pharmacokinetics and pharmacodynamics, advantages in comparison with common heparin. The second section presents the results of fraxiparin and clivarin use in 43 children aged 9 months to 14 years with acute/subacute DIC syndrome of infectious origin. Therapeutic and maintenance doses, the mode of injection of low-molecular-weight heparins, and methods for laboratory monitoring of their efficiency and safety are presented.

Bilateral femoral shaft fractures complicated by fat and pulmonary embolism: a case report.

PubMed

Randelli, Filippo; Capitani, Paolo; Pace, Fabrizio; Favilla, Sara; Galante, Claudio; Randelli, Pietro

2015-12-01

A 25-year-old man was admitted to our hospital because of pulmonary embolism and suspected fat embolism after sustaining bilateral femoral shaft fracture. A left arm weakness, tachycardia and sudden hemoglobin drop delayed his definitive fixation with intramedullary nailing. His clinical course was further complicated by bleeding from the pin sites of the external fixators which had initially been used to temporarily stabilize his femoral fractures (clotting disturbances). A lower leg Doppler ultrasound and a new pelvic-chest CT angiography excluded any remaining thrombus, meanwhile the embolus had broken in smaller pieces, more distally. His unfractionated heparin was revised to a Low Molecular Weight Heparin at prophylactic dose. After a 10 day period and when his condition had been improved bilateral reamed nailing was performed. Although bilateral closed femoral shaft fractures should be stabilized early, fat embolism syndrome (FES) and thromboembolic events (TEV) should always be kept in mind in these patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Preparation of Low Molecular Weight Heparin by Microwave Discharge Electrodeless Lamp/TiO2 Photo-Catalytic Reaction.

PubMed

Lee, Do-Jin; Kim, Byung Hoon; Kim, Sun-Jae; Kim, Jung-Sik; Lee, Heon; Jung, Sang-Chul

2015-01-01

An MDEL/TiO2 photo-catalyst hybrid system was applied, for the first time, for the production of low molecular weight heparin. The molecular weight of produed heparin decreased with increasing microwave intensity and treatment time. The abscission of the chemical bonds between the constituents of heparin by photo-catalytic reaction did not alter the characteristics of heparin. Formation of by-products due to side reaction was not observed. It is suggested that heparin was depolymerized by active oxygen radicals produced during the MDEL/TiO2 photo-chemical reaction.

A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer - A real world experience.

PubMed

Phelps, Megan K; Wiczer, Tracy E; Erdeljac, H Paige; Van Deusen, Kelsey R; Porter, Kyle; Philips, Gary; Wang, Tzu-Fei

2018-01-01

Introduction Low-molecular-weight heparins are the standard treatment for cancer-associated thrombosis. Recently, direct oral anticoagulants are a new option for thrombosis treatment; however, data supporting the use of direct oral anticoagulants for cancer-associated thrombosis are limited. Objectives The primary objective of this study was to determine the rate of recurrent cancer-associated thrombosis and major bleeding within 6 months of starting either low-molecular-weight heparin or direct oral anticoagulant for treatment of cancer-associated thrombosis. Secondary objectives were to determine the rates of clinically relevant-non-major bleeding and all-cause mortality. Patients/methods This is a retrospective cohort study including adults with cancer-associated thrombosis treated with low-molecular-weight heparin or direct oral anticoagulant between 2010 and 2016 at the Ohio State University. Medical records were reviewed for 6 months after initiation of anticoagulation or until the occurrence of recurrent cancer-associated thrombosis, major bleeding, cessation of anticoagulation of interest, or death, whichever occurred first. Results Four hundred and eighty patients were included (290 low-molecular-weight heparin and 190 direct oral anticoagulant). Patients treated with direct oral anticoagulant were found to carry "lower risk" features including cancer with lower VTE risk and lower rate of metastatic disease. After adjustment for baseline differences, there was no significant difference in the rate of recurrent cancer-associated thrombosis (7.2% low-molecular-weight heparin vs 6.3% direct oral anticoagulant, p = 0.71) or major bleeding (7.6% low-molecular-weight heparin vs 2.6% direct oral anticoagulant, p = 0.08). Conclusions Our study demonstrates that in a select population of cancer patients with VTE, direct oral anticoagulant use can be as effective and safe compared to the standard therapy with low-molecular-weight heparin.

Analysis of the complex formation of heparin with protamine by light scattering and analytical ultracentrifugation: implications for blood coagulation management.

PubMed

Maurer, Jürgen; Haselbach, Stephanie; Klein, Oliver; Baykut, Doan; Vogel, Vitali; Mäntele, Werner

2011-02-02

Heparin, a linear glycosaminoglycan, is used in different forms in anticoagulation treatment. Protamine, a highly positive charged peptide containing about 32 amino acids, acts as an antagonist for heparin to restore normal blood coagulation. The complex formation of protamine with heparin was analyzed by a combination of analytical ultracentrifugation and light scattering. Titration of heparin with protamine in blood plasma preparations results in a drastic increase of turbidity, indicating the formation of nanoscale particles. A similar increase of turbidity was observed in physiological saline solution with or without human serum albumin (HSA). Particle size analysis by analytical ultracentrifugation revealed a particle radius of approximately 30 nm for unfractionated heparin and of approximately 60 nm for low molecular weight heparin upon complexation with excess protamine, in agreement with atomic force microscopy data. In the absence of HSA, larger and more heterogeneous particles were observed. The particles obtained were found to be stable for hours. The particle formation kinetics was analyzed by light scattering at different scattering angles and was found to be complete within several minutes. The time course of particle formation suggests a condensation reaction, with sigmoidal traces for low heparin concentrations and quasi-first-order reaction for high heparin concentrations. Under all conditions, the final scattering intensity reached after several minutes was found to be proportional to the amount of heparin in the blood plasma or buffer solution, provided that excess protamine was available and no multiple scattering occurred. On the basis of a direct relation between particle concentration and the heparin concentration present before protaminization, a light scattering assay was developed which permits the quantitative analysis of the heparin concentration in blood plasma and which could complement or even replace the activated clotting time test, which is currently the most commonly used method for blood coagulation management.

Low-molecular-weight heparin in pediatric patients.

PubMed

Sutor, Anton Heinz; Chan, Anthony K C; Massicotte, Patricia

2004-02-01

The incidence of thromboembolic events (TEs) in childhood is greatly underestimated. Two age groups account for approximately 70% of TEs in childhood: infants and teenagers. There are several predisposing risk factors for newborns such as small vessels, high hematocrit, and a unique neonatal hemostatic system. Central venous lines contribute to 80% of deep vein thrombosis in newborns. Other risk factors for all children are shock syndromes, trauma, surgery, heart and kidney disease, and acquired or hereditary thrombophilias. The best prophylaxis is to recognize, avoid, and remove risk factors if possible. This is particularly relevant in childhood, where risk factors can be found in the majority of TEs. The serious sequelae of TEs (mortality, and short- and long-term morbidity) require therapeutic intervention. Unfractionated heparin (UFH) has the following disadvantages: age-dependent unpredictable pharmacokinetics, the need for intravenous access for therapy and monitoring, delays in achieving therapeutic ranges, bleeding risk, the risk of heparin-induced thrombocytopenia, and osteoporosis with long-term use. Oral anticoagulants, in addition to some of these disadvantages, show considerable variation by diet (especially if there is a change from breast to bottle feeding), medication, and intercurrent illness. Review of case reports and cohort studies on 728 children treated with low-molecular-weight heparin (LMWH) indicate the following advantages over UFH: minimal monitoring, ease of administration (subcutaneous), and possibly equivalent efficacy and safety. Dose recommendations for pediatric patients cannot be directly extrapolated from those for adult patients. If dosages are calculated according to body weight, infants < 3 months (or < 5 kg) need approximately 50% more LMWH than older children or adults to reach prophylactic or therapeutic anti-factor Xa levels. Further studies are necessary to address the following: the importance of risk factors, the necessity of screening for hereditary thrombophilia, the efficacy and safety of treatment, and side effects and duration of treatment. Thromboembolic events (TEs) are considered to be rare in children. However, recent surveys reveal that TEs in children occur more often than suspected. The incidence is greatly underestimated because TEs are usually overlooked. Retrospective surveys in children treated for acute lymphoblastic leukemia with corticosteroids and asparaginase revealed clinically symptomatic TE in only 2 to 12% of patients. However, in prospective studies with routine imaging, the incidence was more than 20%. The objectives of this article are to update the present knowledge on TEs in children, including incidence, predominant age groups, risk factors, diagnosis, and indications for prophylaxis and therapy; and to discuss the use of low-molecular-weight heparin (LMWH) in children.

Economic impact of enoxaparin versus unfractionated heparin for venous thromboembolism prophylaxis in patients with acute ischemic stroke: a hospital perspective of the PREVAIL trial.

PubMed

Pineo, Graham; Lin, Jay; Stern, Lee; Subrahmanian, Tarun; Annemans, Lieven

2012-03-01

The PREVAIL (Prevention of VTE [venous thromboembolism] after acute ischemic stroke with LMWH [low-molecular-weight heparin] and UFH [unfractionated heparin]) study demonstrated a 43% VTE risk reduction with enoxaparin versus UFH in patients with acute ischemic stroke (AIS). A 1% rate of symptomatic intracranial and major extracranial hemorrhage was observed in both groups. To determine the economic impact, from a hospital perspective, of enoxaparin versus UFH for VTE prophylaxis after AIS. A decision-analytic model was constructed and hospital-based costs analyzed using clinical information from PREVAIL. Total hospital costs were calculated based on mean costs in the Premier™ database and from wholesalers acquisition data. Costs were also compared in patients with severe stroke (National Institutes of Health Stroke Scale [NIHSS] score ≥14) and less severe stroke (NIHSS score <14). The average cost per patient due to VTE or bleeding events was lower with enoxaparin versus UFH ($422 vs $662, respectively; net savings $240). The average anticoagulant cost, including drug-administration cost per patient, was lower with UFH versus enoxaparin ($259 vs $360, respectively; net savings $101). However, when both clinical events and drug-acquisition costs were considered, the total hospital cost was lower with enoxaparin versus UFH ($782 vs $922, respectively; savings $140). Hospital cost-savings were greatest ($287) in patients with NIHSS scores ≥14. The higher drug cost of enoxaparin was offset by the reduction in clinical events as compared to the use of UFH for VTE prophylaxis after an AIS, particularly in patients with severe stroke. Copyright © 2011 Society of Hospital Medicine.

Think of HIT.

PubMed

Warkentin, Theodore E

2006-01-01

Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common-isolated thrombocytopenia, venous thromboembolism, acute limb ischemia-to less common but specific presentations-necrotizing skin lesions at heparin injection sites, post-bolus acute systemic reactions, and adrenal hemorrhagic necrosis (secondary to adrenal vein thrombosis). Many patients with HIT have mild or moderate thrombocytopenia: the median platelet count nadir is 60 x 10(9)/L, and ranges from 15 to 150 x 10(9)/L in 90% of patients, most of whom evince a 50% or greater fall in the platelet count. HIT that begins after stopping heparin ("delayed-onset HIT") is increasingly recognized. Factors influencing risk of HIT include type of heparin (unfractionated heparin > low-molecular-weight heparin), type of patient (surgical > medical), and gender (female > male). Since timely diagnosis and treatment of HIT may reduce the risk of adverse outcomes, this review focuses on those clinical circumstances that should prompt the clinician to "think of HIT." Coumarin anticoagulants such as warfarin are ineffective in acute HIT and can even be deleterious by predisposing to micro-thrombosis via protein C depletion (venous limb gangrene and skin necrosis syndromes). Thus, it is important to avoid or postpone coumarin while managing HIT hypercoagulability, focusing on agents that inhibit thrombin directly (lepirudin, argatroban) or that inhibit its generation (danaparoid, fondaparinux). Post-marketing experience suggests that standard dosing of lepirudin is too high; current recommendations are to avoid the initial lepirudin bolus and to begin with lower infusion rates, even in patients without overt renal dysfunction.

Venous thromboembolism: epidemiology and magnitude of the problem.

PubMed

Goldhaber, Samuel Z

2012-09-01

Pulmonary embolism is the third most common cardiovascular disease after myocardial infarction and stroke. The death rate from pulmonary embolism exceeds the death rate from myocardial infarction, because myocardial infarction is much easier to detect and to treat. Among survivors of pulmonary embolism, chronic thromboembolic pulmonary hypertension occurs in 2-4 of every 100 patients. Post-thrombotic syndrome of the legs, characterized by chronic venous insufficiency, occurs in up to half of patients who suffer deep vein thrombosis or pulmonary embolism. We have effective pharmacological regimens using fixed low dose unfractionated or low molecular weight heparin to prevent venous thromboembolism among hospitalized patients. There remains the problem of low rates of utilization of pharmacological prophylaxis. The biggest change in our understanding of the epidemiology of venous thromboembolism is that we now believe that deep vein thrombosis and pulmonary embolism share similar risk factors and pathophysiology with atherothrombosis and coronary artery disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Customizing our approach in deep vein thrombosis and pulmonary embolism treatment: overview of our clinical experience.

PubMed

Turpie, A G

1999-08-01

Until recently, the management of established deep vein thrombosis (DVT) and pulmonary embolism remained largely unchanged and unchallenged. Treatment comprised an initial intravenous bolus of unfractionated heparin (UFH), followed by dose-adjusted intravenous UFH for 5-7 days, and oral warfarin for three months. UFH is traditionally administered in hospital, and monitoring and dose adjustment remain essential features of both UFH and warfarin treatment, making therapy both costly and inconvenient. Recent clinical trials have shown that subcutaneous UFH, or low-molecular-weight heparins (LMWHs), administered subcutaneously at a weight-adjusted fixed dose, are at least as effective as standard UFH given intravenously in the treatment of DVT. The feasibility of initial treatment of DVT at home in selected patients, with associated cost-savings and improved convenience have also been demonstrated with LMWHs. Clinical trials are currently investigating the potential value of LMWHs in the treatment of pulmonary embolism and as an alternative to warfarin in secondary prevention of DVT. The role of newer anticoagulants, such as recombinant hirudin, in initial treatment of DVT, and of thrombolysis in the management of pulmonary embolism remain to be defined.

Shifting from inpatient to outpatient treatment of deep vein thrombosis in a tertiary care center: a cost-minimization analysis.

PubMed

Boucher, Michel; Rodger, Marc; Johnson, Jeffrey A; Tierney, Mike

2003-03-01

To compare the cost of contemporary outpatient and historical inpatient management of proximal lower limb deep vein thrombosis (DVT) in adults. Prospective, observational study with historical inpatient cases as controls. Ambulatory thrombosis clinic of a tertiary care teaching center in Canada. Forty-nine inpatients with DVT from a previous study in 1996 at the same institution who would have been eligible for outpatient therapy if this option had been available, and 51 consecutive patients referred to the ambulatory thrombosis clinic for treatment of DVT between March 2000 and January 2001. The 49 inpatients received unfractionated heparin, and the 51 outpatients received low-molecular-weight heparin (LMWH). A cost-minimization analysis restricted to the hospital perspective was conducted. This design was justified based on the clinical equivalence of the two treatment strategies. All direct hospital costs for treating the 51 consecutive outpatients with LMWH were measured. These data were compared with the cost of treating the inpatients with unfractionated heparin. The analysis horizon was limited to 7 days, based on the duration of hospitalization and length of heparin therapy for DVT before conversion to oral warfarin. The mean cost (in Canadian dollars) per outpatient case was 248 Canadian dollars (95% confidence interval 216-280 Canadian dollars) and was significantly different from the mean cost/inpatient case of 2826 Canadian dollars (adjusted for the difference in fiscal years) (p<0.0005). A breakdown of the outpatient cost showed that nursing time contributed to 51% of the cost, monitoring laboratory tests 5%, drugs 2%, and other costs (diagnostic laboratory tests and medical imaging) 42%. Converting from inpatient to outpatient treatment of proximal DVT was associated with a significant cost savings for our institution. Accordingly, it is financially advantageous for hospitals to offer this service as it reduces direct costs and does not appear to compromise patient care.

Venous thromboembolism prophylaxis in gynecologic surgery: a systematic review.

PubMed

Rahn, David D; Mamik, Mamta M; Sanses, Tatiana V D; Matteson, Kristen A; Aschkenazi, Sarit O; Washington, Blair B; Steinberg, Adam C; Harvie, Heidi S; Lukban, James C; Uhlig, Katrin; Balk, Ethan M; Sung, Vivian W

2011-11-01

To comprehensively review and critically assess the available gynecologic surgery venous thromboembolism prophylaxis literature and provide clinical practice guidelines. MEDLINE and Cochrane databases from inception to July 2010. We included randomized controlled trials in gynecologic surgery populations. Interventions and comparators included graduated compression stockings, intermittent pneumatic compression, unfractionated heparin, and low molecular weight heparin; placebo and routine postoperative care were allowed as comparators. One thousand two hundred sixty-six articles were screened, and 14 randomized controlled trials (five benign gynecologic, nine gynecologic oncology) met eligibility criteria. In addition, nine prospective or retrospective studies with at least 150 women were identified and provided data on venous thromboembolism risk stratification, gynecologic laparoscopy, and urogynecologic populations. Two reviewers independently screened articles with discrepancies adjudicated by a third. Eligible randomized controlled trials were extracted for these characteristics: study, participant, surgery, intervention, comparator, and outcomes data, including venous thromboembolism incidence and bleeding complications. Studies were individually and collectively assessed for methodologic quality and strength of evidence. Overall incidence of clinical venous thromboembolism was 0-2% in the benign gynecologic population. With use of intermittent pneumatic compression for benign major procedures, venous thromboembolism incidence was less than 1%. No venous thromboembolisms were identified in prospective studies of benign laparoscopic procedures. Overall quality of evidence in the benign gynecologic literature was poor. Gynecologic-oncology randomized controlled trials reported venous thromboembolism incidence (including "silent" venous thromboembolisms) of 0-14.8% with prophylaxis and up to 34.6% without prophylaxis. Fair quality of evidence supports that unfractionated heparin and intermittent pneumatic compression are both superior to placebo or no intervention but insufficient to determine whether heparins are superior to intermittent pneumatic compression for venous thromboembolism prevention. Combining two of three risks (aged 60 years or older, cancer, or personal venous thromboembolism history) substantially elevated the risk of venous thromboembolism. Intermittent pneumatic compression provides sufficient prophylaxis for the majority of gynecology patients undergoing benign surgery. Additional risk factors warrant the use of combined mechanical and pharmacologic prophylaxis.

Low-molecular-weight heparins : mechanisms, trials, and role in contemporary interventional medicine.

PubMed

Canales, John F; Ferguson, James J

2008-01-01

The clinical spectrum of acute coronary syndromes (ACS) encompasses unstable angina, non-ST-elevation, and ST-elevation myocardial infarction (STEMI). Within an atherosclerotic plaque, disruption of the endothelium can lead to exposure of tissue factor, with platelet adhesion, activation and aggregation, along with activation of the coagulation cascade, culminating in thrombin formation and the development of a cross-linked fibrin clot at the site of injury. Therapy aimed at blocking thrombin formation is now an integral part of the current cardiovascular guidelines in the treatment of ACS. Although unfractionated heparin (UFH) has been the mainstay of antithrombin therapy in the past, it has numerous clinical and biochemical limitations, including substantial protein binding (leading to inconsistent bioavailability), a need for frequent monitoring and adjustment, unreliable and variable degrees of anticoagulation, significant platelet activation, risk of heparin-induced thrombocytopenia, and the inability to block clot bound thrombin. With all of these limitations of UFH, low-molecular-weight heparins (LMWHs) have emerged as attractive alternatives. This review discusses the mechanism of action of LMWHs, and summarizes available literature concerning the use of LMWHs in a variety of clinical settings. Included in this review is an analysis of both current and prior data showing LMWH is as effective as UFH in the conservative and invasive management of patients with ACS. As well, very recent data are evaluated showing the safety and efficacy of LMWHs used in patients transitioning to the cardiac catheterization laboratory, and in those patients undergoing elective or urgent percutaneous coronary intervention (PCI). We also appraise the literature, along with the very recent studies investigating the use of LMWHs as adjunctive therapy to fibrinolytics in patients with STEMI. Finally, we set forth real-world conclusions concerning the use of LMWHs in contemporary interventional practice, including elective PCI and the treatment of ischemic coronary artery disease in the context of rapid invasive management of ACS.

An economic evaluation of the costs and benefits of heparin rationalisation in a hospital pharmacy.

PubMed

Reeves, Penny; Cooke, Jonathan; Lloyd, Adam; Hutchings, Adam

2004-06-01

To estimate the costs and benefits for a UK hospital pharmacy of stocking a single low molecular weight heparin (LMWH), enoxaparin, compared to stocking unfractionated heparin (UFH) and stocking both UFH and multiple different LMWHs. A decision-tree model was developed which considered the use of heparins for five indications: prophylaxis against venous thromboembolism (VTE) in major orthopaedic surgery; VTE prophylaxis in major general surgery; VTE prophylaxis in acute medical inpatients; treatment of diagnosed VTE; and anticoagulation for patients with unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI). Previously published cost-effectiveness analyses for each indication were combined into a single model and updated to 2002 prices. The number of patients given heparin in each indication was estimated from the pharmacy records of a large UK teaching hospital. The model estimated the use of drugs, staff time, clinical events and resource use resulting from anti-coagulation. Costs were estimated from the perspective of the hospital and the UK National Health Service. Total annual cost was estimated to be pounds sterling 3.2 m (single LMWH), pounds sterling 4.4 m (UFH only) and pounds sterling 3.7 m (multiple heparins). The largest expected cost savings from using a single LMWH compared to UFH only resulted from reduced hospital stay for DVT treatment, reduced revascularisation in UA/NSTEMI and fewer VTE events in orthopaedic surgery. Expected cost savings from using a single LMWH compared to multiple heparins were more modest Sub-optimal choice of anticoagulants may result in substantial excess costs elsewhere in the hospital.

PF4-HIT antibody (KKO) complexes activate broad innate immune and inflammatory responses.

PubMed

Haile, Lydia A; Rao, Roshni; Polumuri, Swamy K; Arepally, Gowthami M; Keire, David A; Verthelyi, Daniela; Sommers, Cynthia D

2017-11-01

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin anticoagulation therapy resulting in thrombocytopenia frequently accompanied by thrombosis. Current evidence suggests that HIT is associated with antibodies developed in response to multi-molecular complexes formed by platelet factor 4 (PF4) bound to heparin or cell surface glycosaminoglycans. These antibody complexes activate platelets and monocytes typically through FcγRIIA receptors increasing the production of PF4, inflammatory mediators, tissue factor and thrombin. The influence of underlying events in HIT including complex-induced pro-inflammatory cell activation and structural determinants leading to local inflammatory responses are not fully understood. The stoichiometry and complex component requirements were determined by incubating fresh peripheral blood mononuclear cells (PBMC) with different concentrations of unfractionated heparin (H), low molecular weight heparin (LMWH), PF4- and anti-PF4-H complex antibodies (KKO). Cytokine mRNA or protein were measured by qRT-PCR or Meso Scale Discovery technology, respectively. Gene expression profile analysis for 594 genes was performed using Nanostring technology and analyzed using Ingenuity Pathway Analysis software. The data show that antibodies magnify immune responses induced in PBMCs by PF4 alone or in complex with heparin or LMWH. We propose that following induction of HIT antibodies by heparin-PF4 complexes, binding of the antibodies to PF4 is sufficient to induce a local pro-inflammatory response which may play a role in the progression of HIT. In vitro assays using PBMCs may be useful in characterizing local inflammatory and innate immune responses induced by HIT antibodies in the presence of PF4 and different sources of heparins. The findings and conclusions in this article are solely the responsibility of the authors and are not being formally disseminated by the Food and Drug Administration. Thus, they should not be construed to represent any Agency determination or policy. Published by Elsevier Ltd.

Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients.

PubMed

Fowler, Robert A; Mittmann, Nicole; Geerts, William; Heels-Ansdell, Diane; Gould, Michael K; Guyatt, Gordon; Krahn, Murray; Finfer, Simon; Pinto, Ruxandra; Chan, Brian; Ormanidhi, Orges; Arabi, Yaseen; Qushmaq, Ismael; Rocha, Marcelo G; Dodek, Peter; McIntyre, Lauralyn; Hall, Richard; Ferguson, Niall D; Mehta, Sangeeta; Marshall, John C; Doig, Christopher James; Muscedere, John; Jacka, Michael J; Klinger, James R; Vlahakis, Nicholas; Orford, Neil; Seppelt, Ian; Skrobik, Yoanna K; Sud, Sachin; Cade, John F; Cooper, Jamie; Cook, Deborah

2014-11-26

Venous thromboembolism (VTE) is a common complication of acute illness, and its prevention is a ubiquitous aspect of inpatient care. A multicenter blinded, randomized trial compared the effectiveness of the most common pharmocoprevention strategies, unfractionated heparin (UFH) and the low-molecular-weight heparin (LMWH) dalteparin, finding no difference in the primary end point of leg deep-vein thrombosis but a reduced rate of pulmonary embolus and heparin-induced thrombocytopenia among critically ill medical-surgical patients who received dalteparin. To evaluate the comparative cost-effectiveness of LMWH vs UFH for prophylaxis against VTE in critically ill patients. Prospective economic evaluation concurrent with the Prophylaxis for Thromboembolism in Critical Care Randomized Trial (May 2006 to June 2010). The economic evaluation adopted a health care payer perspective and in-hospital time horizon; derived baseline characteristics and probabilities of intensive care unit and in-hospital events; and measured costs among 2344 patients in 23 centers in 5 countries and applied these costs to measured resource use and effects of all enrolled patients. Costs, effects, incremental cost-effectiveness of LMWH vs UFH during the period of hospitalization, and sensitivity analyses across cost ranges. Hospital costs per patient were $39,508 (interquartile range [IQR], $24,676 to $71,431) for 1862 patients who received LMWH compared with $40,805 (IQR, $24,393 to $76,139) for 1862 patients who received UFH (incremental cost, -$1297 [IQR, -$4398 to $1404]; P = .41). In 78% of simulations, a strategy using LMWH was most effective and least costly. In sensitivity analyses, a strategy using LMWH remained least costly unless the drug acquisition cost of dalteparin increased from $8 to $179 per dose and was consistent among higher- and lower-spending health care systems. There was no threshold at which lowering the acquisition cost of UFH favored prophylaxis with UFH. From a health care payer perspective, the use of the LMWH dalteparin for VTE prophylaxis among critically ill medical-surgical patients was more effective and had similar or lower costs than the use of UFH. These findings were driven by lower rates of pulmonary embolus and heparin-induced thrombocytopenia and corresponding lower overall use of resources with LMWH.

Low-molecular-weight heparin for thromboprophylaxis.

PubMed

Camporese, Giuseppe; Bernardi, Enrico

2009-09-01

Venous thromboembolism represents a potentially threatening complication in surgical and medical patients. Thromboprophylaxis showed a significant reduction of venous thromboembolic events, and low-molecular-weight heparins have been considered the standardized prophylactic regimen for a long time. The purpose of this review is to provide updated evidence on the use of low-molecular-weight heparins for prevention of venous thromboembolism after the publication of the latest American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on antithrombotic and thrombolytic therapy. Low-molecular-weight heparins, used as comparator or investigational drug, have been investigated in several studies not included in the analysis of the latest American College of Chest Physicians Guidelines on Antithrombotic and Thrombolytic Therapy. Data gathered from studies published from December 2007 up to May 2009 dealing with surgical and medical patients have been collected and discussed. Low-molecular-weight heparins are expanding their application, but progressively they will be replaced by other new antithrombotics for the prophylaxis of venous thromboembolism. Surgical patients undergo a more concerted approach to thromboprophylaxis than medical patients. Future research should aim at improving prophylaxis in the latter setting in order to significantly reduce the rate of venous thromboembolic events.

Clinical use of parnaparin in major and minor orthopedic sugery: a review

PubMed Central

Bugamelli, Stefano; Zangheri, Elena; Montebugnoli, Milena; Guerra, Lucia

2008-01-01

Patients undergoing arthroplasty or other orthopedic surgery show a high risk of venous thromboembolism (VTE), involving mortality, morbidity, and social costs; however, the risk for VTE in minor orthopedic surgery should not be underestimated and antithrombotic prophylaxis may be required. According to the literature, low-molecular-weight heparins (LMWHs) are more effective in preventing VTE than unfractionated heparins (UFHs) or vitamin K antagonists, and have a lower hemorrhagic risk. By comparing different prophylactic regimens, it has been shown that starting the prophylaxis near the time of the operation is the most critical point for efficacy, whether or not the first dose is administered pre- or post-operatively. Moreover, most thromboembolic complications are observed after discharge and, therefore, many clinicians advocate continuing prophylaxis for longer times (6–8 weeks) in order to further reduce the rate for VTE. The literature on parnaparin, a new LMWH, in VTE prophylaxis was reviewed. Parnaparin is equally effective as UFH, but it offers the advantages of a once-daily administration and improved tolerability, thus allowing the home management of patients with no need for laboratory coagulation tests. PMID:19183746

Perioperative venous thromboembolism in patients with gynecological malignancies: a lesson from four years of recent clinical experience.

PubMed

Morimoto, Akiko; Ueda, Yutaka; Yokoi, Takeshi; Tokizawa, Yuki; Yoshino, Kiyoshi; Fujita, Masami; Kimura, Toshihiro; Kobayashi, Eiji; Matsuzaki, Shinya; Egawa-Takata, Tomomi; Sawada, Kenjiro; Tsutsui, Tateki; Kimura, Tadashi

2014-07-01

To analyze clinical characteristics of venous thromboembolisms (VTE) in gynecological malignancies, and to find a cost-effective prophylaxis procedure for post-operative VTE. We analyzed clinical characteristics of 751 patients who underwent definitive surgery for gynecologic malignancies, and cost-effectiveness of VTE prophylaxis. VTE was diagnosed preoperatively in 4.5% of ovarian cancer cases, more frequently than any other type (p<0.005). Older age and greater length of operation were independent risk factors for postoperative VTE. To prevent eight VTEs in 738 malignant cases, which occurred during day 2 to 10, $617,783, $726,185, or $994,222 were necessary for continuous VTE prophylaxis, using either unfractionated heparin (UFH), low-molecular weight heparin or fondaparinux, respectively. A strategy which might be cost-effective for post-surgical management of gynecological malignances is use of UFH three times combined with graduated compression stockings and intermittent pneumatic compression, thorough SpO2 monitoring, and perioperative measurements of the circumference of both sides of thighs and calves. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Establishment of replacement batches for heparin low-molecular-mass for calibration CRS, and the International Standard Low Molecular Weight Heparin for Calibration.

PubMed

Mulloy, B; Heath, A; Behr-Gross, M-E

2007-12-01

An international collaborative study involving fourteen laboratories has taken place, organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM) with National Institute for Biological Standards & Control (NIBSC) (in its capacity as a World Health Organisation (WHO) Laboratory for Biological Standardisation) to provide supporting data for the establishment of replacement batches of Heparin Low-Molecular-Mass (LMM) for Calibration Chemical Reference Substance (CRS), and of the International Reference Reagent (IRR) Low Molecular Weight Heparin for Molecular Weight Calibration. A batch of low-molecular-mass heparin was donated to the organisers and candidate preparations of freeze-dried heparin were produced at NIBSC and EDQM. The establishment study was organised in two phases: a prequalification (phase 1, performed in 3 laboratories in 2005) followed by an international collaborative study (phase 2). In phase 2, started in March 2006, molecular mass parameters were determined for seven different LMM heparin samples using the current CRS batch and two batches of candidate replacement material with a defined number average relative molecular mass (Mn) of 3,700, determined in phase 1. The values calculated using the candidates as standard were systematically different from values calculated using the current batch with its assigned number-average molecular mass (Mna) of 3,700. Using raw data supplied by participants, molecular mass parameters were recalculated using the candidates as standard with values for Mna of 3,800 and 3,900. Values for these parameters agreed more closely with those calculated using the current batch supporting the fact that the candidates, though similar to batch 1 in view of the production processes used, differ slightly in terms of molecular mass distribution. Therefore establishment of the candidates was recommended with an assigned Mna value of 3,800 that is both consistent with phase 1 results and guarantees continuity with the current CRS batch. In phase 2, participants also determined molecular weight parameters for the seven different LMM heparin samples using both the 1st IRR (90/686) and its Broad Standard Table and the candidate World Health Organization (WHO) 2nd International Standard (05/112) (2nd IS) using a Broad Standard Table established in phase 1. Mean molecular weights calculated using 2nd IS were slightly higher than with 1st IRR, and participants in the study indicated that this systematic difference precluded establishment of 2nd IS with the table supplied. A replacement Broad Standard Table has been devised on the basis of the central recalculations of raw data supplied by participants; this table gives improved agreement between values derived using the 1st IRR and the candidate 2nd IS. On the basis of this study a recommendation was made for the establishment of 2nd IS and its proposed Broad Standard Table as a replacement for the 1st International Reference Reagent Low Molecular Weight Heparin for Molecular Weight Calibration. Unlike the 1st IRR however, the candidate material 2nd IS is not suitable for use with the method of Nielsen. The candidate materials were established as heparin low-molecular-mass for calibration batches 2 and 3 by the Ph. Eur. Commission in March 2007 and as 2nd IS low-molecular-weight heparin for molecular weight calibration (05/112) by the Expert Committee on Biological Standardization in November 2007.

[Intraoperative administration of low-molecular-weight heparins in reconstructive vascular operations].

PubMed

Pokrovskiĭ, A V; Demidova, V S; Titova, M I; Gontarenko, V N; Burtseva, E A

2008-01-01

The article deals with analysing the outcomes of administering low-molecular-weight heparins (LMWH) by the example of nadroparin ("Fraxiparin") during the intraoperative period in patients diagnosed with atherosclerotic lesions of femoropoplietal-crural segment of the lower-limb arteries as compared with non-fractionated heparin (NFH). Studied were the alterations in the parameters of the plasmatic and thrombocytic links of haemostasis on the background of administering various molecular-weight fractions of heparin. A conclusion was drawn on advantageous use of LMWH in the cohort of the patients involved. Also presented herein is an analysis of the literature data concerning appropriate usage of LMWH during the intraoperative period.

Prevention of VTE in Orthopedic Surgery Patients

PubMed Central

Francis, Charles W.; Johanson, Norman A.; Curley, Catherine; Dahl, Ola E.; Schulman, Sam; Ortel, Thomas L.; Pauker, Stephen G.; Colwell, Clifford W.

2012-01-01

Background: VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. Methods: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). Conclusions: Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches. PMID:22315265

Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis.

PubMed

Chande, N; McDonald, J W; Macdonald, J K

2008-04-16

There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis. The MEDLINE (PUBMED), and EMBASE databases, The Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on ulcerative colitis, and references from identified papers were searched in an effort to identify all randomized trials studying UFH or LMWH use in patients with ulcerative colitis. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above. The Jadad scale was used to assess study quality. Studies published in abstract form only were included if the authors could be contacted for further information. A data extraction form was developed and used to extract data from included studies. At least 2 authors independently extracted data. Any disagreements were resolved by consensus. Data were analyzed using Review Manager (RevMan 4.2.9). Data were analyzed on an intention-to-treat basis, and treated dichotomously. In cross-over studies, only data from the first arm were included. The primary endpoint was induction of remission, as defined by the studies. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). If a comparison was only assessed in a single trial, P-values were derived using the chi-square test. If the comparison was assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals (95% CI). The presence of heterogeneity among studies was assessed using the chi-square test (a P value of 0.10 was regarded as statistically significant). If statistically significant heterogeneity was identified the odds ratio and 95% CI were calculated using a random effects model. There were 2 randomized, double-blind studies assessing LMWH versus placebo for the treatment of mild-moderate active UC. Various outcomes were assessed in the 2 studies. LMWH showed no benefit over placebo in any outcome, including clinical remission (OR 1.09; 95% CI 0.26 to 4.63; P = 0.91), clinical improvement (OR 0.73; 95% CI 0.32 to 1.66; P = 0.45 and OR 1.09; 95% CI 0.18 to 6.58; P = 0.92 in the two studies, respectively), endoscopic improvement (OR 1.35; 95% CI 0.29 to 6.18; P = 0.70), or histological improvement (OR 2.00; 95% CI 0.45 to 8.96; P = 0.37). LMWH was also not beneficial when added to standard therapy in a randomized open-label trial in which the outcome measures included clinical remission (OR 0.71; 95% CI 0.17 to 2.95; P = 0.64), clinical improvement (OR 2.00; 95% CI 0.31 to 12.75; P = 0.46), endoscopic remission (OR 0.71; 95% CI 0.17 to 2.95; P = 0.64), or endoscopic improvement (OR 1.40; 95% CI 0.34 to 5.79; P = 0.64). LMWH was well-tolerated and provided no significant benefit for quality of life. One study examining UFH versus corticosteroids in the treatment of severe UC demonstrated inferiority of UFH in clinical improvement as an outcome measure (OR 0.02; 95% CI 0 to 0.40; P = 0.01). Patients assigned to UFH did not improve clinically. More patients assigned to UFH had rectal hemorrhage as an adverse event. There is no evidence to support the use of UFH or LMWH for the treatment of active UC. No further trials examining these drugs for patients with UC are warranted, except perhaps a trial of UFH in patients with mild disease. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.

Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes (FUTURA/OASIS 8): a randomized trial of intravenous unfractionated heparin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux.

PubMed

Steg, Philippe Gabriel; Mehta, Shamir; Jolly, Sanjit; Xavier, Denis; Rupprecht, Hans-Juergen; Lopez-Sendon, Jose Luis; Chrolavicius, Susan; Rao, Sunil V; Granger, Christopher B; Pogue, Janice; Laing, Shiona; Yusuf, Salim

2010-12-01

There is uncertainty regarding the optimal adjunctive unfractionated heparin (UFH) regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with fondaparinux. The aim of this study is to evaluate the safety of 2 dose regimens of adjunctive intravenous UFH during PCI in high-risk patients with NSTE-ACS initially treated with fondaparinux and referred for early coronary angiography. This is an international prospective cohort study of approximately 4,000 high-risk patients presenting to hospital with unstable angina or non-ST-segment elevation myocardial infarction, treated with fondaparinux as initial medical therapy, and referred for early coronary angiography with a view to revascularization. Within this cohort, 2,000 patients undergoing PCI will be eligible for enrollment into a double-blind international randomized parallel-group trial evaluating standard activated clotting time (ACT)-guided doses of intravenous UFH versus a non-ACT-guided weight-adjusted low dose. The standard regimen uses an 85-U/kg bolus of UFH if there is no platelet glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitor or 60 U/kg if GpIIb-IIIa inhibitor use is planned, with additional bolus guided by blinded ACT measurements. The low-dose regimen uses a 50 U/kg UFH bolus, irrespective of planned GpIIb-IIIa use. The primary outcome is the composite of peri-PCI major bleeding, minor bleeding, or major vascular access site complications. The assessment of net clinical benefit is a key secondary outcome: it addresses the composite of peri-PCI major bleeding with death, myocardial infarction, or target vessel revascularization at day 30. FUTURA/OASIS 8 will help define the optimal UFH regimen as adjunct to PCI in high-risk NSTE-ACS patients treated with fondaparinux. Copyright © 2010 Mosby, Inc. All rights reserved.

Determination of Oversulphated Chondroitin Sulphate and Dermatan Sulphate in unfractionated heparin by (1)H-NMR - Collaborative study for quantification and analytical determination of LoD.

PubMed

McEwen, I; Mulloy, B; Hellwig, E; Kozerski, L; Beyer, T; Holzgrabe, U; Wanko, R; Spieser, J-M; Rodomonte, A

2008-12-01

Oversulphated Chondroitin Sulphate (OSCS) and Dermatan Sulphate (DS) in unfractionated heparins can be identified by nuclear magnetic resonance spectrometry (NMR). The limit of detection (LoD) of OSCS is 0.1% relative to the heparin content. This LoD is obtained at a signal-to-noise ratio (S/N) of 2000:1 of the heparin methyl signal. Quantification is best obtained by comparing peak heights of the OSCS and heparin methyl signals. Reproducibility of less than 10% relative standard deviation (RSD) has been obtained. The accuracy of quantification was good.

Controllable production of low molecular weight heparins by combinations of heparinase I/II/III.

PubMed

Wu, Jingjun; Zhang, Chong; Mei, Xiang; Li, Ye; Xing, Xin-Hui

2014-01-30

Enzymatic depolymerization of heparin by heparinases is promising for production of low molecular weight heparins (LMWHs) as anticoagulants, due to its mild reaction conditions and high selectivity. Here, different heparinase combinations were used to depolymerize heparin. Heparinase I and heparinase II can depolymerize heparin more efficiently than heparinase III, respectively, but heparinase III was the best able to protect the anticoagulant activities of LMWHs. Heparinase III and heparinase I/II combinations were able to efficiently depolymerize heparin to LMWHs with higher anticoagulant activity than the LMWHs produced by the respective heparinase I and heparinase II. HepIII and HepI is the best combination for maintaining high anti-IIa activity (75.7 ± 4.21 IU/mg) at the same Mw value. Furthermore, considering both the changes in molecular weight and anticoagulant activity, the action patterns of heparinase I and heparinase II were found not to follow the exolytic and processive depolymerizing mechanism from the reducing end of heparin. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pulmonary embolism during and after pregnancy.

PubMed

Stone, Sarah E; Morris, Timothy A

2005-10-01

Venous thromboembolic disease is among the most common causes of morbidity and mortality during pregnancy. The clinical evaluation alone is insufficient for the diagnosis of venous thromboembolic disease, and the normal pregnant state makes this evaluation even more challenging. Objective testing is the mainstay of diagnosis, including compression ultrasound, impedance plethysmography, ventilation-perfusion scanning, computed tomography scanning, and pulmonary angiography. All of these tests can be safety performed during pregnancy. If deep vein thrombosis or pulmonary embolism is diagnosed, anticoagulation should be initiated. Either (unfractionated) heparin or low molecular weight heparin is an acceptable treatment for acute venous thromboembolic disease. Both have risks and benefits, but both can be used safely during pregnancy. Intravenous heparin is the treatment of choice surrounding delivery due to its short half life. Because of the risk of adverse effects on the fetus, warfarin is not generally used during pregnancy. Unstable pulmonary embolism is difficult to treat during pregnancy, as there are minimal data regarding the safety and efficacy of thrombolytic therapy, inferior vena cava filters, and embolectomy during pregnancy. Case reports and case series suggest that thrombolytic therapy may be associated with lower risks of fetal loss than embolectomy. Venous thromboembolic disease is a significant cause of morbidity and mortality during pregnancy and the puerperal period. Objective testing is critical to establish the diagnosis and can be safely performed during pregnancy. Anticoagulation with heparin is the mainstay of therapy during the pregnancy, but patients may be transitioned to warfarin after delivery.

In vitro and in vivo characterization of a reversible synthetic heparin analog.

PubMed

Whelihan, Matthew F; Cooley, Brian; Xu, Yongmei; Pawlinski, Rafal; Liu, Jian; Key, Nigel S

2016-02-01

The global supply of unfractionated heparin (UFH) and all commercially available low molecular weight heparins (LMWH) remain dependent on animal sources, such as porcine intestine or bovine lung. Recent experience has shown that contamination of the supply chain (with over-sulfated chondroitin sulfates) can result in lethal toxicity. Fondaparinux is currently the only commercially available synthetic analog of heparin. We recently described a new class of chemoenzymatically synthesized heparin analogs. One of these compounds (S12-mer) is a dodecasaccharide consisting of an antithrombin-binding moiety with repeating units of IdoA2S-GlcNS6S and two 3-O-sulfate groups that confer the ability to bind protamine. We sought to further characterize this new compound in vitro using biochemical and global coagulation assays and in vivo using thrombosis and hemostasis assays. The anticoagulant activities of the Super 12-mer (S12-mer) and Enoxaparin in anti-factor Xa and plasma-based thrombin generation assays were roughly equivalent with a 50% reduction in peak thrombin generation occurring at approximately 325nM. When protamine was titrated against a fixed concentration of S12-mer in plasma or blood, the S12-mer displayed a significant restitution of thrombin generation and clot formation. In vivo, S12-mer inhibited venous thrombosis to a similar extent as Enoxaparin, with similar bleeding profiles. These data show that the S12-mer has almost identical efficacy to Enoxaparin in terms of FXa inhibition, while displaying significant reversibility with protamine. Taken together with the ability to ensure purity and homogeneity from batch to batch, the S12-mer is a promising new synthetic heparin analog with a potentially enhanced safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

Low-molecular-weight heparin venous thromboprophylaxis in critically ill patients with renal dysfunction: A subgroup analysis of the PROTECT trial

PubMed Central

Adhikari, Neill K. J.; Ostermann, Marlies; Heels-Ansdell, Diane; Douketis, James D.; Skrobik, Yoanna; Qushmaq, Ismael; Meade, Maureen; Guyatt, Gordon; Geerts, William; Walsh, Michael W.; Crowther, Mark A.; Friedrich, Jan O.; Burry, Lisa; Bellomo, Rinaldo; Brandão da Silva, Nilton; Costa Filho, Rubens; Cox, Michael J.; Alves Silva, Suzana; Cook, Deborah J.

2018-01-01

Introduction There is concern about excessive bleeding when low-molecular-weight heparins (LMWHs) are used for venous thromboembolism (VTE) prophylaxis in renal dysfunction. Our objective was to evaluate whether LMWH VTE prophylaxis was safe and effective in critically ill patients with renal dysfunction by conducting a subgroup analysis of PROTECT, a randomized blinded trial. Methods We studied intensive care unit (ICU) patients with pre-ICU dialysis-dependent end-stage renal disease (ESRD; pre-specified subgroup; n = 118), or severe renal dysfunction at ICU admission (defined as ESRD or non-dialysis dependent with creatinine clearance [CrCl] <30 ml/min; post hoc subgroup; n = 590). We compared dalteparin, 5000 IU daily, with unfractionated heparin (UFH), 5000 IU twice daily, and considered outcomes of proximal leg deep vein thrombosis (DVT); pulmonary embolism (PE); any VTE; and major bleeding. Adjusted hazard ratios [HR] were calculated using Cox regression. Results In patients with ESRD, there was no significant difference in DVT (8.3% vs. 5.2%, p = 0.76), any VTE (10.0% vs. 6.9%; p = 0.39) or major bleeding (5.0% vs. 8.6%; p = 0.32) between UFH and dalteparin. In patients with severe renal dysfunction, there was no significant difference in any VTE (10.0% vs. 6.4%; p = 0.07) or major bleeding (8.9% vs. 11.0%; p = 0.66) but an increase in DVT with dalteparin (7.6% vs. 3.7%; p = 0.04). Interaction p-values for comparisons of HRs (ESRD versus not) were non-significant. Conclusions In critically ill patients with ESRD, or severe renal dysfunction, there was no significant difference in any VTE or major bleeding between UFH and dalteparin. Patients with severe renal dysfunction who received dalteparin had more proximal DVTs than those on UFH; this finding did not hold in patients with ESRD alone. PMID:29856817

Subcutaneous Administration of Low-Molecular-Weight Heparin to Horses Inhibits Ex Vivo Equine Herpesvirus Type 1-Induced Platelet Activation

PubMed Central

Stokol, Tracy; Serpa, Priscila B. S.; Brooks, Marjory B.; Divers, Thomas; Ness, Sally

2018-01-01

Equine herpesvirus type 1 (EHV-1) is a major cause of infectious respiratory disease, abortion and neurologic disease. Thrombosis in placental and spinal vessels and subsequent ischemic injury in EHV-1-infected horses manifests clinically as abortion and myeloencephalopathy. We have previously shown that addition of heparin anticoagulants to equine platelet-rich plasma (PRP) can abolish ex vivo EHV-1-induced platelet activation. The goal of this study was to test whether platelets isolated from horses treated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) were resistant to ex vivo EHV-1-induced activation. In a masked, block-randomized placebo-controlled cross-over trial, 9 healthy adult horses received 4 subcutaneous injections at q. 12 h intervals of one of the following treatments: UFH (100 U/kg loading dose, 3 maintenance doses of 80 U/kg), 2 doses of LMWH (enoxaparin) 80 U/kg 24 h apart with saline at the intervening 12 h intervals, or 4 doses of saline. Blood samples were collected before treatment and after 36 h, 40 h (4 h after the last injection) and 60 h (24 h after the last injection). Two strains of EHV-1, Ab4 and RacL11, were added to PRP ex vivo and platelet membrane expression of P selectin was measured as a marker of platelet activation. Drug concentrations were monitored in a Factor Xa inhibition (anti-Xa) bioassay. We found that LMWH, but not UFH, inhibited platelet activation induced by low concentrations (1 × 106 plaque forming units/mL) of both EHV-1 strains at 40 h. At this time point, all horses had anti-Xa activities above 0.1 U/ml (range 0.15–0.48 U/ml) with LMWH, but not UFH. By 60 h, a platelet inhibitory effect was no longer detected and anti-Xa activity had decreased (range 0.03 to 0.07 U/ml) in LMWH-treated horses. Neither heparin inhibited platelet activation induced by high concentrations (5 × 106 plaque forming units/mL) of the RacL11 strain. We found substantial between horse variability in EHV-1-induced platelet activation at baseline and after treatment. Minor injection site reactions developed in horses given either heparin. These results suggest that LMWH therapy may prevent thrombotic sequelae of EHV-1, however further evaluation of dosage regimens is required. PMID:29892605

[Vitamin K antagonists overdose].

PubMed

Groszek, Barbara; Piszczek, Paweł

2015-01-01

Nowadays, anticoagulant therapy belongs to the most commonly used forms of pharmacotherapy in modern medicine. The most important representatives of anticoagulants are heparins (unfractionated heparin and low-molecular-weight heparin) and coumarin derivatives (vitamin K antagonists--VKA). Next to the many advantages of traditional oral anticoagulants may also have disadvantages. In Poland most often used two VKA: acenocoumarol and warfarin. The aim of the work is the analysis of the causes of the occurrence of bleeding disorders and symptoms of overdose VKA in patients to be hospitalized. In the years 2012 to 2014 were hospitalized 62 patients with overdose VKA (40 women and 22 men). The average age of patients was 75.3 years) and clotting disturbances and/or bleeding. At the time of the admission in all patients a significant increase in the value of the INR was stated, in 22 patients INR result was " no clot detected", on the remaining value of the INR were in the range of 7 to 13.1. On 51 patients observed different severe symptoms of bleeding (hematuria, bleeding from mucous membranes of the nose or gums ecchymoses on the extremities, bleeding from the gastrointestinal tract--as in 5 patients has led to significant anemia and transfusion of concentrated red blood cells. Up on 33 patients kidney function disorder were found--exacerbated chronic renal failure and urinary tract infection. 8 diagnosed inflammatory changes in the airways. On 13 patients, it was found a significant degree of neuropsychiatric disorders (dementia, cognitive impairment), which made impossible the understanding the sense of treatment and cooperation with the patient. In 6 patients the symptoms of overdose were probably dependent on the interaction with the congestants at the same time (change the preparation of anticoagulant, NSAIDs, antibiotics). In 2 cases, the overdose was a suicide attempt in nature. In addition to the above mentioned disorders, on two of those patients diagnosed with a malignant disease. Two patients died, the other has been improving and anticoagulant therapy with VKA was continued, in 4 VKA were changed to low-molecular-weight heparin, and on 4 commissioned new generation anticoagulant (rivaroxaban).

Use of Low Molecular Weight Heparin and Aminocaproic Acid in Chronic DIC Associated with Prostate Cancer- A Case Report

PubMed Central

Shirai, Keisuke; Chaudhary, Uzair B.

2007-01-01

Disseminated Intravascular Coagulopathy (DIC) is the most common coagulopathy in patients with prostate cancer. Though rare, it could be fatal without treatment. Literature suggests that there is significant activation of fibrinolytic pathway. Pathophysiology of DIC in patients with prostate cancer is not completely understood. We present here a case of chronic DIC in a patient with metastatic androgen independent prostate cancer. His DIC was managed successfully with a combination of aminocaproic acid and low weight molecular heparin. The use of low molecular weight heparin may make management of chronic DIC in prostate cancer more feasible in an out patient setting. PMID:17619757

Direct oral anticoagulants for extended thromboprophylaxis in medically ill patients: meta-analysis and risk/benefit assessment.

PubMed

Al Yami, Majed S; Kurdi, Sawsan; Abraham, Ivo

2018-01-01

Standard-duration (7-10 days) thromboprophylaxis with low molecular weight heparin, low dose unfractionated heparin, or fondaparinux in hospitalized medically ill patients is associated with ~50% reduction in venous thromboembolism (VTE) risk. However, these patients remain at high risk for VTE post-discharge. The direct oral anticoagulants (DOACs) apixaban, rivaroxaban and betrixaban have been evaluated for extended-duration (30-42 days) thromboprophylaxis in this population. We review the efficacy and safety results from the 3 pivotal trials of extended-duration DOAC thromboprophylaxis in medically ill patients. We performed a meta-analysis of these pivotal trials focusing on 6 VTE (efficacy) and three bleeding outcomes (safety). These results were integrated into a quantitative risk/benefit assessment. The trials evaluating extended-duration DOAC thromboprophylaxis in medically ill patients failed to establish clear efficacy and/or safety signals for each agent. Our meta-analysis shows that, as a class, DOACs have selective and partial extended-duration prophylactic activity in preventing VTE events. However, this is associated with a marked increase in the risk of various bleeding events. The risk/benefit analyses fail to show a consistent net clinical benefit of extended-duration DOAC prophylaxis in medically ill patients. At this time, the evidence of safe and effective extended-duration thromboprophylaxis with DOACs in this population is inconclusive.

Qualitative and quantitative analysis of heparin and low molecular weight heparins using size exclusion chromatography with multiple angle laser scattering/refractive index and inductively coupled plasma/mass spectrometry detectors.

PubMed

Ouyang, Yilan; Zeng, Yangyang; Yi, Lin; Tang, Hong; Li, Duxin; Linhardt, Robert J; Zhang, Zhenqing

2017-11-03

Heparin, a highly sulfated glycosaminoglycan, has been used as a clinical anticoagulant over 80 years. Low molecular weight heparins (LMWHs), heparins partially depolymerized using different processes, are widely used as clinical anticoagulants. Qualitative molecular weight (MW) and quantitative mass content analysis are two important factors that contribute to LMWH quality control. Size exclusion chromatography (SEC), relying on multiple angle laser scattering (MALS)/refractive index (RI) detectors, has been developed for accurate analysis of heparin MW in the absence of standards. However, the cations, which ion-pair with the anionic polysaccharide chains of heparin and LMWHs, had not been considered in previous reports. In this study, SEC with MALS/RI and inductively coupled plasma/mass spectrometry detectors were used in a comprehensive analytical approach taking both anionic polysaccharide and ion-paired cations heparin products. This approach was also applied to quantitative analysis of heparin and LMWHs. Full profiles of MWs and mass recoveries for three commercial heparin/LMWH products, heparin sodium, enoxaparin sodium and nadroparin calcium, were obtained and all showed higher MWs than previously reported. This important improvement more precisely characterized the MW properties of heparin/LMWHs and potentially many other anionic polysaccharides. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of a low-carbohydrate diet-based preparation protocol without fasting for cardiac PET/MR imaging.

PubMed

Nensa, Felix; Tezgah, E; Schweins, K; Goebel, J; Heusch, P; Nassenstein, K; Schlosser, T; Poeppel, T D

2017-06-01

Assessment of increased glucose uptake in inflammatory or malignant myocardial disease using PET/MRI relies on uptake suppression in normal myocardium. We evaluated the efficacy of a ≥24 hours high-fat, low-carbohydrate, and protein-permitted diet (HFLCPP) in combination with unfractionated heparin for suppression of "physiologic" myocardial glucose uptake. PET/MRI was successfully performed in 89 patients. HFLCPP was started ≥24 hours prior to PET/MRI. All patients received i.v. injection of unfractionated heparin (50 IU·kg -1 ) 15 minutes prior to FDG administration. Left ventricular FDG uptake was visually evaluated by two readers. Diffuse myocardial uptake exceeding liver uptake, isolated uptake in the lateral wall, or diffuse uptake in the entire circumference of the heart base were defined as failed suppression. Homogeneous myocardial uptake below liver uptake with/without focal uptake was defined as successful suppression. Success rate was 84%. Suppression was unsuccessful in 14 patients. No significant influence of gender (P = .40) or age (P = .21) was found. However, insufficient suppression was more common in patients younger than 45 years (20% vs 7%). PET/MR imaging completion rate was >97%. A HFLCPP diet in combination with unfractionated heparin was successfully implemented for cardiac PET/MRI and resulted in a sufficient suppression of myocardial FDG uptake in 84% of patients.

Arterial thrombosis after vehicular trauma and humeral fracture in a dog.

PubMed

DePaula, Kristina M; deLaorcade, Armelle M; King, Ryan G; Hughs, Holly; Boudrieau, Randy J

2013-08-01

A 3-year-old 19-kg (42-lb) spayed female mixed-breed dog was referred after being hit by a car. Injuries included pneumothorax, hemothorax, pulmonary contusions, a full-thickness axillary skin wound, and a grade I transverse fracture of the midshaft of the right humerus. Following patient stabilization, open reduction and internal fixation of the fracture were performed. The dog had weight-bearing lameness at the time of discharge. Eight days after fracture repair, the dog was reevaluated for acute onset of signs of pain and non-weight-bearing lameness in the right forelimb. Physical examination findings in the right forelimb (knuckling and coolness, with absent digital pulses) were suggestive of a thrombus. Ultrasonography confirmed a right brachial artery thrombus with minimal blood flow to the affected limb. Unfractionated heparin was administered via continuous IV infusion for the first 36 hours of hospitalization. Clopidogrel administration was also started at this time. During hospitalization, rapid clinical improvement occurred, and the dog was discharged 48 hours after admission. The transition to outpatient therapy was achieved by discontinuation of the unfractionated heparin infusion at 36 hours and beginning SC administration of dalteparin. Outpatient treatment with dalteparin and clopidogrel was continued. Repeated physical examination and ultrasonography 5 weeks later revealed resolution of the thrombus and normal blood flow to the limb. Anticoagulant administration was discontinued at that time. Thrombosis should be suspected in any dog with signs of acute pain after severe trauma or fracture repair, with or without concurrent lameness, that do not resolve with appropriate treatment. Restoration of blood flow to the affected limb after initiation of unfractionated heparin and clopidogrel administration followed by outpatient treatment with dalteparin and clopidogrel was achieved in this case.

Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM)

PubMed Central

2014-01-01

Background Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications. Methods/Design We conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy. Discussion The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin. Systematic review registration PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249 PMID:24969227

[A contribution safety on using low molecular weight heparin in patients with renal failure].

PubMed

Gea Rodríguez, E; Barral Viñals, N; Manso Mardones, P; Indo Berges, O

2004-01-01

1. To promote safe and appropriate use of low molecular weight heparins in patients with renal failure. 2. To analyze results from a pharmaceutical intervention program. Data from a prospective, 16-month study are presented. The entire adult population of a general hospital with 41,792 stays/year is included. An intensive monitoring program for low molecular weight heparin prescriptions in patients with renal failure is implemented. This program identifies patients using a computerized unit dose system, and is aided by a software able to calculate creatinine clearance using the Cockroft-Gault formula from an interphase between laboratory, pharmacy and admissions data, and by an algorithm to establish a recommended pharmaceutical intervention according to renal failure severity and low molecular weight heparin indication, either with prophylactic or therapeutic purposes. In all, 221 patients were identified, corresponding to 2.9% of admitted patients and 25.5% of patients with renal failure. Answers were assessable for 128 patients (61%). Extent of program acceptance according to physician-accepted pharmaceutical interventions was proportional to renal failure severity and therapy intensiveness. An acceptance of 70% was obtained for treatments with clearance < 30 mL/min, of 41.8% for treatments with 30-60 mL/min, of 31.5% for prophylaxis, and of 21.4% for low-risk patients. 1. Program repercussions improve prescription safety. 2. Scarce literature and a belief in low molecular weight heparin safety account for responses regarding pharmaceutical intervention. 3. Integrated computerized systems are essential for the implementation of intensive pharmaceutical care programs.

GlycCompSoft: Software for Automated Comparison of Low Molecular Weight Heparins Using Top-Down LC/MS Data

PubMed Central

Li, Lingyun; Zhang, Fuming; Hu, Min; Ren, Fuji; Chi, Lianli; Linhardt, Robert J.

2016-01-01

Low molecular weight heparins are complex polycomponent drugs that have recently become amenable to top-down analysis using liquid chromatography-mass spectrometry. Even using open source deconvolution software, DeconTools, and automatic structural assignment software, GlycReSoft, the comparison of two or more low molecular weight heparins is extremely time-consuming, taking about a week for an expert analyst and provides no guarantee of accuracy. Efficient data processing tools are required to improve analysis. This study uses the programming language of Microsoft Excel™ Visual Basic for Applications to extend its standard functionality for macro functions and specific mathematical modules for mass spectrometric data processing. The program developed enables the comparison of top-down analytical glycomics data on two or more low molecular weight heparins. The current study describes a new program, GlycCompSoft, which has a low error rate with good time efficiency in the automatic processing of large data sets. The experimental results based on three lots of Lovenox®, Clexane® and three generic enoxaparin samples show that the run time of GlycCompSoft decreases from 11 to 2 seconds when the data processed decreases from 18000 to 1500 rows. PMID:27942011

Obstacles in the diagnostics and therapy of heparin-induced thrombocytopenia.

PubMed

Antonijević, Nebojsa M; Radovanović, Nebojsa; Obradović, Slobodan; Vucelić, Dragica; Stojanović, Bojan; Miković, Danijela; Kovac, Mirjana; Kocica, Tina; Tadić, Svetlana; Antonijević, Irina; Drasković, Snezana; Djordjević, Valentina; Calija, Branko; Perunicić, Jovan; Vasiljević, Zorana

2010-01-01

An immune-mediated, severe, acquired prothrombotic disorder, heparin-induced thrombocytopenia type II (HIT II) occurs in 0.5-5% of patients exposed to unfractionated heparin longer than 5-7 days. Arterial and venous thromboses are induced by HIT II in about 35-50% of patients. Typical death rate for HIT is about 29%, while 21% of HIT patients result in amputation of a limb. The trend towards the occurrence of HIT due to the administration of low molecular weight heparins (LMWH) taking ever conspicuous place in the standard venous thromboembolism (VTE) prophylaxis has been more frequently observed recently. It is considered that LMWH may cause HIT II in about 0.25-1%. The need for further modification of HIPA assays with LMWH has been imposed in the HIT laboratory diagnostics, heretofore overburdened with complexity. There are several constantly opposing problems arising in HIT laboratory diagnostics, one of which is that in a certain number of patients immunologic assays detect nonpathogenic antibodies (mainly IgM or IgA heparin-PF4 antibodies) while, on the other hand, the occurrence of HIT pathogenetically mediated by minor antigens (neutrophil-activating peptide 2 or interleukin 8) may be neglected in certain cases. The following factors play an important role in the interpretation of each laboratory HIT assays performed: 1. correlation with HIT clinical probability test, the best known of which is 4T'score, 2. the interpretation of the laboratory findings dependent on the time of the thrombocytopenia onset, as well as 3. the sensitivity and specificity of each test respectively. The HIT diagnostics in the presence of other comorbid states which may also induce thrombocytopenia, more precisely known as pseudo HIT (cancer, sepsis, disseminated intravascular coagulation, pulmonary embolism, antiphospholipid syndrome, etc), represents a specific clinical problem.

Management of inherited thrombophilia in pregnancy

PubMed Central

Ormesher, Laura; Simcox, Louise; Tower, Clare; Greer, Ian A

2016-01-01

Adverse pregnancy outcomes, such as pregnancy loss and pre-eclampsia, are associated with thrombotic mechanisms and thrombophilia. Antithrombotic interventions, particularly low-molecular-weight heparin, have been investigated in women identified by previous pregnancy outcome; however, the results have been inconsistent. This may reflect heterogeneity of both the study groups and the disease processes resulting in inadequate stratification to guide antithrombotic interventions. Furthermore, the variation in gestation at initiation of low-molecular-weight heparin treatment might be important. Despite limited evidence of efficacy, low-molecular-weight heparin is often used in an attempt to prevent these complications, owing to the lack of other effective treatments and its perceived safety in pregnancy. Research is required to better understand the disease processes, identify possible biomarkers and thereby more homogeneous groups for targeted treatment. PMID:27638899

Top-down and bottom-up analysis of commercial enoxaparins.

PubMed

Liu, Xinyue; St Ange, Kalib; Lin, Lei; Zhang, Fuming; Chi, Lianli; Linhardt, Robert J

2017-01-13

A strategy for the comprehensive analysis of low molecular weight (LMW) heparins is described that relies on using an integrated top-down and bottom-up approach. Liquid chromatography-mass spectrometry, an essential component of this approach, is rapid, robust, and amenable to automated processing and interpretation. Nuclear magnetic resonance spectroscopy provides complementary top-down information on the chirality of the uronic acid residues comprising a low molecular weight heparin. Using our integrated approach four different low molecular weight heparins prepared from porcine heparin through chemical β-eliminative cleavage were comprehensively analyzed. Lovenox™ and Clexane™, the innovator versions of enoxaparin marketed in the US and Europe, respectively, and two generic enoxaparins, from Sandoz and Teva, were analyzed. The results which were supported by analysis of variation (ANOVA), while showing remarkable similarities between different versions of the product and good lot-to-lot consistency of each product, also detects subtle differences that may result from differences in their manufacturing processes or differences in the source (or parent) porcine heparin from which each product is prepared. Copyright © 2016 Elsevier B.V. All rights reserved.

Structure and Activity of a New Low Molecular Weight Heparin Produced by Enzymatic Ultrafiltration

PubMed Central

FU, LI; ZHANG, FUMING; LI, GUOYUN; ONISHI, AKIHIRO; BHASKAR, UJJWAL; SUN, PEILONG; LINHARDT, ROBERT J.

2014-01-01

The standard process for preparing the low molecular weight heparin (LMWH) tinzaparin, through the partial enzymatic depolymerization of heparin, results in a reduced yield due to the formation of a high content of undesired disaccharides and tetrasaccharides. An enzymatic ultrafiltration reactor for LMWH preparation was developed to overcome this problem. The behavior, of the heparin oligosaccharides and polysaccharides using various membranes and conditions, was investigated to optimize this reactor. A novel product, LMWH-II, was produced from the controlled depolymerization of heparin using heparin lyase II in this optimized ultrafiltration reactor. Enzymatic ultrafiltration provides easy control and high yields (>80%) of LMWH-II. The molecular weight properties of LMWH-II were similar to other commercial LMWHs. The structure of LMWH-II closely matched heparin’s core structural features. Most of the common process artifacts, present in many commercial LWMHs, were eliminated as demonstrated by 1D and 2D nuclear magnetic resonance spectroscopy. The antithrombin III and platelet factor-4 binding affinity of LMWH-II were comparable to commercial LMWHs, as was its in vitro anticoagulant activity. PMID:24634007

Outpatient treatment of deep venous thrombosis in diverse inner-city patients.

PubMed

Dunn, A S; Schechter, C; Gotlin, A; Vomvolakis, D; Jacobs, E; Sacks, H S; Coller, B

2001-04-15

We sought to describe the development and outcomes of a hospital-based program designed to provide safe and effective outpatient treatment to a diverse group of patients with acute deep venous thrombosis. Patients enrolled in the program were usually discharged on the day of or the day after presentation. Low- molecular-weight heparin was administered for a minimum of 5 days and warfarin was given for a minimum of 3 months. The hospital provided low-molecular-weight heparin free of charge to patients. Patients received daily home nursing visits to monitor the prothrombin time, assess compliance, and detect complications. The inpatient and outpatient records of the first 89 consecutive patients enrolled in the program were reviewed. Patients were observed for a 3-month period after enrollment. The median length of stay was 1 day. Low-molecular-weight heparin was administered for a mean (+/- standard deviation [SD]) of 4.7 +/- 2.4 days at home. Recurrent thromboembolism was noted in 1 patient (1%), major bleeding in 2 patients (2%), and minor bleeding in 2 patients (2%). No patients died or developed thrombocytopenia. Assuming that patients would have been hospitalized for the duration of treatment with low-molecular-weight heparin, the program eliminated a mean of 4.7 days of hospitalization, with an estimated reduction of $1,645 in total health care costs per patient. This hospital-based program to provide outpatient treatment of deep venous thrombosis to a diverse group of inner-city patients achieved a low incidence of adverse events and substantial health care cost savings. Specific strategies, including providing low-molecular-weight heparin free of charge and daily home nursing visits, can be utilized to facilitate access to outpatient treatment and ensure high-quality care.

Structure and activity of a new low-molecular-weight heparin produced by enzymatic ultrafiltration.

PubMed

Fu, Li; Zhang, Fuming; Li, Guoyun; Onishi, Akihiro; Bhaskar, Ujjwal; Sun, Peilong; Linhardt, Robert J

2014-05-01

The standard process for preparing the low-molecular-weight heparin (LMWH) tinzaparin, through the partial enzymatic depolymerization of heparin, results in a reduced yield because of the formation of a high content of undesired disaccharides and tetrasaccharides. An enzymatic ultrafiltration reactor for LMWH preparation was developed to overcome this problem. The behavior, of the heparin oligosaccharides and polysaccharides using various membranes and conditions, was investigated to optimize this reactor. A novel product, LMWH-II, was produced from the controlled depolymerization of heparin using heparin lyase II in this optimized ultrafiltration reactor. Enzymatic ultrafiltration provides easy control and high yields (>80%) of LMWH-II. The molecular weight properties of LMWH-II were similar to other commercial LMWHs. The structure of LMWH-II closely matched heparin's core structural features. Most of the common process artifacts, present in many commercial LWMHs, were eliminated as demonstrated by 1D and 2D nuclear magnetic resonance spectroscopy. The antithrombin III and platelet factor-4 binding affinity of LMWH-II were comparable to commercial LMWHs, as was its in vitro anticoagulant activity. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Heparins With Enoxaparin.

PubMed

Liu, Xinyue; St Ange, Kalib; Fareed, Jawed; Hoppensteadt, Debra; Jeske, Walter; Kouta, Ahmed; Chi, Lianli; Jin, Caijuan; Jin, Yongsheng; Yao, Yiming; Linhardt, Robert J

2017-09-01

Heparin and its low-molecular-weight heparin (LMWH) derivatives are widely used clinical anticoagulants. These drugs are critical for the practice of medicine in applications including kidney dialysis, cardiopulmonary bypass, and in the management of venous thromboembolism. Currently, these drugs are derived from livestock, primarily porcine intestine. The worldwide dependence on a single animal species has made the supply chain for this critical drug quite fragile, leading to the search for other sources of these drugs, including bovine tissues such as bovine intestine or lung. A number of laboratories are currently examining the similarities and differences between heparins prepared from porcine and bovine tissues. The current study is designed to compare LMWH prepared from bovine heparins through chemical β-elimination, a process currently used to prepare the LMWH, enoxaparin, from porcine heparin. Using top-down, bottom-up, compositional analysis and bioassays, LMWHs, derived from bovine lung and intestine, are shown to closely resemble enoxaparin.

Risk of gastrointestinal bleeding with direct oral anticoagulants: a systematic review and network meta-analysis.

PubMed

Burr, Nick; Lummis, Katie; Sood, Ruchit; Kane, John Samuel; Corp, Aaron; Subramanian, Venkataraman

2017-02-01

Direct oral anticoagulants are increasingly used for a wide range of indications. However, data are conflicting about the risk of major gastrointestinal bleeding with these drugs. We compared the risk of gastrointestinal bleeding with direct oral anticoagulants, warfarin, and low-molecular-weight heparin. For this systematic review and meta-analysis, we searched MEDLINE and Embase from database inception to April 1, 2016, for prospective and retrospective studies that reported the risk of gastrointestinal bleeding with use of a direct oral anticoagulant compared with warfarin or low-molecular-weight heparin for all indications. We also searched the Cochrane Library for systematic reviews and assessment evaluations, the National Health Service (UK) Economic Evaluation Database, and ISI Web of Science for conference abstracts and proceedings (up to April 1, 2016). The primary outcome was the incidence of major gastrointestinal bleeding, with all gastrointestinal bleeding as a secondary outcome. We did a Bayesian network meta-analysis to produce incidence rate ratios (IRRs) with 95% credible intervals (CrIs). We identified 38 eligible articles, of which 31 were included in the primary analysis, including 287 692 patients exposed to 230 090 years of anticoagulant drugs. The risk of major gastrointestinal bleeding with direct oral anticoagulants did not differ from that with warfarin or low-molecular-weight heparin (factor Xa vs warfarin IRR 0·78 [95% CrI 0·47-1·08]; warfarin vs dabigatran 0·88 [0·59-1·36]; factor Xa vs low-molecular-weight heparin 1·02 [0·42-2·70]; and low-molecular-weight heparin vs dabigatran 0·67 [0·20-1·82]). In the secondary analysis, factor Xa inhibitors were associated with a reduced risk of all severities of gastrointestinal bleeding compared with warfarin (0·25 [0.07-0.76]) or dabigatran (0.24 [0.07-0.77]). Our findings show no increase in risk of major gastrointestinal bleeding with direct oral anticoagulants compared with warfarin or low-molecular-weight heparin. These findings support the continued use of direct oral anticoagulants. Leeds Teaching Hospitals Charitable Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of enoxaparin and unfractionated heparin in prophylactic and therapeutic doses on the fertility of female Wistar rats.

PubMed

Figueiró-Filho, Ernesto Antonio; Aydos, Ricardo Dutra; Senefonte, Flávio Renato de Almeida; Ferreira, Cristiane Munaretto; Pereira, Erica Freire de Vasconcelos; Oliveira, Vanessa Marcon de; Menezes, Giovanna Pádoa de; Bósio, Marco Antonio Costa

2014-07-01

To evaluate the effects of exposure of enoxaparin and unfractionated heparin (UFH) in prophylactic and therapeutic doses on the fertility rates of pregnant healthy Wistar rats. Enoxaparin and UFH were administered in prophylactic doses 1 mg/Kg/day 72 UI/Kg/day, and in therapeutic doses at 2 mg/kg/day 400UI/Kg/day. The rats were divided into five groups. The number of live and dead foetuses was quantified. The uterine horns were dissected and the presence of early and late reabsorptions (abortions) was determined. A p<0.05 was considered statistically significant. We did not observe statistically significant differences between groups when comparing the average weight of the foetuses and placentas, rate of female VS males, rates of pre-implantation loss (RPL), rates of efficiency implantation (REI), rates of post-implantation loss (RPIL) and rates of foetal viability (RFV). There was no significant effect on fertility with the use of anticoagulant drugs in pregnant healthy Wistar rats.

Risk of Deep vein thrombosis in neurosurgery: State of the art on prophylaxis protocols and best clinical practices.

PubMed

Ganau, Mario; Prisco, Lara; Cebula, Helene; Todeschi, Julien; Abid, Houssem; Ligarotti, Gianfranco; Pop, Raoul; Proust, Francois; Chibbaro, Salvatore

2017-11-01

To analytically discuss some protocols in Deep vein thrombosis (DVT)/pulmonary Embolism (PE) prophylaxis currently use in Neurosurgical Departments around the world. Analysis of the prophylaxis protocols in the English literature: An analytical and narrative review of literature concerning DVT prophylaxis protocols in Neurosurgery have been conducted by a PubMed search (back to 1978). 80 abstracts were reviewed, and 74 articles were extracted. The majority of DVT seems to develop within the first week after a neurosurgical procedure, and a linear correlation between the duration of surgery and DVT occurrence has been highlighted. The incidence of DVT seems greater for cranial (7.7%) than spinal procedures (1.5%). Although intermittent pneumatic compression (IPC) devices provided adequate reduction of DVT/PE in some cranial and combined cranial/spinal series, low-dose subcutaneous unfractionated heparin (UFH) or low molecular-weight heparin (LMWH) further reduced the incidence, not always of DVT, but of PE. Nevertheless, low-dose heparin-based prophylaxis in cranial and spinal series risks minor and major postoperative haemorrhages: 2-4% in cranial series, 3.4% minor and 3.4% major haemorrhages in combined cranial/spinal series, and a 0.7% incidence of major/minor haemorrhages in spinal series. This analysis showed that currently most of the articles are represented by case series and case reports. As long as clear guidelines will not be defined and universally applied to this diverse group of patients, any prophylaxis for DVT and PE should be tailored to the individual patient with cautious assessment of benefits versus risks. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antiplatelet and Anticoagulant Drugs in Interventional Radiology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altenburg, Alexander; Haage, Patrick, E-mail: patrick.haage@helios-kliniken.de

In treating peripheral arterial disease, a profound knowledge of antiplatelet and anticoagulative drug therapy is helpful to assure a positive clinical outcome and to anticipate and avoid complications. Side effects and drug interactions may have fatal consequences for the patient, so interventionalists should be aware of these risks and able to control them. Aspirin remains the first-line agent for antiplatelet monotherapy, with clopidogrel added where dual antiplatelet therapy is required. In case of suspected antiplatelet drug resistance, the dose of clopidogrel may be doubled; prasugrel or ticagrelor may be used alternatively. Glycoprotein IIb/IIIa inhibitors (abciximab or eptifibatide) may help inmore » cases of hypercoagulability or acute embolic complications. Desmopressin, tranexamic acid, or platelet infusions may be used to decrease antiplatelet drug effects in case of bleeding. Intraprocedurally, anticoagulant therapy treatment with unfractionated heparin (UFH) still is the means of choice, although low molecular-weight heparins (LMWH) are suitable, particularly for postinterventional treatment. Adaption of LMWH dose is often required in renal insufficiency, which is frequently found in elderly patients. Protamine sulphate is an effective antagonist for UFH; however, this effect is less for LMWH. Newer antithrombotic drugs, such as direct thrombin inhibitors or factor X inhibitors, have limited importance in periprocedural treatment, with the exception of treating patients with heparin-induced thrombocytopenia (HIT). Nevertheless, knowing pharmacologic properties of the newer drugs facilitate correct bridging of patients treated with such drugs. This article provides a comprehensive overview of antiplatelet and anticoagulant drugs for use before, during, and after interventional radiological procedures.« less

Rectus sheath hematoma with low molecular weight heparin administration: a case series.

PubMed

Sullivan, Laura E J; Wortham, Dale C; Litton, Kayleigh M

2014-09-01

Rectus sheath hematoma is an uncommon but potentially serious bleeding complication that can occur spontaneously or as a result of anticoagulation administration. Case number one: A 62 year old chronically ill Caucasian female develops a rectus sheath hematoma seven days after hospital discharge. The previous hospitalization included low molecular weight heparin administration for deep vein thrombosis prophylaxis. The patient ultimately chooses comfort care and expires due to sepsis and respiratory failure. Case number two: A 79 year old Caucasian male develops a rectus sheath hematoma during hospital admission where LMWH is used for deep vein thrombosis prophylaxis. He is managed conservatively; however, his hematocrit drops from 46 to 25.8%. Case number three: A 44 year old chronically ill Caucasian female is treated with therapeutic low molecular weight heparin for recent deep vein thrombosis during a hospital admission. She develops a large rectus sheath hematoma requiring embolization as well as blood transfusion. We believe this reflects an underreported significant cause of morbidity and mortality with low molecular weight heparin administration. We review the pathophysiology of rectus sheath hematoma as well as its presentation, diagnosis, and treatment. We identify at-risk populations and proposed contributing factors. We also discuss factors leading to underreporting as well as preventive strategies implemented at our institution.

Real-life Use of Anticoagulants in Venous Thromboembolism With a Focus on Patients With Exclusion Criteria for Direct Oral Anticoagulants.

PubMed

Moustafa, Farès; Pesavento, Raffaele; di Micco, Pierpaolo; González-Martínez, José; Quintavalla, Roberto; Peris, Maria-Luisa; Porras, José Antonio; Falvo, Nicolas; Baños, Pilar; Monreal, Manuel

2018-04-01

We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47-3.88), major bleeds (HR: 4.10; 95% CI: 3.38-4.96), and deaths (HR: 9.47; 95% CI: 8.46-10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04-0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08-1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15-1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy. © 2017 American Society for Clinical Pharmacology and Therapeutics.

[Present and future of antithrombotic therapy in acute coronary syndromes].

PubMed

Antman, Elliott M

2003-02-01

Antithrombotic therapy in the management of an acute coronary syndrome is designed to inhibit both the coagulation cascade and platelet activation, thus preventing the development of the pathophysiological consequences of these processes. The main therapeutic approaches used for this purpose are unfractionated heparin, low-molecular-weight heparins, or direct antithrombins, all of them being molecules that interfere with the formation of a thrombin clot. Numerous clinical studies have investigated the advantages and disadvantages of each of these strategies and the benefits and risks of combined therapy with these drugs or their association with platelet inhibitors. The difficulty of establishing the relative benefits of different therapeutic approaches is due in part to the enormous number of possible combinations and the different clinical situations in which they can be used. In addition, the need for antithrombotic agents with a more specific inhibitor activity and a broader therapeutic range is motivating active investigation in laboratories worldwide. This has lead to the design of recombinant molecules and monoclonal antibodies that interrupt the activation of the coagulation cascade in several strategically important points. The relation between the clinical benefits obtained from this new generation of molecules and the increased health care costs generated by their design and development remains to be seen.

Prevention of VTE in Nonorthopedic Surgical Patients

PubMed Central

Garcia, David A.; Wren, Sherry M.; Karanicolas, Paul J.; Arcelus, Juan I.; Heit, John A.; Samama, Charles M.

2012-01-01

Background: VTE is a common cause of preventable death in surgical patients. Methods: We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations. Conclusions: Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients. PMID:22315263

Capillary Electrophoresis-Mass Spectrometry for the Analysis of Heparin Oligosaccharides and Low Molecular Weight Heparin.

PubMed

Sun, Xiaojun; Lin, Lei; Liu, Xinyue; Zhang, Fuming; Chi, Lianli; Xia, Qiangwei; Linhardt, Robert J

2016-02-02

Heparins, highly sulfated, linear polysaccharides also known as glycosaminoglycans, are among the most challenging biopolymers to analyze. Hyphenated techniques in conjunction with mass spectrometry (MS) offer rapid analysis of complex glycosaminoglycan mixtures, providing detailed structural and quantitative data. Previous analytical approaches have often relied on liquid chromatography (LC)-MS, and some have limitations including long separation times, low resolution of oligosaccharide mixtures, incompatibility of eluents, and often require oligosaccharide derivatization. This study examines the analysis of glycosaminoglycan oligosaccharides using a novel electrokinetic pump-based capillary electrophoresis (CE)-MS interface. CE separation and electrospray were optimized using a volatile ammonium bicarbonate electrolyte and a methanol-formic acid sheath fluid. The online analyses of highly sulfated heparin oligosaccharides, ranging from disaccharides to low molecular weight heparins, were performed within a 10 min time frame, offering an opportunity for higher-throughput analysis. Disaccharide compositional analysis as well as top-down analysis of low molecular weight heparin was demonstrated. Using normal polarity CE separation and positive-ion electrospray ionization MS, excellent run-to-run reproducibility (relative standard deviation of 3.6-5.1% for peak area and 0.2-0.4% for peak migration time) and sensitivity (limit of quantification of 2.0-5.9 ng/mL and limit of detection of 0.6-1.8 ng/mL) could be achieved.

Effects of Long-Term Low-Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review With Meta-Analysis.

PubMed

Gajic-Veljanoski, Olga; Phua, Chai W; Shah, Prakesh S; Cheung, Angela M

2016-08-01

Adults who require long-term anticoagulation with low-molecular-weight heparin (LMWH) such as cancer patients or the elderly may be at increased risk of fractures. To determine the effects of LMWH therapy of at least 3 months' duration on fractures and bone mineral density (BMD) in non-pregnant adult populations. We systematically reviewed electronic databases (e.g., MEDLINE, EMBASE), conferences and bibliographies until June 2015 and included comparative studies in non-pregnant adult populations that examined the effects of LMWH (≥3 months) on fractures and BMD. We synthesized evidence qualitatively and used random-effects meta-analysis to quantify the effect of LMWH on fractures. Sixteen articles reporting 14 studies were included: 10 clinical trials (n = 4865 participants) and four observational cohort studies (3 prospective, n = 221; 1 retrospective, n = 30). BMD and fractures were secondary outcomes in the majority of trials, while they were primary outcomes in the majority of observational studies. In participants with venous thromboembolism and underlying cardiovascular disease or cancer (5 RCTs, n = 2280), LMWH for 3-6 months did not increase the relative risk of all fractures at 6-12 months compared to unfractionated heparin, oral vitamin K antagonists or placebo [pooled risk ratio (RR) = 0.58, 95 % CI: 0.23-1.43; I(2) = 12.5 %]. No statistically significant increase in the risk of fractures at 6-12 months was found for cancer patients (RR = 1.08, 95 % CI: 0.31-3.75; I(2) = 4.4 %). Based on the data from two prospective cohort studies (n = 166), LMWH for 3-24 months decreased mean BMD by 2.8-4.8 % (depending on the BMD site) compared to mean BMD decreases of 1.2-2.5 % with oral vitamin K antagonists. LMWH for 3-6 months may not increase the risk of fractures, but longer exposure for up to 24 months may adversely affect BMD. Clinicians should consider monitoring BMD in adults on long-term LMWH who are at increased risk of bone loss or fracture.

A PK-PD model-based assessment of sugammadex effects on coagulation parameters.

PubMed

Bosch, Rolien; van Lierop, Marie-José; de Kam, Pieter-Jan; Kruithof, Annelieke C; Burggraaf, Jacobus; de Greef, Rik; Visser, Sandra A G; Johnson-Levonas, Amy O; Kleijn, Huub-Jan

2016-03-10

Exposure-response analyses of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PT(INR)) were performed using data from two clinical trials in which subjects were co-treated with anti-coagulants, providing a framework to predict these responses in surgical patients on thromboprophylactic doses of low molecular weight or unfractionated heparin. Sugammadex-mediated increases in APTT and PT(INR) were described with a direct effect model, and this relationship was similar in the presence or absence of anti-coagulant therapy in either healthy volunteers or surgical patients. In surgical patients on thromboprophylactic therapy, model-based predictions showed 13.1% and 22.3% increases in respectively APTT and PT(INR) within 30min after administration of 16mg/kg sugammadex. These increases remain below thresholds seen following treatment with standard anti-coagulant therapy and were predicted to be short-lived paralleling the rapid decline in sugammadex plasma concentrations. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Effect of oral administration of unfractionated heparin (UFH) on coagulation parameters in plasma and levels of urine and fecal heparin in dogs

PubMed Central

Erickson, Malathi; Hiebert, Linda M.; Carr, Anthony P.; Stickney, Jocelyn D.

2014-01-01

The effects of heparin administration, by the oral route, were evaluated in dogs. In single and multiple dose studies (single 7.5 mg/kg, multiple 3 × 7.5 mg/kg per 48 h), plasma, urine, and fecal samples were collected at various times up to 120 h after oral administration of unfractionated heparin. Changes in plasma and urine anti-Xa activity, plasma and urine anti-IIa activity, plasma activated partial thromboplastin time (APTT) and antithrombin (ATIII), and chemical heparin in urine and feces were examined with time. There was support for heparin absorption, with significant differences in APTT, heparin in plasma as determined by anti-Xa activity (Heptest) in the single dose study and plasma anti-Xa activity, anti-IIa activity and ATIII; and chemical heparin in urine in the multiple dose study. No clinical evidence of bleeding was detected in any dog during the studies. Oral heparin therapy may be applicable for thromboembolic disease in animals. Further studies are warranted to determine the effects of oral heparin at the endothelial level in the dog. PMID:24982550

A bioprosthetic total artificial heart for end-stage heart failure: Results from a pilot study.

PubMed

Latrémouille, Christian; Carpentier, Alain; Leprince, Pascal; Roussel, Jean-Christian; Cholley, Bernard; Boissier, Elodie; Epailly, Eric; Capel, Antoine; Jansen, Piet; Smadja, David M

2018-01-01

The electro-hydraulically actuated Carmat total artificial heart (C-TAH) is designed to replace the heart in patients with end-stage heart failure, either as bridge to transplant or destination therapy. It provides pulsatile flow and contains bio-prosthetic blood contacting materials. A clinical feasibility study was conducted to evaluate the C-TAH safety and performance. Hospitalized patients, at imminent risk of death from irreversible biventricular failure despite optimal medical management, and not eligible for transplant or eligible but on extracorporeal life support, were enrolled. The primary endpoint was 30-days survival. Four patients were implanted with the C-TAH, three as destination therapy (ages 76, 68, 74) and one as bridge to transplant (age 58). They had implant times of 74, 270, 254 and 20 days respectively. All patients were free from hemolysis, clinical neurologic events, clinical evidence of thrombus and device-related infections. Hemodynamic and physical recovery allowed two patients to be discharged home for a cumulative duration of 7 months. The anticoagulation management strategy comprised initial unfractionated heparin, from postoperative day 2, followed by low molecular weight heparin and aspirin. An increased D-dimer level was observed in all patients during months 1 to 4. Temporary suspension of heparin anticoagulation resulted in thrombocytopenia and increased fibrin monomer, reversed by resuming anticoagulation with heparin. Causes of death were device-related (2 cases), respiratory failure and multi-organ failure. Preliminary clinical results with the C-TAH demonstrated good safety and performance profiles in patients suffering from biventricular failure, which need to be confirmed in a pivotal study. Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Authentication of animal origin of heparin and low molecular weight heparin including ovine, porcine and bovine species using 1D NMR spectroscopy and chemometric tools.

PubMed

Monakhova, Yulia B; Diehl, Bernd W K; Fareed, Jawed

2018-02-05

High resolution (600MHz) nuclear magnetic resonance (NMR) spectroscopy is used to distinguish heparin and low-molecular weight heparins (LMWHs) produced from porcine, bovine and ovine mucosal tissues as well as their blends. For multivariate analysis several statistical methods such as principal component analysis (PCA), factor discriminant analysis (FDA), partial least squares - discriminant analysis (PLS-DA), linear discriminant analysis (LDA) were utilized for the modeling of NMR data of more than 100 authentic samples. Heparin and LMWH samples from the independent test set (n=15) were 100% correctly classified according to its animal origin. Moreover, by using 1 H NMR coupled with chemometrics and several batches of bovine heparins from two producers were differentiated. Thus, NMR spectroscopy combined with chemometrics is an efficient tool for simultaneous identification of animal origin and process based manufacturing difference in heparin products. Copyright © 2017 Elsevier B.V. All rights reserved.

Interactions of oversulfated chondroitin sulfate (OSCS) from different sources with unfractionated heparin.

PubMed

Gray, Angel; Litinas, Evangelos; Jeske, Walter; Fareed, Jawed; Hoppensteadt, Debra

2012-01-01

In 2008, oversulfated chondroitin sulfate (OSCS) was identified as the main contaminant in recalled heparin. Oversulfated chondroitin sulfate can be prepared from bovine (B), porcine (P), shark (Sh), or skate (S) origin and may produce changes in the antithrombotic, bleeding, and hemodynamic profile of heparins. This study examines the interactions of various OSCSs on heparin in animal models of thrombosis and bleeding, as well as on the anticoagulant and antiprotease effects in in vitro assays. Mixtures of 70% unfractionated heparin (UFH) with 30% OSCS from different sources were tested. In the in vitro activated partial thromboplastin time (aPTT) assay, all contaminant mixtures showed a decrease in clotting times. In addition, a significant increase in bleeding time compared to the control (UFH/saline) was observed. In the thrombosis model, no significant differences were observed. The OSCSs significantly increased anti-Xa activity in ex vivo blood samples. These results indicate that various sources of OSCS affect the hemostatic properties of heparin.

A RCT study of Rivaroxaban, low-molecular-weight heparin, and sequential medication regimens for the prevention of venous thrombosis after internal fixation of hip fracture.

PubMed

Tang, Yilun; Wang, Kunzheng; Shi, Zhibin; Yang, Pei; Dang, Xiaoqian

2017-08-01

The guidelines for the prevention of venous thromboembolism in orthopedic surgeries have reached a consensus on the postoperative conventional anticoagulation. However, the choice of anticoagulant drugs is yet controversial. The use of the drug rivaroxaban is expensive. Since the compliance of patients with low-molecular-weight heparin is considerably low, a cost-effective, efficacious and convenient anticoagulant program is essential. The present study investigated the efficacy, safety, patient compliance, and cost-effectiveness of low-molecular-weight heparin with sequential Rivaroxaban anticoagulant therapy in patients with a hip fracture, following internal fixation. A total of 287 patients with hip fractures were randomized into three groups: Rivaroxaban alone, Enoxaparin alone, and Enoxaparin followed by Rivaroxaban. The primary endpoint was the incidence of postoperative VTE, whereas the secondary endpoints were the compliance and treatment costs. Adverse reactions included bleeding and wound complications. The incidences of VTE were 5.21%, 14.74%, and 10.42% in the Rivaroxaban, low-molecular-weight heparin, and sequential therapy groups, respectively. The VTE-related mortality rates were 0%, 1.05%, and 1.04%. The average hospital stay was 12±8,15±7, and 11±5d, whereas the compliance rates of the three groups were 82.3%, 71.6%, and 88.5%, respectively. The incidences of adverse incisions were 14.6%, 4.2%, and 6.3% for the three groups examined. The effects and the incidence of postoperative bleeding in the treatment of low-molecular-weight heparin followed by Rivaroxaban did not differ significantly from that of Rivaroxaban alone. However, the postoperative drainage, the cost of treatment and the incidence of VTE reduced significantly, whereas the incidences of adverse incisions and the patient compliance were increased. ChiCTR-INR-17010495. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[Meta-analysis on randomized trials comparing the results of low-molecular weight heparins to those of fractioned heparins in the prevention of deep venous thrombosis].

PubMed

Daures, J P; Schved, J F; Momas, I; Gril, J C; Azoulay, P; Gremy, F

1989-01-01

The main reason for using low molecular weight heparin (LMWH) is its capacity to keep the antithrombotic effect of standard non-fractioned heparin (NFH) while reducing its hemorrhagic power. Various studies comparing LMWH to NFH gave contradictory results, so we carried out a meta-analysis of randomized trials comparing these two treatments in prevention of deep-vein thrombosis (DVT) (and in prevention of deep-vein thrombosis or pulmonary embolism). From a selection of ten trials we could not show any significant difference in the DVT rates, as well as for the whole of surgical indications as for the subgroups of abdominal and orthopedic surgery. The weighted global difference between the DVT rates is so low that, in spite of the use of meta-analysis, the power is clearly insufficient. The hemorrhagic risk is not statistically reduced as well for the whole of surgical indications as for the subgroups.

Novel method for the determination of average molecular weight of natural polymers based on 2D DOSY NMR and chemometrics: Example of heparin.

PubMed

Monakhova, Yulia B; Diehl, Bernd W K; Do, Tung X; Schulze, Margit; Witzleben, Steffen

2018-02-05

Apart from the characterization of impurities, the full characterization of heparin and low molecular weight heparin (LMWH) also requires the determination of average molecular weight, which is closely related to the pharmaceutical properties of anticoagulant drugs. To determine average molecular weight of these animal-derived polymer products, partial least squares regression (PLS) was utilized for modelling of diffused-ordered spectroscopy NMR data (DOSY) of a representative set of heparin (n=32) and LMWH (n=30) samples. The same sets of samples were measured by gel permeation chromatography (GPC) to obtain reference data. The application of PLS to the data led to calibration models with root mean square error of prediction of 498Da and 179Da for heparin and LMWH, respectively. The average coefficients of variation (CVs) did not exceed 2.1% excluding sample preparation (by successive measuring one solution, n=5) and 2.5% including sample preparation (by preparing and analyzing separate samples, n=5). An advantage of the method is that the sample after standard 1D NMR characterization can be used for the molecular weight determination without further manipulation. The accuracy of multivariate models is better than the previous results for other matrices employing internal standards. Therefore, DOSY experiment is recommended to be employed for the calculation of molecular weight of heparin products as a complementary measurement to standard 1D NMR quality control. The method can be easily transferred to other matrices as well. Copyright © 2017 Elsevier B.V. All rights reserved.

Low molecular weight heparin restores antithrombin III activity from hyperglycemia induced alterations.

PubMed

Ceriello, A; Marchi, E; Palazzni, E; Quatraro, A; Giugliano, D

1990-01-01

Alteration of antithrombin III (ATIII) activity, glycemia level dependent, exists in diabetes mellitus. In this study the ability of a low molecular weight heparin (LMWH) (Fluxum, Alfa-Wassermann S.p.A., Bologna, Italy), as well as unfractioned héparin, to preserve ATIII activity from glucose-induced alterations, both in vitro and in vivo, is reported. The subcutaneous and intravenous LMWH and heparin administration increases basal depressed ATIII activity in diabetic patients. Heparin shows an equivalent effect on both anti-IIa and anti-Xa activity of ATIII, while LMWH is more effective in preserving the anti-Xa activity. Similarity, heparin preserves ATIII activity from hyperglycemia-induced alterations, during hyperglycemic clamp, and LMWH infusion is able to preserve a significant amount of anti-Xa activity from glucose-induced alterations. Since diabetic patients show a high incidence of thrombotic accidents, LMWH appears to be a promising innovation for the prevention of diabetic thrombophylia.

Chromatographic molecular weight measurements for heparin, its fragments and fractions, and other glycosaminoglycans.

PubMed

Mulloy, Barbara; Hogwood, John

2015-01-01

Glycosaminoglycan samples are usually polydisperse, consisting of molecules with differing length and differing sequence. Methods for measuring the molecular weight of heparin have been developed to assure the quality and consistency of heparin products for medicinal use, and these methods can be applied in other laboratory contexts. In the method described here, high-performance gel permeation chromatography is calibrated using appropriate heparin molecular weight markers or a single broad standard calibrant, and used to characterize the molecular weight distribution of polydisperse samples or the peak molecular weight of monodisperse, or approximately monodisperse, heparin fractions. The same technology can be adapted for use with other glycosaminoglycans.

Bilateral rectal sheath hematomas after low-molecular weight heparin treatment in uremia.

PubMed

Xu, Lu; Liu, Lei; Li, Xinjian

2017-11-01

Rectus sheath hematomas (RSHs) are uncommon. They are usually unilateral and rarely bilateral. In this paper, we report the first case of spontaneous bilateral RSHs in a uremic patient after the administration of the first dose of low-molecular weight heparin during hemodialysis. The most interesting aspect of this case is that the main symptom of RSH in our patient was urinary bladder irritation. We highlight the importance of the prompt diagnosis and management of this medical emergency.

Recombinant Escherichia coli K5 strain with the deletion of waaR gene decreases the molecular weight of the heparosan capsular polysaccharide.

PubMed

Huang, Haichan; Liu, Xiaobo; Lv, Shencong; Zhong, Weihong; Zhang, Fuming; Linhardt, Robert J

2016-09-01

Heparosan, the capsular polysaccharide of Escherichia coli K5 having a carbohydrate backbone similar to that of heparin, has become a potential precursor for bioengineering heparin. In the heparosan biosynthesis pathway, the gene waaR encoding α-1-, 2- glycosyltransferase catalyze s the third glucosyl residues linking to the oligosaccharide chain. In the present study, a waaR deletion mutant of E. coli K5 was constructed. The mutant showed improvement of capsule polysaccharide yield. It is interesting that the heparosan molecular weight of the mutant is reduced and may become more suitable as a precursor for the production of low molecular weight heparin derived from the wild-type K5 capsular polysaccharide.

Correlation of the physicochemical properties of natural organic matter samples from different sources to their effects on gold nanoparticle aggregation in monovalent electrolyte.

PubMed

Louie, Stacey M; Spielman-Sun, Eleanor R; Small, Mitchell J; Tilton, Robert D; Lowry, Gregory V

2015-02-17

Engineered nanoparticles (NPs) released into natural environments will interact with natural organic matter (NOM) or humic substances, which will change their fate and transport behavior. Quantitative predictions of the effects of NOM are difficult because of its heterogeneity and variability. Here, the effects of six types of NOM and molecular weight fractions of each on the aggregation of citrate-stabilized gold NPs are investigated. Correlations of NP aggregation rates with electrophoretic mobility and the molecular weight distribution and chemical attributes of NOM (including UV absorptivity or aromaticity, functional group content, and fluorescence) are assessed. In general, the >100 kg/mol components provide better stability than lower molecular weight components for each type of NOM, and they contribute to the stabilizing effect of the unfractionated NOM even in small proportions. In many cases, unfractionated NOM provided better stability than its separated components, indicating a synergistic effect between the high and low molecular weight fractions for NP stabilization. Weight-averaged molecular weight was the best single explanatory variable for NP aggregation rates across all NOM types and molecular weight fractions. NP aggregation showed poorer correlation with UV absorptivity, but the exponential slope of the UV-vis absorbance spectrum was a better surrogate for molecular weight. Functional group data (including reduced sulfur and total nitrogen content) were explored as possible secondary parameters to explain the strong stabilizing effect of a low molecular weight Pony Lake fulvic acid sample to the gold NPs. These results can inform future correlations and measurement requirements to predict NP attachment in the presence of NOM.

A common standard is inappropriate for determining the potency of ultra low molecular weight heparins such as semuloparin and bemiparin.

PubMed

Jeske, Walter P; Hoppensteadt, Debra; Gray, Angel; Walenga, Jeanine M; Cunanan, Josephine; Myers, Lauren; Fareed, Jawed; Bayol, Alain; Rigal, Hélène; Viskov, Christian

2011-10-01

Lower low-molecular-weight heparins are being developed to improve on the safety and efficacy of antithrombotic therapy. Semuloparin and bemiparin are two depolymerized heparins produced by distinct manufacturing processes. The objective of this investigation was to determine whether a common standard could be used to define their potency. Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. The activity of semuloparin and bemiparin was comparable in FXa-based assays (anti-FXa, Heptest). However, bemiparin produced a stronger effect in the aPTT, ACT and anti-thrombin assays. Assessment of the parallelism of the concentration-response curves indicated that bemiparin and semuloparin are not equivalent in terms of anti-FIIa activity. Bemiparin had a stronger inhibitory effect on thrombin induced platelet aggregation, and a stronger interaction with HIT antibodies. These data demonstrate that depolymerized heparins can exhibit a range of biologic activities making them unique agents. Pharmacopoeial parameters such as anti-IIa and anti-Xa potency and molecular weight are insufficient to characterize such agents. Copyright © 2011 Elsevier Ltd. All rights reserved.

Anticoagulant effects of inhaled unfractionated heparin in the dog as determined by partial thromboplastin time and factor Xa activity.

PubMed

Manion, Jill S; Thomason, John M; Langston, Vernon C; Claude, Andrew K; Brooks, Marjory B; Mackin, Andrew J; Lunsford, Kari V

2016-01-01

To evaluate the anticoagulant effects of inhaled heparin in dogs. This study was conducted in 3 phases. In phase 1, bronchoalveolar lavage fluid (BALf) was collected to generate an in vitro calibration curve to relate heparin concentration to the activated partial thromboplastin time (aPTT). In phase 2, heparin was administered via nebulization to determine the threshold dose needed to prolong systemic aPTT. In phase 3, the local anticoagulant activity of inhaled heparin was determined by measurement of BALf anti-Xa activity and aPTT. University teaching hospital. Six healthy intact female Walker Hounds were used in this study. Two dogs were used for each phase. Inhaled unfractionated sodium heparin was administered in doses ranging from 50,000 to 200,000 IU. In vitro addition of heparin to BALf caused a prolongation in aPTT. Inhaled heparin at doses as high as 200,000 IU failed to prolong systemic aPTT, and a threshold dose could not be determined. No significant local anticoagulant effects were detected. Even at doses higher than those known to be effective in people, inhaled heparin appears to have no detectable local or systemic anticoagulant effects in dogs with the current delivery method. © Veterinary Emergency and Critical Care Society 2015.

Occurrence and extent of bruising according to duration of administration of subcutaneous low-molecular-weight heparin: a quasi-experimental case-crossover study.

PubMed

Palese, Alvisa; Aidone, Elena; Dante, Angelo; Pea, Federico

2013-01-01

Several authors have documented the role of low-molecular-weight heparin injection techniques in bruising. However, few researchers have measured the influence of injection duration on the occurrence and extent of bruising. The aim of this study was to evaluate the influence of different durations of subcutaneous heparin injection on the occurrence and extent of bruising. A quasi-experimental case-crossover study design was adopted in 2010. A consecutive series of patients admitted to 2 orthopedic units in a large (600 beds) teaching hospital located in northern Italy were eligible for enrolment. Injections were administered following a standard procedure. The manipulated variable was the duration of the injection, 10 seconds (treatment A) and 30 seconds (treatment B). The evaluation of bruise occurrence and extension performed after 48 hours and data analysis were conducted in a blinded fashion. A total of 150 patients receiving their first and second subcutaneous heparin injections (300 injections) were enrolled. Eighty-seven bruises were observed out of 300 injections (29%): 57 of 150 (38%) after injections lasting 10 seconds and 30 of 150 (20%) after injections lasting 30 seconds (relative risk, 1.50; 95% confidence interval, 1.21-1.86; P = .00). Of the 87 bruises that occurred, 69 (79.3%) were small (2-5 mm) and 18 (20.6%) were large (>5 mm), with no difference in size between 10- and 30-second injections (relative risk, 0.91; 95% confidence interval, 0.39-2.12; P = .83). Low-molecular-weight heparin injection should be administered over 30 seconds to decrease bruising. There is a need to reflect on the feasibility of such a practice because injecting low-molecular-weight heparin at 30 seconds requires accuracy, a steady hand, the absence of tremor, a calm environment, and the ability to administer an infinitesimally small amount of liquid (eg, 0.4 mL) per second.

A photoacoustic tool for therapeutic drug monitoring of heparin (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wang, Junxin; Hartanto, James; Jokerst, Jesse V.

2017-03-01

Heparin is used broadly in cardiac, pulmonary, surgical, and vascular medicine to treat thrombotic disorders with over 500 million doses per year globally. Despite this widespread use, it has a narrow therapeutic window and is one of the top three medication errors. The active partial thromboplastin time (PTT) monitors heparin, but this blood test suffers from long turnaround times, a variable reference range, and limited utility with low molecular weight heparin. Here, we describe an imaging technique that can monitor heparin concentration and activity in real time using photoacoustic spectroscopy via methylene blue as a simple and Federal Drug Agency-approved contrast agent. We found a strong correlation between heparin concentration and photoacoustic signal measured in phosphate buffered saline (PBS) and blood (R2>0.90). Clinically relevant concentrations were detected in blood with a heparin detection limit of 0.28 U/mL and a low molecular weight heparin (enoxaparin) detection limit of 72 μg/mL. We validated this imaging approach by correlation to the PTT (Pearson's r = 0.86; p<0.05) as well as with protamine sulfate treatment. To the best of our knowledge, this is the first report to use imaging data to monitor anticoagulation.

Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin.

PubMed

O'Donnell, Martin J; Kearon, Clive; Johnson, Judy; Robinson, Marlene; Zondag, Michelle; Turpie, Irene; Turpie, Alexander G

2007-02-06

Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. Prospective cohort study. Single university hospital. Consecutive patients who had warfarin therapy interrupted before an invasive procedure. Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. Blood anti-factor Xa heparin levels measured shortly before surgery. Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.

Low incidence of heparin-induced skin lesions in orthopedic surgery patients with low-molecular-weight heparins.

PubMed

Schindewolf, M; Paulik, M; Kroll, H; Kaufmann, R; Wolter, M; Boehncke, W-H; Lindhoff-Last, E; Recke, A; Ludwig, R J

2018-04-23

Heparins are widely prescribed for prevention and therapy of arterial and venous thromboembolic diseases. Heparin-induced skin lesions are the most frequent adverse effects of subcutaneous heparin treatment in non-surgical patients (7.5-39.8%); no data exist on surgical patients. Commonly, they are due to a delayed-type hypersensitivity reaction (DTH), but may also be a manifestation of life-threatening heparin-induced thrombocytopenia (HIT). Lesions of both entities resemble initially. The risk of HIT is highest among heparin-anticoagulated orthopedic surgery patients. To determine incidence and causes of heparin-induced skin lesions in major orthopedic surgery patients. In a prospective cohort study consecutive patients with subcutaneous low-molecular-weight heparin (LMWH) treatment were examined for cutaneous adverse effects. Further diagnostics (skin biopsy, clinical/laboratory assessment for thrombosis, bleeding, HIT, cross-allergies) were performed. Six of 316 enrolled patients (1.9%; 95% CI 0.4%-3.4%) developed heparin-induced skin lesions. All were caused by a DTH reaction, none was due to HIT or other rare heparin-associated skin diseases. Therapeutic use (dosage) of LMWH was identified as only risk factor (odds ratio: 3.1, 95%CI: 1.4-4.9; p=0.00141). In addition to DTH, 5 thromboembolic, 4 major bleeding complications but no cases of HIT or cross-allergies were observed. Orthopedic surgery patients have - unlike non-surgical patients - a low risk for heparin-induced skin lesions during LMWH treatment; all lesions were due to a DTH reaction. The risk for DTH differs considerably between individual patient cohorts. No association with HIT was observed. These data help to tailor anticoagulatory treatment individually and to increase patient safety. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Competing Risk Analysis for Evaluation of Dalteparin Versus Unfractionated Heparin for Venous Thromboembolism in Medical-Surgical Critically Ill Patients.

PubMed

Li, Guowei; Cook, Deborah J; Levine, Mitchell A H; Guyatt, Gordon; Crowther, Mark; Heels-Ansdell, Diane; Holbrook, Anne; Lamontagne, Francois; Walter, Stephen D; Ferguson, Niall D; Finfer, Simon; Arabi, Yaseen M; Bellomo, Rinaldo; Cooper, D Jamie; Thabane, Lehana

2015-09-01

Failure to recognize the presence of competing risk or to account for it may result in misleading conclusions. We aimed to perform a competing risk analysis to assess the efficacy of the low molecular weight heparin dalteparin versus unfractionated heparin (UFH) in venous thromboembolism (VTE) in medical-surgical critically ill patients, taking death as a competing risk.This was a secondary analysis of a prospective randomized study of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) database. A total of 3746 medical-surgical critically ill patients from 67 intensive care units (ICUs) in 6 countries receiving either subcutaneous UFH 5000 IU twice daily (n = 1873) or dalteparin 5000 IU once daily plus once-daily placebo (n = 1873) were included for analysis.A total of 205 incident proximal leg deep vein thromboses (PLDVT) were reported during follow-up, among which 96 were in the dalteparin group and 109 were in the UFH group. No significant treatment effect of dalteparin on PLDVT compared with UFH was observed in either the competing risk analysis or standard survival analysis (also known as cause-specific analysis) using multivariable models adjusted for APACHE II score, history of VTE, need for vasopressors, and end-stage renal disease: sub-hazard ratio (SHR) = 0.92, 95% confidence interval (CI): 0.70-1.21, P-value = 0.56 for the competing risk analysis; hazard ratio (HR) = 0.92, 95% CI: 0.68-1.23, P-value = 0.57 for cause-specific analysis. Dalteparin was associated with a significant reduction in risk of pulmonary embolism (PE): SHR = 0.54, 95% CI: 0.31-0.94, P-value = 0.02 for the competing risk analysis; HR = 0.51, 95% CI: 0.30-0.88, P-value = 0.01 for the cause-specific analysis. Two additional sensitivity analyses using the treatment variable as a time-dependent covariate and using as-treated and per-protocol approaches demonstrated similar findings.This competing risk analysis yields no significant treatment effect on PLDVT but a superior effect of dalteparin on PE compared with UFH in medical-surgical critically ill patients. The findings from the competing risk method are in accordance with results from the cause-specific analysis.clinicaltrials.gov Identifier: NCT00182143.

Competing Risk Analysis for Evaluation of Dalteparin Versus Unfractionated Heparin for Venous Thromboembolism in Medical-Surgical Critically Ill Patients

PubMed Central

Li, Guowei; Cook, Deborah J.; Levine, Mitchell A.H.; Guyatt, Gordon; Crowther, Mark; Heels-Ansdell, Diane; Holbrook, Anne; Lamontagne, Francois; Walter, Stephen D.; Ferguson, Niall D.; Finfer, Simon; Arabi, Yaseen M.; Bellomo, Rinaldo; Cooper, D. Jamie; Thabane, Lehana

2015-01-01

Abstract Failure to recognize the presence of competing risk or to account for it may result in misleading conclusions. We aimed to perform a competing risk analysis to assess the efficacy of the low molecular weight heparin dalteparin versus unfractionated heparin (UFH) in venous thromboembolism (VTE) in medical-surgical critically ill patients, taking death as a competing risk. This was a secondary analysis of a prospective randomized study of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) database. A total of 3746 medical-surgical critically ill patients from 67 intensive care units (ICUs) in 6 countries receiving either subcutaneous UFH 5000 IU twice daily (n = 1873) or dalteparin 5000 IU once daily plus once-daily placebo (n = 1873) were included for analysis. A total of 205 incident proximal leg deep vein thromboses (PLDVT) were reported during follow-up, among which 96 were in the dalteparin group and 109 were in the UFH group. No significant treatment effect of dalteparin on PLDVT compared with UFH was observed in either the competing risk analysis or standard survival analysis (also known as cause-specific analysis) using multivariable models adjusted for APACHE II score, history of VTE, need for vasopressors, and end-stage renal disease: sub-hazard ratio (SHR) = 0.92, 95% confidence interval (CI): 0.70–1.21, P-value = 0.56 for the competing risk analysis; hazard ratio (HR) = 0.92, 95% CI: 0.68–1.23, P-value = 0.57 for cause-specific analysis. Dalteparin was associated with a significant reduction in risk of pulmonary embolism (PE): SHR = 0.54, 95% CI: 0.31–0.94, P-value = 0.02 for the competing risk analysis; HR = 0.51, 95% CI: 0.30–0.88, P-value = 0.01 for the cause-specific analysis. Two additional sensitivity analyses using the treatment variable as a time-dependent covariate and using as-treated and per-protocol approaches demonstrated similar findings. This competing risk analysis yields no significant treatment effect on PLDVT but a superior effect of dalteparin on PE compared with UFH in medical-surgical critically ill patients. The findings from the competing risk method are in accordance with results from the cause-specific analysis. clinicaltrials.gov Identifier: NCT00182143 PMID:26356708

Thromboprophylaxis after vaginal delivery: a district general hospital experience.

PubMed

Potdar, N; Jabbar, B; Burrell, S J

2006-01-01

The Confidential Enquiries into Maternal Deaths (RCOG 2001) recommends risk assessment and appropriate thromboprophylaxis after vaginal delivery. This study examines the risk group and the need for thromboprophylaxis after vaginal delivery in our local population and the cost implications for the same. It is a retrospective study of women who delivered in the month of November 2003. There were 307 deliveries, of these 251 (81.7%) were vaginal deliveries. Confidential Enquiries into Maternal Deaths (CEMD) risk classification was possible for 243 women. A total of 170 women were low risk, 66 (27.16%) moderate risk and 7 (2.88%) high risk. The costs of thromboprophylaxis for the year in our unit were calculated as pound7,339.71 for unfractionated heparin (UFH) 5,000 IU twice daily and pound7,098.27 for 40 mg enoxaparin once daily. A total of 30% of our District General Hospital population were classified as moderate or high risk for thromboprophylaxis after vaginal delivery. It is less expensive to use enoxaparin compared with unfractionated heparin for thromboprophylaxis.

Purification, structural characterization and anticoagulant properties of fucosylated chondroitin sulfate isolated from Holothuria mexicana.

PubMed

Mou, Jiaojiao; Wang, Cong; Li, Wenjing; Yang, Jie

2017-05-01

A novel fucosylated chondroitin sulfate (HmG) was isolated from sea cucumber Holothuria mexicana, the structure of which was characterized by monosaccharide composition, disaccharide composition, IR, 1 H and 13 C NMR spectrum, additionally with two dimensional NMR spectrum of degraded HmG (DHmG). The backbone of HmG was identified as chondroitin 6-O sulfate, while the major O-4 sulfated fucose branches linked to O-3 position of glucuronic acid in almost every disaccharide unit. The anticoagulant activities of HmG and DHmG were assessed and compared with heparin and low molecular weight heparin. The results indicated that HmG and DHmG both could significantly prolong the activated partial thrombo-plastin time, and the properties were well related to its molecular weight. DHmG showed similar anticoagulant properties to low molecular weight heparin with less bleeding risks, making it a safer anticoagulant drug. Copyright © 2017 Elsevier B.V. All rights reserved.

Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants.

PubMed

Iorio, A; Guercini, F; Pini, M

2003-09-01

The management of venous thromboembolism (VTE) requires an initial treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), followed by oral anticoagulants (OA) for at least 3 months. OA treatment however, requires laboratory monitoring of anticoagulation, carries a definite risk of bleeding, and may be contraindicated in some patients. As an alternative to vitamin K antagonists, subcutaneous LMWH has been proposed and evaluated in randomized clinical trials, but they are all small studies that lack the power to establish if these two treatment modalities are equivalent in efficacy or safety. The objective of this review was to evaluate the efficacy (VTE recurrence) and safety (bleeds and deaths) of long-term treatment of VTE with LMWH compared with OA. A secondary endpoint was to evaluate the effect of LMWH on cancer mortality. Computerized searches of MedLine and EmBase were performed. In addition, randomized clinical trials were located through personal communication with colleagues, and through the manual scanning of meeting proceedings and reference lists of relevant studies. When necessary, the authors of the selected papers were called to obtain additional information. Two reviewers (AI and FG) reviewed and extracted data independently using a standard form. The primary analysis was performed for efficacy and safety endpoints on an intention-to-treat basis for the study period of randomized treatment. A meta-regression analysis was used to investigate the relationship between daily dose and clinical outcome. Seven studies that fulfillled our predefined criteria were identified, for a total of 1379 patients. When all studies were combined, a statistically non-significant reduction in the risk of VTE (OR 0.66; 95% confidence interval [CI] 0.41, 1.07) and in the risk of major bleeding (OR 0.45; 95% CI 0.18, 1.11) in favor of LMWH treatment was found. No difference in total mortality (OR 1.19; 95% CI 0.78, 1.83) or in cancer-related mortality was observed between the LMWH and the OA treatment. The results of this meta-analysis indicate that a 3-month course of LMWH is as effective and safe as a corresponding period of OA treatment, and may thus be considered as a valuable alternative option for patients in whom OA treatment appears contraindicated or problematic.

Collaborative study for the calibration of replacement batches for the heparin low-molecular-mass for assay biological reference preparation.

PubMed

Terao, E; Daas, A

2016-01-01

The European Pharmacopoeia (Ph. Eur.) prescribes the control of the activity of low molecular mass heparins by assays for anti-Xa and anti-IIa activities (monograph 0828), using a reference standard calibrated in International Units (IU). An international collaborative study coded BSP133 was launched in the framework of the Biological Standardisation Programme (BSP) run under the aegis of the Council of Europe and the European Commission to calibrate replacement batches for the dwindling stocks of the Heparin low-molecular-mass for assay Biological Reference Preparation (BRP) batch 8. Thirteen official medicines control and manufacturers laboratories from European and non-European countries took part in this study to calibrate two freeze-dried candidate batches against the 3rd International Standard (IS) for heparin, low molecular weight (11/176; 3rd IS). The Heparin low-molecular-mass for assay BRP (batch 8) was also included in the test panel to check the continuity between subsequent BRP batches. Taking into account the stability data, the results of this collaborative study and on the basis of the central statistical analysis performed at the European Directorate for the Quality of Medicines & HealthCare (EDQM), the 2 candidate batches were officially adopted by the Commission of the European Pharmacopoeia as Heparin low-molecular-mass for assay BRP batches 9 and 10 with assigned anti-Xa activities of 102 and 100 IU/vial and anti-IIa activities of 34 and 33 IU/vial respectively.

Low-molecular-weight heparin biosimilars: potential implications for clinical practice. Australian Low-Molecular-Weight Heparin Biosimilar Working Group (ALBW).

PubMed

Nandurkar, H; Chong, B; Salem, H; Gallus, A; Ferro, V; McKinnon, R

2014-05-01

A working group of clinicians and scientists was formed to review the clinical considerations for use of low-molecular-weight heparin (LMWH) biosimilars. LMWH are biological molecules of significant complexity; the full complexity of chemical structure is still to be elucidated. LMWH biosimilars are products that are biologically similar to their reference product and rely on clinical data from a reference product to establish safety and efficacy. The complex nature of LMWH molecules means that it is uncertain whether a LMWH biosimilar is chemically identical to its reference product; this introduces the possibility of differences in activity and immunogenicity. The challenge for regulators and clinicians is to evaluate the level of evidence required to demonstrate that a LMWH is sufficiently similar to the reference product. The consensus opinion of the working group is that prior to clinical use a LMWH biosimilar should have proven efficacy and safety, similar to the reference product with prospective studies, which should be confirmed with a proactive post-marketing pharmacovigilance programme. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Sulfated Low Molecular Weight Lignins, Allosteric Inhibitors of Coagulation Proteinases via the Heparin Binding Site, Significantly Alter the Active Site of Thrombin and Factor Xa Compared to Heparin

PubMed Central

Henry, Brian L.; Desai, Umesh R.

2014-01-01

Sulfated low molecular weight lignins (LMWLs) have been found to bind in the heparin binding sites of coagulation proteinases. LMWLs represent a library of diverse non-carbohydrate, aromatic molecules which are structures different from heparin, but still potently inhibit thrombin and factor Xa. To better understand their mechanism of action, we studied the effects of three sulfated LMWLs (CDSO3, FDSO3, and SDSO3) on the active sites of thrombin and factor Xa. LMWLs were found to uniformly inhibit the catalytic activity of thrombin and factor Xa, regardless of the substrate used. Michaelis-Menten kinetic studies indicate that maximal velocity of hydrolysis of each chromogenic substrate decreases significantly in the presence of sulfated LMWLs, while the effect on Michaelis constant is dependent on the nature of the substrate. These studies indicate that LMWLs inhibit thrombin and factor Xa through allosteric disruption of the catalytic apparatus, specifically through the catalytic step. As opposed to heparin, LMWLs significantly alter the binding of the active site fluorescent ligand p-aminobenzamidine. LMWLs also had a greater effect on the molecular orientation of fluorescein-labeled His 57 than heparin. The molecular geometry surrounding the most important catalytic amino acid, Ser 195, was significantly altered by the binding of LMWLs while heparin had no measurable effect on Ser 195. These results further advance the concept of sulfated LMWLs as heparin mimics and will aid the design of anticoagulants based on their novel scaffold. PMID:25242245

Sulfated low molecular weight lignins, allosteric inhibitors of coagulation proteinases via the heparin binding site, significantly alter the active site of thrombin and factor xa compared to heparin.

PubMed

Henry, Brian L; Desai, Umesh R

2014-11-01

Sulfated low molecular weight lignins (LMWLs) have been found to bind in the heparin binding sites of coagulation proteinases. LMWLs represent a library of diverse non-carbohydrate, aromatic molecules which are structures different from heparin, but still potently inhibit thrombin and factor Xa. To better understand their mechanism of action, we studied the effects of three sulfated LMWLs (CDSO3, FDSO3, and SDSO3) on the active sites of thrombin and factor Xa. LMWLs were found to uniformly inhibit the catalytic activity of thrombin and factor Xa, regardless of the substrate used. Michaelis-Menten kinetic studies indicate that maximal velocity of hydrolysis of each chromogenic substrate decreases significantly in the presence of sulfated LMWLs, while the effect on Michaelis constant is dependent on the nature of the substrate. These studies indicate that LMWLs inhibit thrombin and factor Xa through allosteric disruption of the catalytic apparatus, specifically through the catalytic step. As opposed to heparin, LMWLs significantly alter the binding of the active site fluorescent ligand p-aminobenzamidine. LMWLs also had a greater effect on the molecular orientation of fluorescein-labeled His 57 than heparin. The molecular geometry surrounding the most important catalytic amino acid, Ser 195, was significantly altered by the binding of LMWLs while heparin had no measurable effect on Ser 195. These results further advance the concept of sulfated LMWLs as heparin mimics and will aid the design of anticoagulants based on their novel scaffold. Copyright © 2014 Elsevier Ltd. All rights reserved.

A comparison of effectiveness among frequent treatments of recurrent spontaneous abortion: A Bayesian network meta-analysis.

PubMed

Lv, Sha; Yu, Jing; Xu, Xiaoxiao

2018-04-30

A comprehensive network meta-analysis was designed to clarify contradictions and offer valuable clinical guidance in the treatment of recurrent spontaneous abortion (RSA). The included clinical trials were selected from the relevant medical journal databases and screened. Treatments were ranked by the surface under the cumulative ranking curve. Heat plots were constructed to analyze the inconsistency between direct data and network results, and adjusted funnel plots were constructed to assess publication bias. Forty-nine randomized controlled trials involving a total of 8496 RSA patients were selected. With placebo as control, corticosteroid plus low dose aspirin (LDA) plus unfractionated heparin (UFH), granulocyte colony-stimulating factor (G-CSF) alone, and LDA plus low molecular weight heparin (LMWH) all demonstrated effectiveness in increasing successful live birth rates and reducing the incidences of miscarriage. However, no treatment was demonstrably superior to placebo in terms of pregnancy success. For all 3 endpoints (live birth, abortion and success pregnancy), the adjusted funnel plots were symmetric to zero and indicated no publication bias. In terms of live birth and abortion rates, no treatment outperformed placebo in patients with antiphospholipid syndrome. In consideration of live birth and abortion rates, corticosteroid plus LDA plus UFH appeared to be the optimum treatment strategy; G-CSF was second, followed by LDA with LMWH, LDA plus LMWH plus intravenous immunoglobulin, corticosteroid with LDA and others. Subgroup analysis demonstrated no benefit of antithrombotic therapy in patients with antiphospholipid syndrome. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Development of hydrophilic interaction chromatography with quadruple time-of-flight mass spectrometry for heparin and low molecular weight heparin disaccharide analysis.

PubMed

Ouyang, Yilan; Wu, Chengling; Sun, Xue; Liu, Jianfen; Linhardt, Robert J; Zhang, Zhenqing

2016-01-30

Heparin and low molecular weight heparin (LMWH) are widely used as clinical anticoagulants. The determination of their composition and structural heterogeneity still challenges analysts. Disaccharide compositional analysis, utilizing heparinase-catalyzed depolymerization, is one of the most important ways to evaluate the sequence, structural composition and quality of heparin and LMWH. Hydrophilic interaction chromatography coupled with quadruple time-of-flight mass spectrometry (HILIC/QTOFMS) has been developed to analyze the resulting digestion products. HILIC shows good resolution and excellent MS compatibility. Digestion products of heparin and LMWHs afforded up to 16 compounds that were separated using HILIC and analyzed semi-quantitatively. These included eight common disaccharides, two disaccharides derived from chain termini, three 3-O-sulfo-group-containing tetrasaccharides, along with three linkage region tetrasaccharides and their derivatives. Structures of these digestion products were confirmed by mass spectral analysis. The disaccharide compositions of a heparin, two batches of the LMWH, enoxaparin, and two batches of the LMWH, nadroparin, were compared. In addition to identifying disaccharides, 3-O-sulfo-group-containing tetrasaccharides, linkage region tetrasaccharides were observed having slightly different compositions and contents in these heparin products suggesting that they had been prepared using different starting materials or production processes. Thus, compositional analysis using HILIC/QTOFMS offers a unique insight into different heparin products. Copyright © 2015 John Wiley & Sons, Ltd.

Quantitative PCR and disaccharide profiling to characterize the animal origin of low-molecular-weight heparins.

PubMed

Houiste, Céline; Auguste, Cécile; Macrez, Céline; Dereux, Stéphanie; Derouet, Angélique; Anger, Pascal

2009-02-01

Low-molecular-weight heparins (LMWHs) are widely used in the management of thrombosis and acute coronary syndromes. They are obtained by the enzymatic or chemical depolymerization of porcine intestinal heparin. Enoxaparin sodium, a widely used LMWH, has a unique and reproducible oligosaccharide profile which is determined by the origin of the starting material and a tightly controlled manufacturing process. Although other enoxaparin-like LMWHs do exist, specific release criteria including the origin of the crude heparin utilized for their production, have not been established. A quantitative polymerase chain reaction method has been developed to ensure the purity of the porcine origin of crude heparin, with a DNA detection limit as low as 1 ppm for bovine, or 10 ppm for ovine contaminants. This method is routinely used as the release acceptance criterion during enoxaparin sodium manufacturing. Furthermore, when the process removes DNA, other analytical techniques can be used to assess any contamination. Disaccharide profiling after exhaustive depolymerization can determine the presence of at least 10% bovine or 20% ovine material; multivariate analysis is useful to perform the data analysis. Consistent with the availability of newer technology, these methods should be required as acceptance criteria for crude heparins used in the manufacture of LMWHs to ensure their safety, quality, and immunologic profile.

Ethanol combined with heparin as a locking solution for the prevention of catheter related blood stream infections in hemodialysis patients: A prospective randomized study.

PubMed

Sofroniadou, Sofia; Revela, Ioanna; Kouloubinis, Alexandros; Makriniotou, Ioanna; Zerbala, Sinodi; Smirloglou, Despina; Kalocheretis, Petros; Drouzas, Apostolos; Samonis, George; Iatrou, Christos

2017-10-01

Ethanol lock solution has been mainly administered in paediatric and home parenteral nutrition patients in order to prevent catheter related blood stream infections (CRBSI). Its utility in hemodialysis (HD) patients with non-tunneled-uncuffed catheter (NTC) has been poorly explored. We conducted a prospective randomized study in chronic HD patients requiring a newly inserted NTC-while awaiting for the maturation of an already established arteriovenous fistula (AVF) or arteriovenous graft (AVG) or tunneled-cuffed catheter insertion. Patients were randomized in two groups: Group A, where the lock solution was ethanol 70% + unfractionated heparin 2000 U/mL and group B, that received only unfractionated heparin 2000 U/mL. Primary end point was CRBSIs whereas exit site infections, thrombotic and bleeding episodes were the secondary end points. One hundred three HD patients were enrolled in the study (group A, n = 52; group B, n = 51). The median number of catheter days was 32 for group A (range: 23-39) and 34 (range: 27-40) for group B with no statistically significant difference between the two groups. Group A (ethanol + heparin) demonstrated 4/52 episodes (7.69%) of CRBSI whereas Group B (heparin) 11/51 episodes (21.57%) (P = 0.04). CRBSI rates per 1000 catheter days were 2.53/1000 catheter days for group A and 6.7/1000 catheter days for group B (P = 0.04). Mean cumulative infection-free catheter survival in the ethanol group did not differ significantly compared to the heparin group (log-rank test = 2.99, P = 0.08). Thrombotic episodes did not differ between the two groups. Locking of NTCs in HD patients with ethanol 70% + unfractionated heparin reduces CRBSI rates without increasing the thrombotic episodes. © 2017 International Society for Hemodialysis.

Liquid chromatography-diode array detection-mass spectrometry for compositional analysis of low molecular weight heparins.

PubMed

Wang, Zhangjie; Li, Daoyuan; Sun, Xiaojun; Bai, Xue; Jin, Lan; Chi, Lianli

2014-04-15

Low molecular weight heparins (LMWHs) are important artificial preparations from heparin polysaccharide and are widely used as anticoagulant drugs. To analyze the structure and composition of LMWHs, identification and quantitation of their natural and modified building blocks are indispensable. We have established a novel reversed-phase high-performance liquid chromatography-diode array detection-electrospray ionization-mass spectrometry approach for compositional analysis of LMWHs. After being exhaustively digested and labeled with 2-aminoacridone, the structural motifs constructing LMWHs, including 17 components from dalteparin and 15 components from enoxaparin, were well separated, identified, and quantified. Besides the eight natural heparin disaccharides, many characteristic structures from dalteparin and enoxaparin, such as modified structures from the reducing end and nonreducing end, 3-O-sulfated tetrasaccharides, and trisaccharides, have been unambiguously identified based on their retention time and mass spectra. Compared with the traditional heparin compositional analysis methods, the approach described here is not only robust but also comprehensive because it is capable of identifying and quantifying nearly all components from lyase digests of LMWHs. Copyright © 2014 Elsevier Inc. All rights reserved.

Hospital variability in use of anticoagulant strategies during acute myocardial infarction treated with an early invasive strategy.

PubMed

Arnold, Suzanne V; Li, Shu-Xia; Alexander, Karen P; Spertus, John A; Nallamothu, Brahmajee K; Curtis, Jeptha P; Kosiborod, Mikhail; Gupta, Aakriti; Wang, Tracy Y; Lin, Haiqun; Dharmarajan, Kumar; Strait, Kelly M; Lowe, Timothy J; Krumholz, Harlan M

2015-06-15

During a myocardial infarction, no single best approach of systemic anticoagulation is recommended, likely due to a lack of comparative effectiveness studies and trade-offs between treatments. We investigated the patterns of use and site-level variability in anticoagulant strategies (unfractionated heparin [UFH] only, low-molecular-weight heparin [LMWH] only, UFH+LMWH, any bivalirudin) of 63 796 patients with a principal diagnosis of myocardial infarction treated with an early invasive strategy with percutaneous coronary intervention at 257 hospitals. About half (47%) of patients received UFH only, 6% UFH+LMWH, 7% LMWH only, and 40% bivalirudin. Compared with UFH, the median odds ratio was 2.90 for LMWH+UFH, 4.70 for LMWH only, and 3.09 for bivalirudin, indicating that 2 "identical" patients would have a 3- to 4-fold greater likelihood of being treated with anticoagulants other than UFH at one hospital compared with another. We then categorized hospitals as low- or high-users of LMWH and bivalirudin. Using hierarchical, multivariate regression models, we found that low bivalirudin-using hospitals had higher unadjusted bleeding rates, but the risk-adjusted and anticoagulant-adjusted bleeding rates did not differ across the hospital anticoagulation phenotypes. Risk-standardized mortality and risk-standardized length of stay also did not differ across hospital phenotypes. We found substantial site-level variability in the choice of anticoagulants for invasively managed acute myocardial infarction patients, even after accounting for patient factors. No single hospital-use pattern was found to be clinically superior. More studies are needed to determine which patients would derive the greatest benefit from various anticoagulants and to support consistent treatment of patients with the optimal anticoagulant strategy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Advances in Inhibitors of FXa.

PubMed

Guo, Liwei; Ma, Shutao

2015-01-01

Thromboembolic diseases such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and ischemic strokes are mainly responsible for people's morbidity and mortality and have severely affected the people's quality of life all over the world. According to WHO statistics, an average of 17 million people are killed by the thromboembolic diseases each year globally. Therefore, the prevention and treatment of thromboembolic diseases have received widespread attention in recent years. Based on thrombotic mechanism, anti-thrombotic drugs are mainly divided into anticoagulants, antiplatelet agents and direct thrombolytic drugs. In particular, anticoagulants such as vitamin K antagonists (VKAs), unfractionated heparin (UFH), and low-molecular-weight heparins (LMWHs) have become the main therapies for pre-treatment of thromboembolic disorders. However, the limitations of traditional anticoagulants such as slow onset of action, dose-adjusted requirement, drug-drug and drug-food interactions have restricted their improvement in the clinical treatment. The mechanism of the thromboembolic disorders has indicated that coagulation factor Xa (fXa) plays a pivotal role in the blood coagulation cascade. Thus, selective inhibition of fXa by diminishing the amplified generation of thrombin without affecting the pre-existing thrombin levels can provide better antithrombotic effect, thereby causing less impairment of primary hemostasis. In this paper, we mainly introduce the recent advances of fXa inhibitors, with focus on their biological activity and structure-activity relationship (SAR) information. In particular, the inspirations from the structures of the fXa inhibitors and their future direction are highlighted.

Comparing multiple competing interventions in the absence of randomized trials using clinical risk-benefit analysis

PubMed Central

2012-01-01

Background To demonstrate the use of risk-benefit analysis for comparing multiple competing interventions in the absence of randomized trials, we applied this approach to the evaluation of five anticoagulants to prevent thrombosis in patients undergoing orthopedic surgery. Methods Using a cost-effectiveness approach from a clinical perspective (i.e. risk benefit analysis) we compared thromboprophylaxis with warfarin, low molecular weight heparin, unfractionated heparin, fondaparinux or ximelagatran in patients undergoing major orthopedic surgery, with sub-analyses according to surgery type. Proportions and variances of events defining risk (major bleeding) and benefit (thrombosis averted) were obtained through a meta-analysis and used to define beta distributions. Monte Carlo simulations were conducted and used to calculate incremental risks, benefits, and risk-benefit ratios. Finally, net clinical benefit was calculated for all replications across a range of risk-benefit acceptability thresholds, with a reference range obtained by estimating the case fatality rate - ratio of thrombosis to bleeding. Results The analysis showed that compared to placebo ximelagatran was superior to other options but final results were influenced by type of surgery, since ximelagatran was superior in total knee replacement but not in total hip replacement. Conclusions Using simulation and economic techniques we demonstrate a method that allows comparing multiple competing interventions in the absence of randomized trials with multiple arms by determining the option with the best risk-benefit profile. It can be helpful in clinical decision making since it incorporates risk, benefit, and personal risk acceptance. PMID:22233221

"Leaning" the process of venous thromboembolism prophylaxis.

PubMed

Biffl, Walter L; Beno, Matthew; Goodman, Philip; Bahia, Amit; Sabel, Allison; Snow, Karen; Steele, Andrew W; Swartwood, Claire; Thienelt, Christiane; MacKenzie, Thomas D; Mehler, Philip S

2011-03-01

Lean principles have been used at Denver Health Medical Center since 2005 to streamline nonclinical processes. Despite allocation of significant resources, particularly the expense of low molecular weight heparin (LMWH), to prophylaxis of venous thromboembolism (VTE), the incidence of postoperative VTE was significantly worse than national benchmarks. VTE risk factors were not consistently assessed, and the prescribing of prophylaxis varied widely. Lean was employed to standardize and implement risk assessment and evidence-based VTE prophylaxis for the institution. In a rapid improvement event, a multidisciplinary group formulated an evidence-based risk assessment tool and clinical practice guideline for VTE prophylaxis, with plans for hospitalwide implementation and monitoring. The effects were immediate and improved steadily with feedback to clinicians. Within six months, compliance with the standard approached 100%. One year after implementation, the use of LMWH decreased more than 60% below baseline, and the use of sequential compression devices decreased by nearly 30%. With increased use of unfractionated heparin, the cost savings on VTE prophylaxis exceeded $15,000 per month, for a total of $425,000 since implementation. Moreover, the incidence of VTE decreased markedly during the same period. By reducing VTE rates, a total cost savings of $6.2 million was estimated for the past 28 months. Applying Lean to the clinical management of VTE prophylaxis improved compliance with standards and saved the hospital a significant amount of money. This was achieved without compromising clinical outcomes. This experience could be replicated at other institutions.

Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT®).

PubMed

Schaden, E; Jilch, S; Hacker, S; Schober, A; Kozek-Langenecker, S

2012-12-24

To achieve sufficient and safe anticoagulation with unfractionated heparin (UFH) a close and reliable drug monitoring is necessary. In general, the activated partial thromboplastin time (APTT) is used for this purpose. In acute phase response, however, the APTT test procedure might be unreliable e.g. with false low results in the presence of elevated factor VIII. In this so called heparin resistance, measurement of anti-Xa activity is recommended over APTT to avoid potentially harmful dose escalation. A combination of anti-Xa measurement and global hemostatic testing with ROTEM® employing the anti-Xa sensitive PiCT® reagent showed high correlation with enoxaparin levels. This test modification could also be suitable for monitoring UFH. Aim of the study was to evaluate the correlation between PiCT®-ROTEM® and levels of UFH. In this in-vitro study blood samples from healthy volunteers were spiked with UFH and subjected to different ROTEM® tests. There was a linear correlation between UFH level and clotting time (CT) in the PiCT®-ROTEM® test with an excellent correlation coefficient of 0.92. Additional endpoints showed similar results (PiCT®-ROTEM® MaxVel r = -0.85 and PiCT®-ROTEM® t_MaxVel r = 0.88). As a point-of-care applicable tool ROTEM® is immediately at hand. If further clinical studies confirm sensitivity in heparin resistance, PiCT®-ROTEM® could permit rapid UFH dose adjustments especially required in critical illness with acute phase response. Copyright © 2012 Elsevier B.V. All rights reserved.

Similar Success Rates with Bivalirudin and Unfractionated Heparin in Bare-Metal Stent Implantation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hallak, Omar; Shams, S. Ali; Broce, Mike

Background. Unfractionated heparin (UFH) is the traditional agent utilized during percutaneous peripheral interventions (PPIs) despite its well-known limitations. Bivalirudin, a thrombin-specific anticoagulant, overcomes many of the limitations of UFH and has consistently demonstrated comparable efficacy with significantly fewer bleeding complications. The purpose of this study was to compare procedural success in patients undergoing bare-metal stent implantation for atherosclerotic blockage of the renal, iliac, and femoral arteries and receiving either bivalirudin (0.75 mg/kg bolus/1.75 mg/kg/hr infusion) or UFH (50-70 U/kg/hr bolus) as the primary anticoagulant. Methods. This study was an open-label, nonrandomized retrospective registry with the primary endpoint of procedural success.more » Secondary endpoints included incidence of: death, myocardial infarction (MI), urgent revascularization, amputation, and major and minor bleeding. Results. One hundred and five consecutive patients were enrolled (bivalirudin = 53; heparin = 52). Baseline demographics were comparable between groups. Patients were pretreated with clopidogrel (approx. 71%) and aspirin (approx. 79%). Procedural success was achieved in 97% and 96% of patients in the bivalirudin- and heparin-treated groups, respectively. Event rates were low and similar between groups. Conclusion. Bivalirudin maintained an equal rate of procedural success in this cohort without sacrificing patient safety. Results of this study add to the growing body of evidence supporting the safety and efficacy of bivalirudin as a possible substitute for UFH in anticoagulation during peripheral vascular bare-metal stent implantation.« less

Molecular Weights of Bovine and Porcine Heparin Samples: Comparison of Chromatographic Methods and Results of a Collaborative Survey.

PubMed

Bertini, Sabrina; Risi, Giulia; Guerrini, Marco; Carrick, Kevin; Szajek, Anita Y; Mulloy, Barbara

2017-07-19

In a collaborative study involving six laboratories in the USA, Europe, and India the molecular weight distributions of a panel of heparin sodium samples were determined, in order to compare heparin sodium of bovine intestinal origin with that of bovine lung and porcine intestinal origin. Porcine samples met the current criteria as laid out in the USP Heparin Sodium monograph. Bovine lung heparin samples had consistently lower average molecular weights. Bovine intestinal heparin was variable in molecular weight; some samples fell below the USP limits, some fell within these limits and others fell above the upper limits. These data will inform the establishment of pharmacopeial acceptance criteria for heparin sodium derived from bovine intestinal mucosa. The method for MW determination as described in the USP monograph uses a single, broad standard calibrant to characterize the chromatographic profile of heparin sodium on high-resolution silica-based GPC columns. These columns may be short-lived in some laboratories. Using the panel of samples described above, methods based on the use of robust polymer-based columns have been developed. In addition to the use of the USP's broad standard calibrant for heparin sodium with these columns, a set of conditions have been devised that allow light-scattering detected molecular weight characterization of heparin sodium, giving results that agree well with the monograph method. These findings may facilitate the validation of variant chromatographic methods with some practical advantages over the USP monograph method.

Characterization of currently marketed heparin products: key tests for LMWH quality assurance.

PubMed

Ye, Hongping; Toby, Timothy K; Sommers, Cynthia D; Ghasriani, Houman; Trehy, Michael L; Ye, Wei; Kolinski, Richard E; Buhse, Lucinda F; Al-Hakim, Ali; Keire, David A

2013-11-01

During the 2007-2008 heparin crisis it was found that the United States Pharmacopeia (USP) testing monograph for heparin sodium or low molecular weight heparins did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS). In response to this concern, new tests and specifications were developed by the Food and Drug Administration (FDA) and USP and put in place to detect not only the contaminant OSCS, but also to improve assurance of quality and purity of these drug products. The USP monographs for the low molecular weight heparins (LMWHs) approved for use in the United States (dalteparin, tinzaparin and enoxaparin) are also undergoing revision to include many of the same tests used for heparin sodium, including; one-dimensional (1D) 500 MHz (1)H NMR, SAX-HPLC, percent galactosamine in total hexosamine and anticoagulation time assays with purified Factor IIa or Factor Xa. These tests represent orthogonal approaches for heparin identification, measurement of bioactivity and for detection of process impurities or contaminants in these drug products. Here we describe results from a survey of multiple lots from three types of LMWHs in the US market which were collected after the 2009 heparin sodium monograph revision. In addition, innovator and generic versions of formulated enoxaparin products purchased in 2011 are compared using these tests and found to be highly similar within the discriminating power of the assays applied. Published by Elsevier B.V.

Analysis of sulfates on low molecular weight heparin using mass spectrometry: structural characterization of enoxaparin.

PubMed

Gupta, Rohitesh; Ponnusamy, Moorthy P

2018-05-31

Structural characterization of low molecular weight heparin (LMWH) is critical to meet biosimilarity standards. In this context, the review focuses on structural analysis of labile sulfates attached to the side-groups of LMWH using mass spectrometry. A comprehensive review of this topic will help readers to identify key strategies for tackling the problem related to sulfate loss. At the same time, various mass spectrometry techniques are presented to facilitate compositional analysis of LMWH, mainly enoxaparin. Areas covered: This review summarizes findings on mass spectrometry application for LMWH, including modulation of sulfates, using enzymology and sample preparation approaches. Furthermore, popular open-source software packages for automated spectral data interpretation are also discussed. Successful use of LC/MS can decipher structural composition for LMWH and help evaluate their sameness or biosimilarity with the innovator molecule. Overall, the literature has been searched using PubMed by typing various search queries such as 'enoxaparin', 'mass spectrometry', 'low molecular weight heparin', 'structural characterization', etc. Expert commentary: This section highlights clinically relevant areas that need improvement to achieve satisfactory commercialization of LMWHs. It also primarily emphasizes the advancements in instrumentation related to mass spectrometry, and discusses building automated software for data interpretation and analysis.

Heparin monotherapy or bivalirudin during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease: results from the Evaluation of Drug-Eluting Stents and Ischemic Events registry.

PubMed

Bangalore, Sripal; Pencina, Michael J; Kleiman, Neal S; Cohen, David J

2014-06-01

The use of bivalirudin versus unfractionated heparin monotherapy in patients without ST-segment-elevation myocardial infarction is not well defined. The study population consisted of patients enrolled in the Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry with either non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease, who underwent percutaneous coronary intervention with either unfractionated heparin or bivalirudin monotherapy. Propensity score matching was used to adjust for baseline characteristics. The primary bleeding (in-hospital composite bleeding-access site bleeding, thrombolysis in myocardial infarction major/minor bleeding, or transfusion) and primary (in-hospital death/myocardial infarction) and secondary ischemic outcomes (death/myocardial infarction/unplanned repeat revascularization at 12 months) were evaluated. Propensity score matching yielded 1036 patients with non-ST-segment-elevation acute coronary syndromes and 2062 patients with stable ischemic heart disease. For the non-ST-segment-elevation acute coronary syndrome cohort, bivalirudin use was associated with lower bleeding (difference, -3.3% [-0.8% to -5.8%]; P=0.01; number need to treat=30) without increase in either primary (difference, 1.2% [4.1% to -1.8%]; P=0.45) or secondary ischemic outcomes, including stent thrombosis (difference, 0.0% [1.3% to -1.3%]; P=1.00). Similarly, in the stable ischemic heart disease cohort, bivalirudin use was associated with lower bleeding (difference, -1.8% [-0.4% to -3.3%]; P=0.01; number need to treat=53) without increase in either primary (difference, 0.4% [2.3% to -1.5%]; P=0.70) or secondary ischemic outcomes, including stent thrombosis (difference, 0.0% [0.7% to -0.7%]; P=1.00) when compared with unfractionated heparin monotherapy. Among patients with non-ST-segment-elevation acute coronary syndromes or stable ischemic heart disease undergoing percutaneous coronary intervention, bivalirudin use during percutaneous coronary intervention when compared with unfractionated heparin monotherapy was associated with lower bleeding without significant increase in ischemic outcomes or stent thrombosis. © 2014 American Heart Association, Inc.

The use of low molecular weight heparin-pluronic nanogels to impede liver fibrosis by inhibition the TGF-β/Smad signaling pathway.

PubMed

Lee, Ju-Hee; Lee, Hyunseung; Joung, Yoon Ki; Jung, Kyung Hee; Choi, Jong-Hoon; Lee, Don-Haeng; Park, Ki Dong; Hong, Soon-Sun

2011-02-01

Low molecular weight heparin (LH) has been reported to have anti-fibrotic and anti-cancer effects. To enhance the efficacy and minimize adverse effects of LH, a low molecular weight heparin-pluronic nanogel (LHP) was synthesized by conjugating carboxylated pluronic F127 to LH. The LHP reduced anti-coagulant activity by about 33% of the innate activity. Liver fibrosis was induced by the injection of 1% dimethylnitrosamine (DMN) in rats, and LH or LHP (1000 IU/kg body weight) was treated once daily for 4 weeks. LHP administration prevented DMN-mediated liver weight loss and decreased the values of aspartate transaminase, alanine transaminase, total bilirubin, and direct bilirubin. LHP markedly reduced the fibrotic area compared to LH. Also, LHP potently inhibited mRNA or protein expression of alpha-smooth muscle actin, collagen type I, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-1 compared to LH, in DMN-induced liver fibrosis. In addition, LHP decreased the expression of transforming growth factor-β(1) (TGF-β(1)), p-Smad 2, and p-Smad 3, which are all important molecules of the TGF-β/Smad signaling pathway. The results support an LHP shows anti-fibrotic effect in the liver via inhibition of the TGF-β/Smad pathway as well as by the elimination of the extracellular matrix. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies.

PubMed

Bisio, Antonella; Urso, Elena; Guerrini, Marco; de Wit, Pauline; Torri, Giangiacomo; Naggi, Annamaria

2017-06-24

A number of low molecular weight heparin (LMWH) products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic and pharmacodynamics differences. While enoxaparin has been extensively investigated, little information is available regarding the LMWH dalteparin. The present study is focused on the detailed structural characterization of Fragmin ® by LC-MS and NMR applied both to the whole drug and to its enzymatic products. For a more in-depth approach, size homogeneous octasaccharide and decasaccharide components together with their fractions endowed with high or no affinity toward antithrombin were also isolated and their structural profiles characterized. The combination of different analytical strategies here described represents a useful tool for the assessment of batch-to-batch structural variability and for comparative evaluation of structural features of biosimilar products.

The design and synthesis of new synthetic low molecular weight heparins

PubMed Central

Chandarajoti, K.; Liu, J.; Pawlinski, R.

2016-01-01

Low molecular weight heparins (LMWH) have remained the most favorable form of heparin in clinics since 1990s’ owing to its predictable pharmacokinetic properties. However, LMWH is mainly eliminated through kidney, thus limits its use in renal-impaired patients. In addition, the anticoagulant activity of LMWH is only partially neutralized by protamine. LMWH is obtained from a full-length, highly sulfated polysaccharide harvested from porcine mucosal tissue. The depolymerization involved in LMWH production generates a broad size distribution of LMWH fragments (6-22 sugar residues). This, combined with the various methods used to produce commercial LMWHs, result in variable pharmacological and pharmacokinetic properties. An alternative, chemoenzymatic approach offers a method for the synthesis of LMWH that has the potential to overcome the limitations of current LMWHs. This review summarizes the application of a chemoenzymatic approach to generate LMWH and the rationale for development of a synthetic LMWH. PMID:26990516

The design and synthesis of new synthetic low-molecular-weight heparins.

PubMed

Chandarajoti, K; Liu, J; Pawlinski, R

2016-06-01

Low-molecular-weight heparin (LMWH) has remained the most favorable form of heparin in clinics since the 1990s owing to its predictable pharmacokinetic properties. However, LMWH is mainly eliminated through the kidney, which limits its use in renal-impaired patients. In addition, the anticoagulant activity of LMWH is only partially neutralized by protamine. LMWH is obtained from a full-length, highly sulfated polysaccharide harvested from porcine mucosal tissue. The depolymerization involved in LMWH production generates a broad distribution of LMWH fragments (6-22 sugar residues). This, combined with the various methods used to produce commercial LMWHs, results in variable pharmacological and pharmacokinetic properties. An alternative chemoenzymatic approach offers a method for the synthesis of LMWH that has the potential to overcome the limitations of current LMWHs. This review summarizes the application of a chemoenzymatic approach to generate LMWH and the rationale for development of a synthetic LMWH. © 2016 International Society on Thrombosis and Haemostasis.

Collaborative study for the establishment of replacement batches of heparin low- molecular-mass for assay biological reference preparations.

PubMed

Terao, E; Daas, A; Rautmann, G; Buchheit, K-H

2010-10-01

A collaborative study was run by the European Directorate for the Quality of Medicines & HealthCare (EDQM) in the context of the Biological Standardisation Programme (BSP), under the aegis of the Council of Europe and the European Commission, to establish replacement batches for the dwindling stocks of the Heparin low-molecular-mass for assay European Pharmacopoeia Biological Reference Preparation (BRP). The replacement batches of BRP are intended to be used in the assays for anti-Xa and anti-IIa activities, as described in the European Pharmacopoeia (Ph. Eur.) monograph Heparins, low-molecular-mass (0828). Three freeze-dried candidate batches were calibrated against the current International Standard (IS) for Heparin, lowmolecular- weight (2nd IS, 01/608). For the purpose of the continuity check between subsequent BRP batches, the current Heparin low-molecular-mass for assay BRP (batch 5) was also included in the test panel. Thirteen official medicines control and manufacturers laboratories from European and non-European countries contributed data. A central statistical analysis of the datasets was performed at the EDQM. On the basis of the results, the 3 candidate materials were assigned a potency of 104 IU/vial for the anti-Xa activity and 31 IU/vial for the anti-IIa activity. Taken into account the preliminary stability data and the results of this collaborative study, the 3 batches of candidate BRP were adopted in June 2010 by the Commission of the Ph. Eur. as Heparin low-molecular-mass for assay BRP batches 6, 7 and 8.

High Sulfation and a High Molecular Weight Are Important for Anti-hepcidin Activity of Heparin

PubMed Central

Asperti, Michela; Naggi, Annamaria; Esposito, Emiliano; Ruzzenenti, Paola; Di Somma, Margherita; Gryzik, Magdalena; Arosio, Paolo; Poli, Maura

2016-01-01

Heparins are efficient inhibitors of hepcidin expression even in vivo, where they induce an increase of systemic iron availability. Heparins seem to act by interfering with BMP6 signaling pathways that control the expression of liver hepcidin, causing the suppression of SMAD1/5/8 phosphorylation. The anti-hepcidin activity persists also when the heparin anticoagulant property is abolished or reduced by chemical reactions of oxidation/reduction (glycol-split, Gs-Heparins) or by high sulfation (SS-Heparins), but the structural characteristics needed to optimize this inhibitory activity have not been studied in detail. To this aim we analyzed three different heparins (Mucosal Heparin, the Glycol split RO-82, the partially desulfated glycol-split RO-68 and the oversulfated SSLMWH) and separated them in fractions of molecular weight in the range 4–16 kD. Since the distribution of the negative charges in heparins contributes to the activity, we produced 2-O- and 6-O-desulfated heparins. These derivatives were analyzed for the capacity to inhibit hepcidin expression in hepatic HepG2 cells and in mice. The two approaches produced consistent results and showed that the anti-hepcidin activity strongly decreases with molecular weight below 7 kD, with high N-acetylation and after 2-O and 6-O desulfation. The high sulfation and high molecular weight properties for efficient anti-hepcidin activity suggest that heparin is involved in multiple binding sites. PMID:26955355

Mapping of low molecular weight heparins using reversed phase ion pair liquid chromatography-mass spectrometry.

PubMed

Li, Daoyuan; Chi, Lequan; Jin, Lan; Xu, Xiaohui; Du, Xuzhao; Ji, Shengli; Chi, Lianli

2014-01-01

Low molecular weight heparins (LMWHs) are structurally complex, highly sulfated and negatively charged, linear carbohydrate polymers prepared by chemical or enzymatic depolymerization of heparin. They are widely used as anticoagulant drugs possessing better bioavailability, longer half-life, and lower side effects than heparin. Comprehensive structure characterization of LMWHs is important for drug quality assurance, generic drug application, and new drug research and development. However, fully characterization of all oligosaccharide chains in LMWHs is not feasible for current available analytical technologies due to their structure complexity and heterogeneity. Fingerprinting profiling is an efficient way for LMWHs' characterization and comparison. In this work, we present a simple, sensitive, and powerful analytical approach for structural characterization of LMWHs. Two different LMWHs, enoxaparin and nadroparin, were analyzed using reversed phase ion pair electrospray ionization mass spectrometry (RPIP-ESI-MS). More than 200 components were identified, including major structures, minor structures, and process related impurities. This approach is robust for high resolution and complementary fingerprinting analysis of LMWHs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Sequencing the oligosaccharide pool in the low molecular weight heparin dalteparin with offline HPLC and ESI-MS/MS.

PubMed

Wang, Zhangjie; Zhang, Tianji; Xie, Shaoshuai; Liu, Xinyue; Li, Hongmei; Linhardt, Robert J; Chi, Lianli

2018-03-01

Low molecular weight heparins (LMWHs) are widely used anticoagulant drugs. The composition and sequence of LMWH oligosaccharides determine their safety and efficacy. The short oligosaccharide pool in LMWHs undergoes more depolymerization reactions than the longer chains and is the most sensitive indicator of the manufacturing process. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) has been demonstrated as a powerful tool to sequence synthetic heparin oligosaccharide but never been applied to analyze complicated mixture like LMWHs. We established an offline strong anion exchange (SAX)-high performance liquid chromatography (HPLC) and ESI-MS/MS approach to sequence the short oligosaccharides of dalteparin sodium. With the help of in-house developed MS/MS interpretation software, the sequences of 18 representative species ranging from tetrasaccharide to octasaccharide were obtained. Interestingly, we found a novel 2,3-disulfated hexauronic acid structure and reconfirmed it by complementary heparinase digestion and LC-MS/MS analysis. This approach provides straightforward and in-depth insight to the structure of LMWHs and the reaction mechanism of heparin depolymerization. Copyright © 2017 Elsevier Ltd. All rights reserved.

New strategies for the treatment of acute venous thromboembolism.

PubMed

Prandoni, Paolo; Lensing, Anthonie W A; Pesavento, Raffaele

2006-11-01

In recent years, new opportunities have emerged that have the potential to change rapidly the therapeutic scenario of patients with acute venous thromboembolism (VTE). Selected patients with deep vein thrombosis (DVT) can be treated effectively and safely at home with fixed doses of low molecular weight heparins. The prompt administration of compression elastic stockings in addition to anticoagulant drugs in patients with acute DVT has the potential to halve the rate of late postthrombotic sequelae. The long-term use of low molecular weight heparins is likely to be more effective than oral anticoagulants for the secondary prevention of VTE in patients with advanced malignancy. Patients with pulmonary embolism and right ventricular dysfunction might benefit from the early administration of thrombolytic drugs in combination with heparin to a greater extent than from heparin alone. Despite an impressive amount of clinical information on the proper duration of oral anticoagulants in patients with unprovoked VTE, the optimal long-term treatment of these patients remains undefined. Finally, new categories of drugs are emerging that have the potential to replace conventional anticoagulants in the near future. They include compounds that inhibit factor Xa or thrombin.

Influence of molecular weight of chemically sulfated citrus pectin fractions on their antithrombotic and bleeding effects.

PubMed

Cipriani, Thales R; Gracher, Ana Helena P; de Souza, Lauro M; Fonseca, Roberto J C; Belmiro, Celso L R; Gorin, Philip A J; Sassaki, Guilherme L; Iacomini, Marcello

2009-05-01

Evaluated were the anticoagulant and antithrombotic activities, and bleeding effect of two chemically sulfated polysaccharides, obtained from citric pectin, with different average molar masses. Both low-molecular-weight (Pec-LWS, 3,600 g/mol) and high-molecular-weight sulfated pectins (Pec-HWS, 12,000 g/mol) had essentially the same structure, consisting of a (1-->4)-linked alpha-D-GalpA chain with almost all its HO-2 and HO-3 groups substituted by sulfate. Both polysaccharides had anticoagulant activity in vitro, although Pec-HWS was a more potent antithrombotic agent in vivo, giving rise to total inhibition of venous thrombosis at a dose of 3.5 mg/kg body weight. Surprisingly, in contrast with heparin, Pec-HWS and Pec-LWS are able to directly inhibit alpha-thrombin and factor Xa by a mechanism independent of antithrombin (AT) and/or heparin co-factor II (HCII). Moreover, Pec-HWS provided a lower risk of bleeding than heparin at a dose of 100% effectiveness against venous thrombosis, indicating it to be a promising antithrombotic agent.

Thrombophilia and Pregnancy Complications

PubMed Central

Simcox, Louise E.; Ormesher, Laura; Tower, Clare; Greer, Ian A.

2015-01-01

There is a paucity of strong evidence associated with adverse pregnancy outcomes and thrombophilia in pregnancy. These problems include both early (recurrent miscarriage) and late placental vascular-mediated problems (fetal loss, pre-eclampsia, placental abruption and intra-uterine growth restriction). Due to poor quality case-control and cohort study designs, there is often an increase in the relative risk of these complications associated with thrombophilia, particularly recurrent early pregnancy loss, late fetal loss and pre-eclampsia, but the absolute risk remains very small. It appears that low-molecular weight heparin has other benefits on the placental vascular system besides its anticoagulant properties. Its use is in the context of antiphospholipid syndrome and recurrent pregnancy loss and also in women with implantation failure to improve live birth rates. There is currently no role for low-molecular weight heparin to prevent late placental-mediated complications in patients with inherited thrombophilia and this may be due to small patient numbers in the studies involved in summarising the evidence. There is potential for low-molecular weight heparin to improve pregnancy outcomes in women with prior severe vascular complications of pregnancy such as early-onset intra-uterine growth restriction and pre-eclampsia but further high quality randomised controlled trials are required to answer this question. PMID:26633369

Low molecular weight protamine (LMWP): a nontoxic protamine substitute and an effective cell-penetrating peptide.

PubMed

He, Huining; Ye, Junxiao; Liu, Ergang; Liang, Qiuling; Liu, Quan; Yang, Victor C

2014-11-10

Low molecular weight protamine (LMWP) is a peptide fragment produced in our laboratory from enzymatic digestion of native protamine. More than 30 papers studying the properties and applications of LMWP have been published by our group in various journals since its initial discovery in 1999. Results have shown that LMWP could completely neutralize the anticoagulant functions of both heparin and low molecular weight heparin (LMWH), with reduced antigenicity and cross-reactivity toward the mice-derived anti-protamine antibodies. Aside from its potential as a heparin/LMWH antagonist, LMWP also shows the ability to retard insulin adsorption by the formation of an insoluble complex, making it a less toxic long-lasting insulin product than the conventional neutral protamine Hagedorn (NPH) insulin for diabetic control. Importantly, LMWP (Sequence: VSRRRRRRGGRRRR), with 10 arginine residues in its structure, could function as a cell-penetrating peptide (CPP), also termed protein transduction domain (PTD), to achieve effective intracellular protein or gene delivery in clinical practice. In this paper, we present a thorough review of our work related to LMWP, with the aim of providing readers an insight into its potential to be a clinical protamine substitute as well as a non-toxic cell penetrating peptide applicable to achieve intracellular protein and gene delivery. Copyright © 2014 Elsevier B.V. All rights reserved.

Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease.

PubMed

Cheer, Susan M; Dunn, Christopher J; Foster, Rachel

2004-01-01

Tinzaparin sodium (tinzaparin; innohep) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH). In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH. Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and home-based treatment with tinzaparin may offer greater cost benefits than hospital-based therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.

Low-molecular-weight heparins: pharmacologic profile and product differentiation.

PubMed

Fareed, J; Jeske, W; Hoppensteadt, D; Clarizio, R; Walenga, J M

1998-09-10

The interchangeability of low-molecular-weight heparins (LMWHs) has been the subject of discussion since these products were first introduced for the prophylaxis of deep vein thrombosis. Experimental evidence now exists to show that LMWHs differ from each other in a number of characteristics. Products have been differentiated on the basis of molecular weight and biologic properties, but only limited information derived from the clinical setting is available. Potency has been described on the basis of anti-Factor Xa activity, but at equivalent anti-Xa activities, the anti-Factor IIa activity of different products shows marked variations. At the relatively small doses used for the management of postsurgical deep vein thrombosis, the effect of these interproduct differences may be relatively minor, but as LMWHs are developed for therapeutic use at much higher doses, such differences may become clinically important. Variations in safety and efficacy reported in clinical trials of LMWHs may reflect the known differences in their molecular composition and pharmacologic properties.

Intentional overdose with tinzaparin: management dilemmas.

PubMed

Balla, Iliana; Karafotias, Ioasaf; Christopoulos, Constantinos

2014-02-01

Low-molecular-weight heparin (LMWH) is increasingly being prescribed for prophylaxis and treatment of thromboembolic diseases. Despite the fact that its therapeutic use is considered to be safe, it can be complicated by major hemorrhage and, in contrast to unfractionated heparin, it can only partially be neutralized by protamine. Recent reports of LMWH overdose illustrate the need for a consensus on its management. To describe a case of self-poisoning with a very large dose of tinzaparin and discuss management options in patients with LMWH overdose. A 69-year-old woman was brought to the Emergency Department 2 h after injecting herself with 280,000 IU of tinzaparin subcutaneously in an attempt to commit suicide. Despite an unrecordable activated partial thromboplastin time (APTT > 180 s) and prolonged prothrombin time, there was no evidence of active bleeding. She was given an intravenous infusion of 100 mg protamine sulfate and was admitted to the intensive care unit, where further infusions of protamine were administered. Normalization of the APTT occurred 40-50 h post admission, reflecting normal tinzaparin clearance rather than neutralization by protamine. No hemorrhagic complications occurred during her hospitalization except for prolonged bleeding from venipuncture sites. In this case of massive tinzaparin overdose, conventional doses of protamine failed to rapidly normalize the deranged coagulation parameters. The favorable clinical outcome suggests that, regardless of the LMWH amount injected, no active treatment is needed in the absence of hemorrhage. This is in accordance with the limited published data concerning cases of overdose with other LMWHs. Copyright © 2014 Elsevier Inc. All rights reserved.

Safety and cost-effectiveness of bridge therapies for invasive dental procedures in patients with mechanical heart valves.

PubMed

Won, Ki-Bum; Lee, Seung-Hyun; Chang, Hyuk-Jae; Shim, Chi-Young; Hong, Gue-Ru; Ha, Jong-Won; Chung, Namsik

2014-07-01

Bridge anticoagulation therapy is mostly utilized in patients with mechanical heart valves (MHV) receiving warfarin therapy during invasive dental procedures because of the risk of excessive bleeding related to highly vascular supporting dental structures. Bridge therapy using low molecular weight heparin may be an attractive option for invasive dental procedures; however, its safety and cost-effectiveness compared with unfractionated heparin (UFH) is uncertain. This study investigated the safety and cost-effectiveness of enoxaparin in comparison to UFH for bridge therapy in 165 consecutive patients (57±11 years, 35% men) with MHV who underwent invasive dental procedures. This study included 75 patients treated with UFH-based bridge therapy (45%) and 90 patients treated with enoxaparin-based bridge therapy (55%). The bleeding risk of dental procedures and the incidence of clinical adverse outcomes were not significantly different between the UFH group and the enoxaparin group. However, total medical costs were significantly lower in the enoxaparin group than in the UFH group (p<0.001). After multivariate adjustment, old age (≥65 years) was significantly associated with an increased risk of total bleeding independent of bridging methods (odds ratio, 2.51; 95% confidence interval, 1.15-5.48; p=0.022). Enoxaparin-based bridge therapy (β=-0.694, p<0.001) and major bleeding (β=0.296, p=0.045) were significantly associated with the medical costs within 30 days after dental procedures. Considering the benefit of enoxaparin in cost-effectiveness, enoxaparin may be more efficient than UFH for bridge therapy in patients with MHV who required invasive dental procedures.

Low molecular weight (LMW) heparin inhibits injury-induced femoral artery remodeling in mouse via upregulating CD44 expression.

PubMed

Zhao, Gaofeng; Shaik, Rahamthulla S; Zhao, Hang; Beagle, John; Kuo, Shuennwen; Hales, Charles A

2011-05-01

The mechanism of postangioplasty restenosis remains poorly understood. Low molecular weight (LMW) heparin has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), which is the principal characteristic of restenosis. Studies have shown that LMW heparin could bind to CD44. We hypothesized that LMW heparin might modulate CD44 expression thereby decreasing vascular remodeling. Vascular remodeling was induced in CD44(+/+) and CD44(-/-) mice and treated with LMW heparin. The arteries were harvested for histologic assessment and determination of CD44 expression. Bone marrow transplantation was introduced to further explore the role and functional sites of CD44. Effects of LMW heparin on growth capacity, CD44 expression were further studied using the cultured mouse VSMCs. Transluminal injury induced remarkable remodeling in mouse femoral artery (sham wall thickness percentage [WT%]: 3.4 ± 1.2% vs injury WT%: 31.8 ± 4.7%; P < .001). LMW heparin reduced the remodeling significantly (WT%: 17.8 ± 3.5%, P < .005). CD44(-/-) mice demonstrated considerably thicker arterial wall remodeling (WT%: 46.2 ± 7.6%, P = .0035), and CD44-chimeric mice exhibited equal contributions of the local and circulating CD44 signal to the neointima formation. LMW heparin markedly upregulated CD44 expression in the injured femoral arteries. In vitro, LMW heparin decreased mouse VSMC growth capacity and upregulated its CD44 expression simultaneously in a dose-dependent and time-dependent manner, which could be partially blocked by CD44 inhibitor. LMW heparin inhibits injury-induced femoral artery remodeling, at least partially, by upregulating CD44 expression. Copyright © 2011. Published by Mosby, Inc.

Chronic In Vivo Testing of the Penn State Infant Ventricular Assist Device

PubMed Central

Weiss, William J.; Carney, Elizabeth L.; Clark, J. Brian; Peterson, Rebecca; Cooper, Timothy K.; Nifong, Thomas P.; Siedlecki, Christopher A; Hicks, Dennis; Doxtater, Bradley; Lukic, Branka; Yeager, Eric; Reibson, John; Cysyk, Joshua; Rosenberg, Gerson; Pierce, William S.

2011-01-01

The Penn State Infant Ventricular Assist Device is a 12-14 ml stroke volume pneumatically actuated pump, with custom Björk-Shiley monostrut valves, developed under the National Heart, Lung, and Blood Institute (NHLBI) Pediatric Circulatory Support program. In this report we describe the 7 most recent chronic animal studies of the Infant VAD in the juvenile ovine model, with a mean body weight of 23.5 +/- 4.1 kg. The goal of 4-6 weeks survival was achieved in 5 of 7 studies, with support duration ranging from 5 to 41 days; mean 26.1 days. Anticoagulation was accomplished using unfractionated heparin, and study animals were divided into 2 protocol groups: the first based on a target activated partial thromboplastin time of 1.5 to 2 times normal, and a second group using a target thromboelastography R-time of 2 times normal. The second group required significantly less heparin, which was verified by barely detectable heparin activity (anti-Xa). In both groups, there was no evidence of thromboembolism except in one animal with a chronic infection and fever. Device thrombi were minimal, and were further reduced by introduction of the custom valve. These results are consistent with results of adult VAD testing in animals, and are encouraging given the extremely low levels of anticoagulation in the second group. PMID:22157073

Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes.

PubMed

Valgimigli, Marco; Frigoli, Enrico; Leonardi, Sergio; Rothenbühler, Martina; Gagnor, Andrea; Calabrò, Paolo; Garducci, Stefano; Rubartelli, Paolo; Briguori, Carlo; Andò, Giuseppe; Repetto, Alessandra; Limbruno, Ugo; Garbo, Roberto; Sganzerla, Paolo; Russo, Filippo; Lupi, Alessandro; Cortese, Bernardo; Ausiello, Arturo; Ierna, Salvatore; Esposito, Giovanni; Presbitero, Patrizia; Santarelli, Andrea; Sardella, Gennaro; Varbella, Ferdinando; Tresoldi, Simone; de Cesare, Nicoletta; Rigattieri, Stefano; Zingarelli, Antonio; Tosi, Paolo; van 't Hof, Arnoud; Boccuzzi, Giacomo; Omerovic, Elmir; Sabaté, Manel; Heg, Dik; Jüni, Peter; Vranckx, Pascal

2015-09-10

Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome. We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin. Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion. Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event). The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events. The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; relative risk, 0.94; 95% confidence interval [CI], 0.81 to 1.09; P=0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; relative risk, 0.89; 95% CI, 0.78 to 1.03; P=0.12). Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; relative risk, 0.91; 95% CI, 0.74 to 1.11; P=0.34). In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion. (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrials.gov number, NCT01433627.).

Determination of the molecular weight of low-molecular-weight heparins by using high-pressure size exclusion chromatography on line with a triple detector array and conventional methods.

PubMed

Bisio, Antonella; Mantegazza, Alessandra; Vecchietti, Davide; Bensi, Donata; Coppa, Alessia; Torri, Giangiacomo; Bertini, Sabrina

2015-03-19

The evaluation of weight average molecular weight (Mw) and molecular weight distribution represents one of the most controversial aspects concerning the characterization of low molecular weight heparins (LMWHs). As the most commonly used method for the measurement of such parameters is high performance size exclusion chromatography (HP-SEC), the soundness of results mainly depends on the appropriate calibration of the chromatographic columns used. With the aim of meeting the requirement of proper Mw standards for LMWHs, in the present work the determination of molecular weight parameters (Mw and Mn) by HP-SEC combined with a triple detector array (TDA) was performed. The HP-SEC/TDA technique permits the evaluation of polymeric samples by exploiting the combined and simultaneous action of three on-line detectors: light scattering detectors (LALLS/RALLS); refractometer and viscometer. Three commercial LMWH samples, enoxaparin, tinzaparin and dalteparin, a γ-ray depolymerized heparin (γ-Hep) and its chromatographic fractions, and a synthetic pentasaccharide were analysed by HP-SEC/TDA. The same samples were analysed also with a conventional HP-SEC method employing refractive index (RI) and UV detectors and two different chromatographic column set, silica gel and polymeric gel columns. In both chromatographic systems, two different calibration curves were built up by using (i) γ-Hep chromatographic fractions and the corresponding Mw parameters obtained via HP-SEC/TDA; (ii) the whole γ-Hep preparation with broad Mw dispersion and the corresponding cumulative distribution function calculated via HP-SEC/TDA. In addition, also a chromatographic column calibration according to European Pharmacopoeia indication was built up. By comparing all the obtained results, some important differences among Mw and size distribution values of the three LMWHs were found with the five different calibration methods and with HP-SEC/TDA method. In particular, the detection of the lower molecular weight components turned out to be the most critical aspect. Whereas HP-SEC/TDA may underestimate species under 2 KDa when present in low concentration, other methods appeared to emphasize their content.

[Perioperative coagulation management in microsurgery: report of the consensus workshops in the course of the 31st and 32nd Annual Meeting of the German-language Working Group for microsurgery of the peripheral nerves and vessels (DAM) November 2009 in Erlangen and November 2010 in Basel].

PubMed

Schmitz, M; Riss, R; Kneser, U; Jokuszies, A; Harder, Y; Beier, J P; Schäfer, D J; Vogt, P M; Fansa, H; Andree, C; Pierer, G; Horch, R E

2011-12-01

Microsurgery is a very relevant component of reconstructive surgery. In this context anticoagulation plays an increasing role. At the moment there are no unanimously accepted prospective studies or generally accepted regimes available that could serve as evidence-based guidelines for the prevention of thrombosis in microsurgery. With regard to this problem the aim of a series of workshops during the annual meetings of the German-speaking group for microsurgery in 2009 and 2010 was to establish a first possible consensus. This article reflects the main aspects of the ongoing development of a generally acceptable guideline for anticoagulation in microsurgery as interim report of these consensus workshops. Basically there are 3 main agents in thromboprophylaxis available: antiplatelet drugs, dextran and heparin. In the course of the workshops no general use of aspirin or dextran for anticoagulation in microsurgery was recommended. The use of heparin as anticoagulation agent is advisable for different indications. Low molecular heparins (LMH) have certain advantages in comparison to unfractionated heparins (UFH) and are therefore preferred by most participants. Indications for UFH are still complex microsurgical revisions, renal failure and some specific constellations in patients undergoing reconstruction of the lower extremity, where the continuous administration of heparin is recommended. At the moment of clamp release a single-shot of UFH is still given by many microsurgeons, despite a lack of scientific evidence. Future prospective clinical trials and the establishment of a generally accepted evidence-based guideline regarding anticoagulation treatment in microsurgery are deemed necessary. © Georg Thieme Verlag KG Stuttgart · New York.

New synthetic peptide with efficacy for heparin reversal and low toxicity and immunogenicity in comparison to protamine sulfate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Tong; Meng, Zhiyun; Zhu, Xiaoxia

Protamine sulfate (PS), the only clinically approved antidote to unfractionated heparin (UFH), is widely used for cardiopulmonary surgery or other extracorporeal circulation situations. However, the applications of PS have accompanied various severe side-effects. In this study, we presented a novel synthesized peptide compound (RRRRR-RRRRR-RRRRR-sulfate, R15S) served as a safer UFH antidote. Comparison studies were conducted between PS and R15S on efficacy and safety, aided by heparin neutralization studies, drug toxicity studies and anaphylactic analysis. Our research demonstrated that R15S contained comparable UFH neutralization activity in vitro and in rats in vivo as to active partial thromboplastin time (APTT) and anti-FXa assays. Theremore » was no cytotoxicity for R15S at 60 μg mg{sup −1} or below and the median lethal dose (LD{sub 50}) of R15S in mice was 35.4 mg kg{sup −1}, both of which were similar to that of PS. Furthermore, R15S exhibited no immunogenicity while it was obvious in guinea pigs immunized with PS. The level of cross-reactivity to anti-PS antibodies of R15S was about 30%. Both of which indicated much safer properties of R15S than PS. In conclusion, we presented a promising candidate R15S for UFH reversal, which is effective in neutralizing UFH and potentially safer in use. - Highlights: • R15 sulfate has a comparable unfractionated heparin neutralization activity to PS. • R15 sulfate avoided severe anaphylactic responses which happened to PS in clinical use. • R15 sulfate could provide a stricter quality control compared to PS which may vary with different batches.« less

Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins.

PubMed

Jeske, Walter P; Walenga, Jeanine M; Hoppensteadt, Debra A; Vandenberg, Curtis; Brubaker, Aleah; Adiguzel, Cafer; Bakhos, Mamdouh; Fareed, Jawed

2008-02-01

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

Continuous infusion of low-dose unfractionated heparin after aneurysmal subarachnoid hemorrhage: a preliminary study of cognitive outcomes.

PubMed

James, Robert F; Khattar, Nicolas K; Aljuboori, Zaid S; Page, Paul S; Shao, Elaine Y; Carter, Lacey M; Meyer, Kimberly S; Daniels, Michael W; Craycroft, John; Gaughen, John R; Chaudry, M Imran; Rai, Shesh N; Everhart, D Erik; Simard, J Marc

2018-05-11

OBJECTIVE Cognitive dysfunction occurs in up to 70% of aneurysmal subarachnoid hemorrhage (aSAH) survivors. Low-dose intravenous heparin (LDIVH) infusion using the Maryland protocol was recently shown to reduce clinical vasospasm and vasospasm-related infarction. In this study, the Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive changes in aSAH patients treated with the Maryland LDIVH protocol compared with controls. METHODS A retrospective analysis of all patients treated for aSAH between July 2009 and April 2014 was conducted. Beginning in 2012, aSAH patients were treated with LDIVH in the postprocedural period. The MoCA was administered to all aSAH survivors prospectively during routine follow-up visits, at least 3 months after aSAH, by trained staff blinded to treatment status. Mean MoCA scores were compared between groups, and regression analyses were performed for relevant factors. RESULTS No significant differences in baseline characteristics were observed between groups. The mean MoCA score for the LDIVH group (n = 25) was 26.4 compared with 22.7 in controls (n = 22) (p = 0.013). Serious cognitive impairment (MoCA ≤ 20) was observed in 32% of controls compared with 0% in the LDIVH group (p = 0.008). Linear regression analysis demonstrated that only LDIVH was associated with a positive influence on MoCA scores (β = 3.68, p =0.019), whereas anterior communicating artery aneurysms and fevers were negatively associated with MoCA scores. Multivariable linear regression analysis resulted in all 3 factors maintaining significance. There were no treatment complications. CONCLUSIONS This preliminary study suggests that the Maryland LDIVH protocol may improve cognitive outcomes in aSAH patients. A randomized controlled trial is needed to determine the safety and potential benefit of unfractionated heparin in aSAH patients.

Characterization of Low-Molecular-Weight Heparins by Strong Anion-Exchange Chromatography.

PubMed

Sadowski, Radosław; Gadzała-Kopciuch, Renata; Kowalkowski, Tomasz; Widomski, Paweł; Jujeczka, Ludwik; Buszewski, Bogusław

2017-11-01

Currently, detailed structural characterization of low-molecular-weight heparin (LMWH) products is an analytical subject of great interest. In this work, we carried out a comprehensive structural analysis of LMWHs and applied a modified pharmacopeial method, as well as methods developed by other researchers, to the analysis of novel biosimilar LMWH products; and, for the first time, compared the qualitative and quantitative composition of commercially available drugs (enoxaparin, nadroparin, and dalteparin). For this purpose, we used strong anion-exchange (SAX) chromatography with spectrophotometric detection because this method is more helpful, easier, and faster than other separation techniques for the detailed disaccharide analysis of new LMWH drugs. In addition, we subjected the obtained results to statistical analysis (factor analysis, t-test, and Newman-Keuls post hoc test).

Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil.

PubMed

Kast, Constantia E; Guggi, Davide; Langoth, Nina; Bernkop-Schnürch, Andreas

2003-06-01

It was the purpose of this study to develop a new oral drug delivery system for low molecular weight heparin (LMWH) providing an improved bioavailability and a prolonged therapeutic effect. The permeation enhancing polycarbophil-cysteine conjugate (PCP-Cys) used in this study displayed 111.4 +/- 6.4 microM thiol groups per gram polymer. Permeation studies on freshly excised intestinal mucosa were performed in Ussing chambers demonstrating a 2-fold improved uptake of heparin as a result of the addition of 0.5% (w/v) PCP-Cys and the permeation mediator glutathione (GSH). Tablets containing PCP-Cys, GSH, and 279 IU of LMWH showed a sustained drug release over 4 h. To guarantee the swelling of the polymeric carrier matrix in the small intestine tablets were enteric coated. They were orally given to rats. For tablets being based on the thiomer/GSH system an absolute bioavailability of 19.9 +/- 9.3% (means +/- SD; n = 5) vs. intravenous injection could be achieved. whereas tablets comprising unmodified PCP did not lead to a significant (p < 0.01) heparin concentration in plasma. The permeation enhancing effect and subsequently a therapeutic heparin level was maintained for 24 h after a single dose. Because of the strong and prolonged lasting permeation enhancing effect of the thiomer/GSH system, the oral bioavailability of LMWH could be significantly improved. This new delivery system represents therefore a promising tool for the oral administration of heparin.

Gold Medal Forum Winner. Unfractionated heparin three times a day versus enoxaparin in the prevention of deep vein thrombosis in trauma patients.

PubMed

Arnold, Joshua D; Dart, Benjamin W; Barker, Donald E; Maxwell, Robert A; Burkholder, Hans C; Mejia, Vicente A; Smith, Philip W; Longley, Joy M

2010-06-01

Venous thromboembolic disease is a significant source of morbidity and mortality in hospitalized trauma patients. Multiple drugs and dosing regimens have been suggested for pharmacoprophylaxis. In this study, we compared efficacy, complications, and cost of unfractionated heparin administered subcutaneously three times a day with standard-dosed enoxaparin for prophylaxis of deep venous thrombosis (DVT) in adult trauma patients over 1 year. Patients admitted for greater than 72 hours who received pharmacoprophylaxis as part of a comprehensive DVT protocol were included. A change was made in the protocol from enoxaparin (30 mg twice a day or 40 mg per day) to heparin (5000 U three times a day) at midyear. Surveillance lower extremity venous ultrasound was performed according to established institutional guidelines. Data, including demographics, associated injuries, complications, and cost, were collected and analyzed. Four hundred seventy-six patients met inclusion criteria. Two hundred thirty-seven (49.8%) patients received enoxaparin and 239 (50.2%) received heparin. Proximal lower extremity DVTs were detected in 16 (6.75%) patients in the enoxaparin group and 17 (7.11%) in the heparin group (P = 0.999). Risk factors for DVT in these patients included spinal cord injury (P = 0.001) and closed head injury (P = 0.031). There was no difference between the incidence of pulmonary emboli and bleeding. There was an estimated yearly pharmacy cost savings of $135,606. In trauma patients, subcutaneous heparin dosed three times a day may be as effective as standard-dosed enoxaparin for prophylaxis of venous thromboembolism without increased complications. Heparin three times a day for venous thromboembolism prophylaxis was associated with significant pharmaceutical cost savings.

Heparin for clearance of peripherally inserted central venous catheter in newborns: an in vitro study

PubMed Central

Balaminut, Talita; Venturini, Danielle; da Silva, Valéria Costa Evangelista; Rossetto, Edilaine Giovanini; Zani, Adriana Valongo

2015-01-01

Objective: To compare the efficacy of two concentrations of heparin to clear the lumen of in vitro clotted neonatal peripherally inserted central catheters (PICCs). Methods: This is an in vitro, experimental quantitative study of 76 neonatal 2.0-Fr PICCs coagulated in vitro. The catheters were divided into two groups of 38 PICCs each. In both groups an infusion of low molecular weight heparin was administered with a dose of 25IU/mL for Group 1 and 50IU/mL for Group 2. The negative pressure technique was applied to the catheters of both groups at 5, 15 and 30min and at 4h to test their permeability. Kaplan-Meier survival analysis was used to verify the outcome of the groups according to time intervals. Results: The comparison between both groups in the first 5min showed that more catheters from Group 2 were cleared compared to Group 1 (57.9 vs. 21.1%, respectively). Kaplan-Meier survival analysis showed that less time was needed to clear catheters treated with 50IU/mL of heparin (p<0.001). Conclusions: The use of low molecular weight heparin at a concentration of 50IU/mL was more effective in restoring the permeability of neonatal PICCs occluded in vitro by a clot, and the use of this concentration is within the safety margin indicated by scientific literature. PMID:26116325

Cerebral Venous Sinus Thrombosis Due to Low-molecular-weight Heparin-induced Thrombocytopenia.

PubMed

Gleichgerrcht, Ezequiel; Lim, Ming Y; Turan, Tanya N

2017-11-01

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin exposure. A limited number of studies have reported cerebral venous sinus thrombosis (CVST) as the presenting thrombotic event induced by HIT, only one of which occurred with exposure to low-molecular-weight heparin (LMWH), with death as outcome. Here, we present a unique case of LMWH-induced HIT leading to CVST but resulting in good clinical outcome. A 52-year-old woman received subcutaneous LMWH for deep vein thrombosis prophylaxis while in rehabilitation following kyphoplasty for spinal fracture related to recent trauma. On postoperative day 15, she developed acute onset altered mental status with significant agitation and nonsensical speech and was found to have brain imaging findings suggestive of CVST. Work-up revealed a drop in platelets associated with HIT, which did not improve off heparin products and with steroids, requiring intravenous immunoglobulin therapy, likely due to an overlapping immune thrombocytopenic purpura. Patient was managed on an argatroban drip until platelet count normalized and was able to transition to warfarin. Her clinical outcome was very favorable with near-normal neurological exam except for subtle cognitive changes. This unique case of LMWH-induced HIT leading to CVST but resulting in good clinical outcome highlights the importance of linking CVST with HIT and of establishing the need for early alternative antithrombotic therapeutic strategies.

Current and emerging drugs for the treatment of inflammatory bowel disease

PubMed Central

Triantafillidis, John K; Merikas, Emmanuel; Georgopoulos, Filippos

2011-01-01

During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn’s disease and ulcerative colitis. PMID:21552489

Antithrombotic Therapy in Neonates and Children

PubMed Central

Monagle, Paul; Chan, Anthony K. C.; Goldenberg, Neil A.; Ichord, Rebecca N.; Journeycake, Janna M.; Nowak-Göttl, Ulrike

2012-01-01

Background: Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children. Methods: The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Results: We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C). Conclusions: The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies. PMID:22315277

Venous thromboembolism prophylaxis in the critically ill: a point prevalence survey of current practice in Australian and New Zealand intensive care units.

PubMed

Robertson, Megan S; Nichol, Alistair D; Higgins, Alisa M; Bailey, Michael J; Presneill, Jeffrey J; Cooper, D James; Webb, Steven A; McArthur, Colin; MacIsaac, Christopher M

2010-03-01

Critically ill patients are at high risk of morbidity and mortality caused by venous thromboembolism (VTE). In addition to premorbid predisposing conditions, critically ill patients may be exposed to prolonged immobility, invasive intravascular catheters and frequent operative procedures, and further may have contraindications to pharmaceutical prophylactic measures designed to attenuate VTE risk. There are limited data describing current VTE prophylaxis regimens in Australia and New Zealand. To document current Australian and New Zealand management of VTE prophylaxis in a large mixed cohort of critically ill patients. Prospective, multicentre point prevalence survey endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). 30 public hospital ICUs in Australia and New Zealand surveyed on Wednesday 9 May 2007. For all patients in each ICU on the study day, demographic data, admission diagnosis and information on VTE prophylaxis were prospectively collected. 502 patients were included in the survey, and 431 of these (86%) received VTE prophylaxis. Of these, 64% (276/431) received pharmacological prophylaxis and 80% (345/431) received mechanical prophylaxis, with 44% (190/431) receiving both. Of those receiving pharmacological prophylaxis, unfractionated heparin was used in 74%, and enoxaparin (low molecular weight heparin) in 23%. Contraindications to pharmacological prophylaxis were reported in 122 patients. Overall, pharmacological prophylaxis was administered to 87% of potentially suitable patients. We observed a high prevalence of VTE prophylaxis, with many critically ill patients receiving two or more modalities of prophylaxis. These results show that the potential risk of VTE in critically ill patients is recognised in Australia and New Zealand, and strategies to mitigate this serious complication are widely implemented.

A Multinational Study of Thromboprophylaxis Practice in Critically Ill Children*

PubMed Central

Faustino, Edward Vincent S.; Hanson, Sheila; Spinella, Philip C.; Tucci, Marisa; O'Brien, Sarah H.; Nunez, Antonio Rodriguez; Yung, Michael; Truemper, Edward; Qin, Li; Li, Simon; Marohn, Kimberly; Randolph, Adrienne G.

2015-01-01

Objectives Although critically ill children are at increased risk for developing deep venous thrombosis, there are few pediatric studies establishing the prevalence of thrombosis or the efficacy of thromboprophylaxis. We tested the hypothesis that thromboprophylaxis is infrequently used in critically ill children even for those in whom it is indicated. Design Prospective multinational cross-sectional study over four study dates in 2012. Setting Fifty-nine PICUs in Australia, Canada, New Zealand, Portugal, Singapore, Spain, and the United States. Patients All patients less than 18 years old in the PICU during the study dates and times were included in the study, unless the patients were 1) boarding in the unit waiting for a bed outside the PICU or 2) receiving therapeutic anticoagulation. Interventions None. Measurements and Main Results Of 2,484 children in the study, 2,159 (86.9%) had greater than or equal to 1 risk factor for thrombosis. Only 308 children (12.4%) were receiving pharmacologic thromboprophylaxis (e.g., aspirin, low-molecular-weight heparin, or unfractionated heparin). Of 430 children indicated to receive pharmacologic thromboprophylaxis based on consensus recommendations, only 149 (34.7%) were receiving it. Mechanical thromboprophylaxis was used in 156 of 655 children (23.8%) 8 years old or older, the youngest age for that device. Using nonlinear mixed effects model, presence of cyanotic congenital heart disease (odds ratio, 7.35; p < 0.001) and spinal cord injury (odds ratio, 8.85; p = 0.008) strongly predicted the use of pharmacologic and mechanical thromboprophylaxis, respectively. Conclusions Thromboprophylaxis is infrequently used in critically ill children. This is true even for children at high risk of thrombosis where consensus guidelines recommend pharmacologic thromboprophylaxis. PMID:24351371

Fondaparinux and acute coronary syndromes: update on the OASIS 5-6 studies.

PubMed

Schiele, François

2010-04-15

Anticoagulant therapy is a major component in the management of acute coronary syndromes (ACS). Four anticoagulant agents are currently commercially available for ACS, namely unfractionated heparin (UFH), enoxaparin, bivalirudin and fondaparinux. We describe the advantages of fondaparinux and the reasons that have hampered its uptake into routine management of ACS. Fondaparinux was shown to be efficacious in the prevention of deep vein thrombosis vs low-molecular-weight heparins, while in the setting of venous thrombo-embolic disease, it was shown to be noninferior to enoxaparin and UFH. Two pivotal studies have demonstrated the efficacy of fondaparinux as an anticoagulant in the setting of ACS, namely OASIS-5 in non-ST elevation ACS, and OASIS-6 in ST elevation myocardial infarction (MI). In OASIS-5, fondaparinux was shown to be noninferior to enoxaparin in terms of death, MI or refractory ischemia at 9 days. Furthermore, a 50% reduction in bleeding complications was obtained with fondaparinux vs enoxaparin, leading to a risk reduction for death. In OASIS-6, fondaparinux was shown to be superior to the comparator (UFH or placebo). European and North American guidelines give fondaparinux a Grade 1A and 1B recommendation respectively, but uptake of fondaparinux in routine practice has been slow. We explore reasons for this, such as prevailing doubts about the efficacy of fondaparinux in the setting of angioplasty, the problem of catheter thrombosis, and the lack of antidote in case of bleeding complications. With the exception of primary angioplasty, fondaparinux is as effective as enoxaparin or UFH, but is also associated with a considerable reduction in bleeding complications, and thus, an undeniable net clinical benefit.

Impact of thromboprophylaxis across the US acute care setting.

PubMed

Huang, Wei; Anderson, Frederick A; Rushton-Smith, Sophie K; Cohen, Alexander T

2015-01-01

The risk of venous thromboembolism (VTE) can be reduced by appropriate use of anticoagulant prophylaxis. VTE prophylaxis does, however, remain substantially underused, particularly among acutely ill medical inpatients. We sought to evaluate the clinical and economic impact of increasing use of American College of Chest Physicians (ACCP)-recommended VTE prophylaxis among medical inpatients from a US healthcare system perspective. In this retrospective database cost-effectiveness evaluation, a decision-tree model was developed to estimate deaths within 30 days of admission and outcomes attributable to VTE that might have been averted by use of low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). Incremental cost-effectiveness ratio was calculated using "no prophylaxis" as the comparator. Data from the ENDORSE US medical inpatients and the US nationwide Inpatient Sample (NIS) were used to estimate the annual number of eligible inpatients who failed to receive ACCP-recommended VTE prophylaxis. The cost-effectiveness analysis indicated that VTE-prevention strategies would reduce deaths by 0.5% and 0.3%, comparing LMWH and UFH strategies with no prophylaxis, translating into savings of $50,637 and $25,714, respectively, per death averted. The ENDORSE findings indicated that 51.1% of US medical inpatients were at ACCP-defined VTE risk, 47.5% of whom received ACCP-recommended prophylaxis. By extrapolating these findings to the NIS and applying cost-effectives analysis results, the full implementation of ACCP guidelines would reduce number of deaths (by 15,875 if using LMWH or 10,201 if using UFH), and was extrapolated to calculate the cost reduction of $803M for LMWH and $262M for UFH. Efforts to improve VTE prophylaxis use in acutely ill inpatients are warranted due to the potential for reducing VTE-attributable deaths, with net cost savings to healthcare systems.

Inherited antithrombin deficiency and anabolic steroids: a risky combination.

PubMed

Choe, Hannah; Elfil, Mohamed; DeSancho, Maria T

2016-09-01

A 20-year-old male with asymptomatic inherited type 1 antithrombin deficiency and a family history of thrombosis started injecting himself with testosterone 250 mg intramuscularly twice weekly for 5 weeks. He presented to the hospital with progressive dyspnea on exertion, chest pain and hemoptysis. Workup revealed bilateral submassive pulmonary embolism and proximal right lower extremity deep vein thrombosis. He was treated with intravenous (IV) unfractionated heparin and underwent catheter-directed thrombolysis with alteplase to the main pulmonary arteries. Postprocedure, he remained on IV alteplase infusion for 24 h and unfractionated heparin in the intensive care unit. Concomitantly he received plasma-derived antithrombin concentrate. He was transitioned to subcutaneous enoxaparin twice daily and discharged from the hospital on oral rivaroxaban 15 mg twice a day. This case highlights the heightened thrombogenic effect of anabolic steroids in the setting of underlying thrombophilia especially in younger subjects.

Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis.

PubMed

Lecarpentier, Edouard; Gris, Jean Christophe; Cochery-Nouvellon, Eva; Mercier, Erick; Touboul, Cyril; Thadhani, Ravi; Karumanchi, S Ananth; Haddad, Bassam

2018-01-01

To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction. This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks. Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery. Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials. ClinicalTrials.gov, NCT00986765.

Profiling analysis of low molecular weight heparins by multiple heart-cutting two dimensional chromatography with quadruple time-of-flight mass spectrometry.

PubMed

Ouyang, Yilan; Zeng, Yangyang; Rong, Yinxiu; Song, Yue; Shi, Lv; Chen, Bo; Yang, Xinlei; Xu, Naiyu; Linhardt, Robert J; Zhang, Zhenqing

2015-09-01

Low molecular weight heparins (LMWHs) are polydisperse and microheterogenous mixtures of polysaccharides used as anticoagulant drugs. Profiling analysis is important for obtaining deeper insights into the structure of LMWHs. Previous oligosaccharide mapping methods are relatively low resolution and are unable to show an entire picture of the structural complexity of LMWHs. In the current study a profiling method was developed relying on multiple heart-cutting, two-dimensional, ultrahigh performance liquid chromatography with quadruple time-of-flight mass spectrometry. This represents an efficient, automated, and robust approach for profiling LMWHs. Using size-exclusion chromatography and ion-pairing reversed-phase chromatography in a two-dimensional separation, LMW components of different sizes and LMW components of the same size but with different charges and polarities can be resolved, providing a more complete picture of a LMWH. Structural information on each component was then obtained with quadrupole time-of-flight mass spectrometry. More than 80 and 120 oligosaccharides were observed and unambiguously assigned from the LMWHs, nadroparin and enoxaparin, respectively. This method might be useful for quality control of LMWHs and as a powerful tool for heparin-related glycomics.

Cost-effectiveness analysis of low-molecular-weight heparin versus aspirin thromboprophylaxis in patients newly diagnosed with multiple myeloma.

PubMed

Chalayer, Emilie; Bourmaud, Aurélie; Tinquaut, Fabien; Chauvin, Franck; Tardy, Bernard

2016-09-01

The aim of this study was to assess the cost-effectiveness of low molecular weight heparin versus aspirin as primary thromboprophylaxis throughout chemotherapy for newly diagnosed multiple myeloma patients treated with protocols including thalidomide from the perspective of French health care providers. We used a modeling approach combining data from the only randomized trial evaluating the efficacy of the two treatments and secondary sources for costs, and utility values. We performed a decision-tree analysis and our base case was a hypothetical cohort of 10,000 patients. A bootstrap resampling technique was used. The incremental cost-effectiveness ratio was calculated using estimated quality-adjusted life years as the efficacy outcome. Incremental costs and effectiveness were estimated for each strategy and the incremental cost-effectiveness ratio was calculated. One-way sensitivity analyses were performed. The number of quality-adjusted life years was estimated to be 0.300 with aspirin and 0.299 with heparin. The estimated gain with aspirin was therefore approximately one day. Over 6months, the mean total cost was € 1518 (SD=601) per patient in the heparin arm and € 273 (SD=1019) in the aspirin arm. This resulted in an incremental cost of € 1245 per patient treated with heparin. The incremental cost-effectiveness ratio for the aspirin versus heparin strategy was calculated to be - 687,398 € (95% CI, -13,457,369 to -225,385). Aspirin rather than heparin thromboprophylaxis, during the first six months of chemotherapy for myeloma, is associated with significant cost savings per patient and also with an unexpected slight increase in quality of life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists.

PubMed

Presta, Marco; Oreste, Pasqua; Zoppetti, Giorgio; Belleri, Mirella; Tanghetti, Elena; Leali, Daria; Urbinati, Chiara; Bugatti, Antonella; Ronca, Roberto; Nicoli, Stefania; Moroni, Emanuela; Stabile, Helena; Camozzi, Maura; Hernandez, German Andrés; Mitola, Stefania; Dell'Era, Patrizia; Rusnati, Marco; Ribatti, Domenico

2005-01-01

Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds. We investigated the fibroblast growth factor-2 (FGF2) antagonist and antiangiogenic activity of a series of LMW N,O-sulfated K5 derivatives. Surface plasmon resonance analysis showed that LMW-K5 derivatives bind FGF2, thus inhibiting its interaction with heparin immobilized to a BIAcore sensor chip. Interaction of FGF2 with tyrosine-kinase receptors (FGFRs), heparan sulfate proteoglycans (HSPGs), and alpha(v)beta3 integrin is required for biological response in endothelial cells. Similar to LMWH, LMW-K5 derivatives abrogate the formation of HSPG/FGF2/FGFR ternary complexes by preventing FGF2-mediated attachment of FGFR1-overexpressing cells to HSPG-bearing cells and inhibit FGF2-mediated endothelial cell proliferation. However, LMW-K5 derivatives, but not LMWH, also inhibit FGF2/alpha(v)beta3 integrin interaction and consequent FGF2-mediated endothelial cell sprouting in vitro and angiogenesis in vivo in the chick embryo chorioallantoic membrane. LMW N,O-sulfated K5 derivatives affect both HSPG/FGF2/FGFR and FGF2/alpha(v)beta3 interactions and are endowed with FGF2 antagonist and antiangiogenic activity. These compounds may provide the basis for the design of novel LMW heparin-like angiostatic compounds.

A randomized two-by-two comparison of high-dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: the tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial.

PubMed

Moliterno, David J

2011-06-01

In the absence of high-dose thienopyridines, placebo-controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head-to-head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high-dose bolus (25 μg/kg) plus 12-hr infusion (0.15 μg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30-day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. With limited assessment, this direct comparison of high-dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations. Copyright © 2010 Wiley-Liss, Inc.

Increase in the growth inhibition of bovine pulmonary artery smooth muscle cells by an O-hexanoyl low-molecular-weight heparin derivative.

PubMed

Garg, Hari G; Hales, Charles A; Yu, Lunyin; Butler, Melissa; Islam, Tasneem; Xie, Jin; Linhardt, Robert J

2006-11-06

Proliferation of pulmonary artery smooth muscle cells (PASMCs) appears to play a significant role in chronic pulmonary hypertension. The proliferation of PASMCs is strongly inhibited by some commercial heparin preparations. Heparin fragments were prepared by periodate treatment, followed by sodium borohydride reduction, to enhance potency. The tributylammonium salt of this fragmented heparin was O-acylated with hexanoic anhydride. Gradient polyacrylamide gel electrophoresis showed that the major heparin fragment contained eight disaccharide units. NMR analysis showed that approximately one hexanoyl group per disaccharide residue was present. The O-hexanoyl heparin fragments were assayed for growth inhibitory effect on bovine PASMCs in culture. This derivative was found to be more effective in growth inhibition of bovine PASMCs in culture than the heparin from which it was derived. In the future, it is envisioned that this or similar derivatives may be an effective treatment for pulmonary hypertension.

Treatment of deep venous thrombosis and pulmonary embolism with low molecular weight heparin in the geriatric patient population.

PubMed

Merli, G J

2001-02-01

Low-molecular-weight heparins have provided a new approach to treating DVT-PE. These anticoagulants have better bioavailability, a longer half-life, and a more predictable antithrombotic effect than UFH. In the studies reviewed, LMWHs were shown to be safe and effective in preventing recurrent thrombotic events when compared with the more precise UFH dosing schedules. There has been no evidence of an increased incidence of major bleeding or recurrent thromboembolic events based on age in these trials. With these findings LMWHs given subcutaneously, without laboratory monitoring, in a dose determined by actual body weight allows clinicians involved in the care of the elderly to manage these patients with DVT with or without PE in the nursing home setting, skilled nursing care facilities, rehabilitation units, acute care hospital setting, or as described in this article at home. These patients can continue their physical therapy programs because intravenous infusion lines and the necessity to be maintained at bedrest do not encumber them.

Fluorophore-assisted carbohydrate electrophoresis for the determination of molecular mass of heparins and low-molecular-weight (LMW) heparins.

PubMed

Buzzega, Dania; Maccari, Francesca; Volpi, Nicola

2008-11-01

We report the use of fluorophore-assisted carbohydrate electrophoresis (FACE) to determine the molecular mass (M) values of heparins (Heps) and low-molecular-weight (LMW)-Hep derivatives. Hep are labeled with 8-aminonaphthalene-1,3,6-trisulfonic acid and FACE is able to resolve each fraction as a discrete band depending on their M. After densitometric acquisition, the migration distance of each Hep standard is acquired and the third-grade polynomial calibration standard curve is determined by plotting the logarithms of the M values as a function of migration ratio. Purified Hep samples having different properties, pharmaceutical Heps and various LMW-Heps were analyzed by both FACE and conventional high-performance size-exclusion liquid chromatography (HPSEC) methods. The molecular weight value on the top of the chromatographic peak (Mp), the number-average Mn, weight-average Mw and polydispersity (Mw/Mn) were examined by both techniques and found to be similar. This approach offers certain advantages over the HPSEC method. The derivatization process with 8-aminonaphthalene-1,3,6-trisulfonic acid is complete after 4 h so that many samples may be analyzed in a day also considering that multiple samples can be run simultaneously and in parallel and that a single FACE analysis requires approx. 15 min. Furthermore, FACE is a very sensitive method as it requires approx. 5-10 microg of Heps, about 10-100-fold lower than samples and standards used in HPSEC evaluation. Finally, the utilization of mini-gels allows the use of very low amounts of reagents with neither expensive equipment nor any complicated procedures having to be applied. This study demonstrates that FACE analysis is a sensitive method for the determination of the M values of Heps and LMW-Heps with possible utilization in virtually any kind of research and development such as quality control laboratories due to its rapid, parallel analysis of multiple samples by means of common and simple largely used analytical laboratory equipment.

Heparin-induced thrombocytopenia: real-world issues.

PubMed

Linkins, Lori-Ann; Warkentin, Theodore E

2011-09-01

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies. HIT sera often activate platelets without needing heparin-such heparin-"independent" platelet activation can be associated with HIT beginning or worsening despite stopping heparin ("delayed-onset HIT"). We address important issues in HIT diagnosis and therapy, using a recent cohort of HIT patients to illustrate influences of heparin type; triggers for HIT investigation; serological features of heparin-independent platelet activation; and treatment. In our cohort of recent HIT cases ( N = 13), low-molecular-weight heparin (dalteparin) was a common causative agent ( N = 8, 62%); most patients were diagnosed after HIT-thrombosis had occurred; and danaparoid was the most frequently selected treatment. Heparin-independent platelet activation was common (7/13 [54%]) and predicted slower platelet count recovery (>1 week) among evaluable patients (5/5 vs 1/6; P = 0.015). In our experience with argatroban-treated patients, HIT-associated consumptive coagulopathy confounds anticoagulant monitoring. Our observations provide guidance on practical aspects of HIT diagnosis and management. Thieme Medical Publishers.

Effects of Chitosan Derivative N-[(2-Hydroxy-3-Trimethylammonium)Propyl]Chloride on Anticoagulant Activity of Guinea Pig Plasma.

PubMed

Drozd, N N; Shagdarova, B Ts; Il'ina, A V; Varlamov, V P

2017-07-01

Intravenous injection of protamine sulfate or quarternized chitosan derivative to guinea pigs after injection of 70 aIIa U/kg non-fractionated heparin shortened plasma clotting time (shown by partial activated thromboplastin time, thrombin time, and prothrombin time). Intravenous injection of protamine sulfate or quarternized chitosan derivative to guinea pigs after injection of 1 mg/kg (100 aXa U/kg) low-molecular-weight heparin (clexane) led to shortening of plasma clotting time in the ReaClot Heparin test and to prolongation of plasma amidolytic activity in the factor Xa chromogenic substrate test.

Recent developments in separation of low molecular weight heparin anticoagulants.

PubMed

Sadowski, Radosław; Gadzała-Kopciuch, Renata; Buszewski, Bogusław

2017-10-05

The general function of anticoagulants is to prevent blood clotting and growing of the existing clots in blood vessels. In recent years, there has been a significant improvement in developing methods of prevention as well as pharmacologic and surgical treatment of thrombosis. For over the last two decades, low molecular weight heparins (LMWHs) have found their application in the antithrombotic diseases treatment. These types of drugs are widely used in clinical therapy. Despite the biological and medical importance of LMWHs, they have not been completely characterized in terms of their chemical structure. Due to both, the structural complexity of these anticoagulants and the presence of impurities, their structural characterization requires the employment of advanced analytical techniques. Since separation techniques play the key role in these endeavors, this review will focus on the presentation of recent developments in the separation of LMWH anticoagulants. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Venous thromboembolism prevention in pregnancy and the postpartum period in Primary and Specialized Care].

PubMed

Gallo-Vallejo, J L; Naveiro-Fuentes, M; Puertas-Prieto, A; Gallo-Vallejo, F J

2017-09-01

After noting that there are a number of risk factors for venous thromboembolism disease during pregnancy, it emphasizes primary prevention and treatment of this serious condition during pregnancy and the postpartum period are essential to reduce maternal morbidity and mortality. Low molecular-weight heparins are under the anticoagulant of choice in pregnancy. Your prescription may make both the primary care physician, as the hematologist and obstetrician. As for prescribing terms, an application protocol in both primary and specialized, multidisciplinary care, based on the existing literature on the subject is presented, which indicated that the hypercoagulable disorders associated with some of the risk factors, forced to do thromboprophylaxis with low molecular-weight heparins throughout pregnancy and the postpartum period presented. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

[Perioperative management of new oral anticoagulants].

PubMed

Samama, Charles-Marc; Pernod, Gilles; Albaladejo, Pierre; Sie, Pierre

2014-06-01

New oral anticoagulants do represent a major step forward as compared to low molecular weight heparins and vitamin K antagonists. Several issues deserve attention regarding their perioperative management. Three (and very soon four or five) active molecules are available on the market, adding to the major intra- and inter-individual variability, to the high number of drug-drug interactions, and to the interferences of renal function and many other parameters. New tests are available including the diluted thrombin time for dabigatran and a specific anti-Xa test for rivaroxaban and apixaban. No antidote is approved yet. Scheduled surgery: the safest suggestion is to mimic the perioperative management of vitamin K antagonist, with a 5-day interruption and low molecular weight heparin bridging whenever necessary. Emergency procedures: several suggestions issued from the Groupe d'Intérêt en Hémostase Péri-opératoire are proposed. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Low-molecular-weight heparins and cancer: focus on antitumoral effect.

PubMed

Franchini, Massimo; Mannucci, Pier Mannuccio

2015-03-01

A close relationship between cancer and thrombosis does exist, documented by the fact that an overall 7-fold increased risk of venous thromboembolism (VTE) has been reported in patients with malignancy compared to non-malignancy. The potential impact of antithrombotic agents in cancer-associated VTE has long been recognized, and, in particular, several clinical trials in the last 20 years have reported the safety and efficacy of low-molecular-weight heparins (LMWHs) for treatment and prophylaxis of VTE in patients with various types of cancer. More recently, a number of preclinical and clinical studies have suggested that LMWHs may improve survival in cancer patients with mechanisms that are different from its antithrombotic effect but are linked to the ability of influencing directly the tumor biology. This paper reviews the evidence around the potential survival benefits of LMWHs by analyzing the suggested mechanisms and the available clinical data.

Evaluation of rivaroxaban use in patients with gynecologic malignancies at an academic medical center: A pilot study.

PubMed

Signorelli, Jessie R; Gandhi, Arpita S

2017-01-01

Background Patients with gynecologic malignancies are at an increased risk for venous thromboembolism. National guidelines recommend treatment of an acute venous thromboembolism with low molecular weight heparin for 5-10 days followed by long-term secondary prophylaxis with low molecular weight heparin for at least six months. Non-vitamin K oral anticoagulants are not currently recommended to be used in cancer patients for the management of venous thromboembolism because robust data on their efficacy and safety have yet to become available in cancer patients. The objectives of this study were to determine the proportion of gynecologic oncology patients with venous thromboembolism using rivaroxaban compared to warfarin or low molecular weight heparin as well as compare the safety and efficacy of these anticoagulants. Methods This study was a retrospective pilot analysis of adult patients with gynecologic malignancies who received either rivaroxaban, warfarin or low molecular weight heparin for treatment of venous thromboembolism at Augusta University Medical Center from 1 July 2013 to 30 June 2015. Statistical comparisons between the enoxaparin and rivaroxaban group were made using T-tests and Chi-square or Fisher's exact tests, where appropriate. Results Out of the 49 patients, 37% (18) patients were on rivaroxaban, 53% (26) on enoxaparin, and 10% (5) on warfarin. Only one patient (4%) in the enoxaparin group experienced a recurrent deep vein thrombosis while there were no cases of recurrent venous thromboembolism in the rivaroxaban and warfarin group. The incidence of major bleeding was 17% ( n = 2), 20% ( n = 1), and 8% ( n = 2) in patients receiving rivaroxaban, enoxaparin, and warfarin, respectively. The rate of switching to a different anticoagulant than originally prescribed was 42% ( n = 14) in the enoxaparin arm, and 5.5% ( n = 1) in the rivaroxaban arm. Conclusion A high proportion of our gynecologic oncology patients received rivaroxaban for the management of venous thromboembolism. The sample size of this pilot analysis was too small to draw any conclusions regarding efficacy and safety of rivaroxaban compared with enoxaparin and warfarin. High rate of rivaroxaban use in gynecologic oncology patients at our institution highlights the need for larger, well-designed randomized controlled trials to confirm the safety and efficacy of its use in this population.

Safety and Efficacy of Bridging With Low-Molecular-Weight Heparin During Temporary Interruptions of Warfarin: A Register-Based Cohort Study.

PubMed

Sjögren, Vilhelm; Grzymala-Lubanski, Bartosz; Renlund, Henrik; Svensson, Peter J; Själander, Anders

2017-11-01

Low-molecular-weight heparin (LMWH) is often recommended as a bridging therapy during temporary interruptions in warfarin treatment, despite lack of evidence. The aim of this study was to see whether we could find benefit from LMWH bridging. We studied all planned interruptions of warfarin within the Swedish anticoagulation register Auricula during 2006 to 2011. Low-molecular-weight heparin bridging was compared to nonbridging (control) after propensity score matching. Complications were identified in national clinical registers for 30 days following warfarin cessation, and defined as all-cause mortality, bleeding (intracranial, gastrointestinal, or other), or thrombosis (ischemic stroke or systemic embolism, venous thromboembolism, or myocardial infarction) that was fatal or required hospital care. Of the 14 556 identified warfarin interruptions, 12 659 with a known medical background had a mean age of 69 years, 61% were males, mean CHADS 2 (1 point for each of congestive heart failure, hypertension, age ≥75 years, diabetes, and 2 points for stroke or transient ischemic attack) score was 1.7, and CHA 2 DS 2 -VASc score was 3.4. The total number of LMWH bridgings was 7021. Major indications for anticoagulation were mechanical heart valve prostheses 4331, atrial fibrillation 1097, and venous thromboembolism 1331. Bridging patients had a higher rate of thrombotic events overall. Total risk of any complication did not differ significantly between bridging (1.5%) and nonbridging (1.2%). Regardless of indication for warfarin treatment, we found no benefit from bridging. The type of procedure prompting bridging was not known, and the likely reason for the observed higher risk of thrombosis with LMWH bridging is that low-risk procedures more often meant no bridging. Results from randomized trials are needed, especially for patients with mechanical heart valves.

[No clinical evidence for an enhanced bleeding tendency due to perioperative treatment with bromelain].

PubMed

Johann, K; Eschmann, K; Meiser, P

2011-06-01

Systemic enzyme therapy with bromelain resembles a sensible alternative to nonsteroidal antiinflammatory drugs for the treatment of sports injuries, with particular consideration of therapeutic benefits and possible risks. Beyond aftertreatment of sports injuries, bromelain is used postoperatively as well. Besides the desired effects remission of oedema and pain relief, however, the postoperative use of bromelain raises uncertainty in some patients and physicians since an enhanced bleeding tendency in case of concomitant therapy with anticoagulants was described as a possible interaction. Therefore, the goal of this study was to investigate the clinical relevance of this interaction. In two non-interventional studies, altogether 260 patients were peri- or postoperatively (cruciate ligament- or coxarthrosis surgery) treated with bromelain (n = 129, 1000 - 3000 F. I. P. units/day) or diclofenac (n = 131; 150 mg/day) under concomitant thrombosis prophylaxis with low molecular weight heparin. Parameters tested were prothrombin time, thrombin time, activated partial thromboplastin time, fibrinogen and tolerability of the medication. Only marginal changes and a low variability of coagulation parameters were observed in both treatment groups (bromelain vs. diclofenac) in both studies. Elevated laboratory parameters were observed in both treatment groups for thrombin time which is very likely attributable to the therapy with low molecular weight heparin, due to the substantially parallel course of this parameter in both treatment groups. Therapy with bromelain was superior to the treatment with diclofenac concerning the number and the severity of undesirable effects, as was expected. The presented studies therefore support the previous clinical evidence that a perioperative treatment with bromelain is well tolerated and does not lead to an increased risk of haemorrhage when used concomitantly with low molecular weight heparin. © Georg Thieme Verlag KG Stuttgart · New York.

Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin

NASA Astrophysics Data System (ADS)

Cheng, Wenming; Zohra Dahmani, Fatima; Zhang, Juan; Xiong, Hui; Wu, Yuanyuan; Yin, Lifang; Zhou, Jianping; Yao, Jing

2017-02-01

Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA-NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy.

Sulfated, low-molecular-weight lignins are potent inhibitorsof plasmin, in addition to thrombin and factor Xa: Novel opportunity for controlling complex pathologies.

PubMed

Henry, Brian L; Abdel Aziz, May; Zhou, Qibing; Desai, Umesh R

2010-03-01

Recently we prepared sulfated, low-molecular-weight lignins (LMWLs) to mimic the biological activities of heparin and heparan sulfate. Chemo-enzymatically prepared sulfated LMWLs represent a library of diverse non-sugar, aromatic molecules with structures radically different from the heparins, and have been found to potently inhibit thrombin and factor Xa. To assess their effect on the fibrinolytic system, we studied the interaction of LMWLs with human plasmin. Enzyme inhibition studies indicate that the three sulfated LMWLs studied inhibit plasmin with IC50 values in the range of 0.24 and 1.3 mM, which are marginally affected in the presence of antithrombin. Similarly, plasmin degradation of polymeric fibrin is also inhibited by sulfated LMWLs. Michaelis-Menten kinetic studies indicate that maximal velocity of hydrolysis of chromogenic substrates decreases nearly 70% in the presence of LMWLs, while the effect on Michaelis constant is dependent on the nature of the substrate. Competitive binding studies indicate that the sulfated LMWLs compete with full-length heparin. Comparison with thrombin-heparin crystal structure identifies an anionic region on plasmin as a plausible sulfated LMWL binding site. Overall, the chemo-enzymatic origin coupled with coagulation and fibrinolysis inhibition properties of sulfated LMWLs present novel opportunities for designing new pharmaceutical agents that regulate complex pathologies in which both systems are known to play important roles such as disseminated intravascular coagulation.

Bottom-up low molecular weight heparin analysis using liquid chromatography-Fourier transform mass spectrometry for extensive characterization.

PubMed

Li, Guoyun; Steppich, Julia; Wang, Zhenyu; Sun, Yi; Xue, Changhu; Linhardt, Robert J; Li, Lingyun

2014-07-01

Low molecular weight heparins (LMWHs) are heterogeneous, polydisperse, and highly negatively charged mixtures of glycosaminoglycan chains prescribed as anticoagulants. The detailed characterization of LMWH is important for the drug quality assurance and for new drug research and development. In this study, online hydrophilic interaction chromatography (HILIC) Fourier transform mass spectrometry (FTMS) was applied to analyze the oligosaccharide fragments of LMWHs generated by heparin lyase II digestion. More than 40 oligosaccharide fragments of LMWH were quantified and used to compare LMWHs prepared by three different manufacturers. The quantified fragment structures included unsaturated disaccharides/oligosaccharides arising from the prominent repeating units of these LMWHs, 3-O-sulfo containing tetrasaccharides arising from their antithrombin III binding sites, 1,6-anhydro ring-containing oligosaccharides formed during their manufacture, saturated uronic acid oligosaccharides coming from some chain nonreducing ends, and oxidized linkage region oligosaccharides coming from some chain reducing ends. This bottom-up approach provides rich detailed structural analysis and quantitative information with high accuracy and reproducibility. When combined with the top-down approach, HILIC LC-FTMS based analysis should be suitable for the advanced quality control and quality assurance in LMWH production.

Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins.

PubMed

Xu, Yongmei; Chandarajoti, Kasemsiri; Zhang, Xing; Pagadala, Vijayakanth; Dou, Wenfang; Hoppensteadt, Debra Moorman; Sparkenbaugh, Erica M; Cooley, Brian; Daily, Sharon; Key, Nigel S; Severynse-Stevens, Diana; Fareed, Jawed; Linhardt, Robert J; Pawlinski, Rafal; Liu, Jian

2017-09-06

Low-molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

High Structural Resolution Hydroxyl Radical Protein Footprinting Reveals an Extended Robo1-Heparin Binding Interface*

PubMed Central

Li, Zixuan; Moniz, Heather; Wang, Shuo; Ramiah, Annapoorani; Zhang, Fuming; Moremen, Kelley W.; Linhardt, Robert J.; Sharp, Joshua S.

2015-01-01

Interaction of transmembrane receptors of the Robo family and the secreted protein Slit provides important signals in the development of the central nervous system and regulation of axonal midline crossing. Heparan sulfate, a sulfated linear polysaccharide modified in a complex variety of ways, serves as an essential co-receptor in Slit-Robo signaling. Previous studies have shown that closely related heparin octasaccharides bind to Drosophila Robo directly, and surface plasmon resonance analysis revealed that Robo1 binds more tightly to full-length unfractionated heparin. For the first time, we utilized electron transfer dissociation-based high spatial resolution hydroxyl radical protein footprinting to identify two separate binding sites for heparin interaction with Robo1: one binding site at the previously identified site for heparin dp8 and a second binding site at the N terminus of Robo1 that is disordered in the x-ray crystal structure. Mutagenesis of the identified N-terminal binding site exhibited a decrease in binding affinity as measured by surface plasmon resonance and heparin affinity chromatography. Footprinting also indicated that heparin binding induces a minor change in the conformation and/or dynamics of the Ig2 domain, but no major conformational changes were detected. These results indicate a second low affinity binding site in the Robo-Slit complex as well as suggesting the role of the Ig2 domain of Robo1 in heparin-mediated signal transduction. This study also marks the first use of electron transfer dissociation-based high spatial resolution hydroxyl radical protein footprinting, which shows great utility for the characterization of protein-carbohydrate complexes. PMID:25752613

Spontaneous Left Renal Subcapsular Hematoma and Right Hip Hematoma in a Hemodialysis Patient: A Case Report and Review of the Literature.

PubMed

Ye, Muyao; Liu, Yinghong; Zhou, Letian; Wang, Chang; Fu, Xiao; Peng, Youming; Liu, Hong

2016-01-01

For maintenance hemodialysis (MHD) patients, the blood is in low hypercoagulable state due to the use of heparin or low molecular weight heparin during dialysis. It is not rare to see hematoma in the puncture site. In recent years, several cases have been reported of spontaneous kidney rupture, but no hip hematoma, let alone both occurred in succession. There was one MHD patient with spontaneous kidney bleeding and hip hematoma in our hospital in 2014, and we provided effective treatment and follow-up. © 2016 S. Karger AG, Basel.

Monitoring therapeutic anticoagulation with low molecular weight heparins: is it useful or misleading?

PubMed

Hammerstingl, C

2008-10-01

Weight adapted low molecular weight heparin (LMWH) treatment is recommended as initial anticoagulant therapy of deep vein thrombosis, pulmonary embolism, in patients with myocardial ischemia or when oral anticoagulation (OAC) must be interrupted peri- operatively. Traditionally unfractioned heparin (UFH) was used as standard short acting anticoagulant, with the therapy monitored by frequent laboratory testing. Currently LMWH have broadly replaced UFH as first- choice anticoagulant due to more preferable pharmacokinetics and a better safety profile. Therapeutic anticoagulation with LMWH can be achieved by subcutaneous weight adapted application and measurement of anti-factor Xa- activity (anti-Xa) has been established as gold standard for LMWH- monitoring. However, since almost all LMWH dosing regimens have been developed empirically without laboratory monitoring, there is still a debate ongoing about the usefulness and impact of anti-Xa-testing. Data are lacking that prove a clear correlation between obtained levels of anti-Xa and the patients' clinical outcome. Newer methods have been developed aiming to determine a broader spectrum of LMWH depending anticoagulant activity. Even though there are some promising preliminary results, these alternative methods are not ready for routine clinical use yet. Nevertheless, current guidelines advise determination of anti-Xa in special patient populations with markedly altered LMWH metabolism or to exclude residual LMWH- activity before surgery at very high risk of bleeding. The aim of this article is to review critically the usefulness of anti- Xa guidance of LMWH- therapy and to give new perspectives on upcoming methods of LMWH- monitoring.

Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses.

PubMed

Rasmark Roepke, Emma; Hellgren, Margareta; Hjertberg, Ragnhild; Blomqvist, Lennart; Matthiesen, Leif; Henic, Emir; Lalitkumar, Sujata; Strandell, Annika

2018-03-30

Medical treatment of women with idiopathic recurrent pregnancy loss is controversial. The objective was to assess the effects of different treatments on live birth rates and complications in women with unexplained recurrent pregnancy loss. We searched MEDLINE, Embase and the Cochrane Library, and identified 1415 publications. This systematic review included 21 randomized controlled trials regarding acetylsalicylic acid, low-molecular-weight heparin, progesterone, intravenous immunoglobulin or leukocyte immune therapy in women with three or more consecutive miscarriages of unknown cause. The study quality was assessed and data was extracted independently by at least two authors. No significant difference in live birth rate was found when acetylsalicylic acid was compared with low-molecular-weight heparin or with placebo. Meta-analyses of low-molecular-weight heparin vs. control found no significant differences in live birth rate [risk ratio (RR) 1.47, 95% CI 0.83-2.61]. Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate (RR 1.18, 95% CI 1.09-1.27) but not when started after conception. Intravenous immunoglobulin showed no effect on live birth rate compared with placebo (RR 1.07, 95% CI 0.91-1.26). Paternal immunization compared with autologous immunization showed a significant difference in outcome (RR 1.8, 95% CI 1.34-2.41), although the studies were small and at high risk of bias. The literature does not allow advice on any specific treatment for idiopathic recurrent pregnancy loss, with the exception of progesterone starting from ovulation. We suggest that any treatment for recurrent pregnancy loss should be used within the context of a randomized controlled trial. © 2018 Nordic Federation of Societies of Obstetrics and Gynecology.

Complex Forms of Soil Organic Phosphorus-A Major Component of Soil Phosphorus.

PubMed

McLaren, Timothy I; Smernik, Ronald J; McLaughlin, Mike J; McBeath, Therese M; Kirby, Jason K; Simpson, Richard J; Guppy, Christopher N; Doolette, Ashlea L; Richardson, Alan E

2015-11-17

Phosphorus (P) is an essential element for life, an innate constituent of soil organic matter, and a major anthropogenic input to terrestrial ecosystems. The supply of P to living organisms is strongly dependent on the dynamics of soil organic P. However, fluxes of P through soil organic matter remain unclear because only a minority (typically <30%) of soil organic P has been identified as recognizable biomolecules of low molecular weight (e.g., inositol hexakisphosphates). Here, we use (31)P nuclear magnetic resonance spectroscopy to determine the speciation of organic P in soil extracts fractionated into two molecular weight ranges. Speciation of organic P in the high molecular weight fraction (>10 kDa) was markedly different to that of the low molecular weight fraction (<10 kDa). The former was dominated by a broad peak, which is consistent with P bound by phosphomonoester linkages of supra-/macro-molecular structures, whereas the latter contained all of the sharp peaks that were present in unfractionated extracts, along with some broad signal. Overall, phosphomonoesters in supra-/macro-molecular structures were found to account for the majority (61% to 73%) of soil organic P across the five diverse soils. These soil phosphomonoesters will need to be integrated within current models of the inorganic-organic P cycle of soil-plant terrestrial ecosystems.

Dalteparin: an update of its pharmacological properties and clinical efficacy in the prophylaxis and treatment of thromboembolic disease.

PubMed

Dunn, C J; Jarvis, B

2000-07-01

Dalteparin is a low molecular weight heparin (LMWH) with a mean molecular weight of 5000. Compared with unfractionated heparin (UFH), the drug has markedly improved bioavailability and increased plasma elimination half-life, and exerts a greater inhibitory effect on plasma activity of coagulation factor Xa relative to its effects on other coagulation parameters. Dalteparin also has less lipolytic activity than UFH. Dalteparin 2500U once daily subcutaneously is of similar antithrombotic efficacy to UFH 5000IU twice daily, and 2 studies have shown superiority over UFH 2 or 3 times daily of dalteparin 5000U once daily in patients requiring surgical thromboprophylaxis. After total hip arthroplasty, dalteparin was superior to adjusted-dosage warfarin and was of greater thromboprophylactic efficacy when given for 35 than for 7 days. Intravenous or subcutaneous dalteparin is as effective as intravenous UFH when given once or twice daily in the initial management of established deep vein thrombosis (DVT). The drug is also effective in long term home treatment. Dalteparin has been shown to be effective in combination with aspirin in the management of unstable coronary artery disease (CAD), with composite end-point data from 1 study suggesting benefit for up to 3 months. Current data indicate potential of the drug in the management of acute myocardial infarction (MI). Dalteparin is also of similar efficacy to UFH, with a single bolus dose being sufficient in some patients, in the prevention of clotting in haemodialysis and haemofiltration circuits. Pharmacoeconomic data indicate that overall costs relative to UFH from a hospital perspective can be reduced through the use of dalteparin in patients receiving treatment for venous thromboembolism. Dalteparin has also been shown to be cost effective when used for surgical thromboprophylaxis. Overall, rates of haemorrhagic complications in patients receiving dalteparin are low and are similar to those seen with UFH. Dalteparin is effective and well tolerated when given subcutaneously once daily in the prophylaxis and treatment of thromboembolic disease. The simplicity of the administration regimens used and the lack of necessity for laboratory monitoring facilitate home or outpatient treatment and appear to translate into cost advantages from a hospital perspective over UFH or warfarin. Dalteparin also maintains the patency of haemodialysis and haemofiltration circuits, with beneficial effects on blood lipid profiles and the potential for prophylaxis with a single bolus injection in some patients. Data are also accumulating to show dalteparin to be an effective and easily administered alternative to UFH in patients with CAD.

[Peripheral arterial thromboembolism in Crohn's disease].

PubMed

Ferrer, Isabel; Benavent, Guillem; Bastida, Guillermo; Arnau, Miguel Ángel; Iborra, Marisa; Beltrán, Belén; Aguas, Mariam; Hinojosa, Joaquín; Nos, Pilar

2013-01-01

Inflammatory Bowel Disease (IBD) usually affects the gastrointestinal tract, although some patients can also develop extraintestinal manifestations, such as vascular symptoms both venous and arterial ones. The former being more frequent than the latter. We report the case of a 62-year-old male, diagnosed of Crohńs disease (CD) (A3,L1+L4,B3), admitted to hospital for treatment of a retroperitoneal abscess. He presented a peripheral arterial thromboembolism during his stay, which required urgent embolectomy. After anticoagulation with low-molecular-weight heparin (LMWH), vascular magnetic resonance imaging revealed a large thrombus involving the descent aorta, which was solved with surgery and long-term anticoagulation. Peripheral arterial thrombosis is a rare extraintestinal manifestation of IBD. Nevertheless it is always important to consider it in patients with IBD. Prophylactic treatment should be made with low-molecular-weight heparin (LMWH) and definitive treatment with a combination of LMWH and surgery. Copyright © 2012 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

Effect of low molecular weight heparin rectal suppository on experimental ulcerative colitis in mice.

PubMed

Luo, Junyong; Cao, Jichao; Jiang, Xueliang; Cui, Huifei

2010-09-01

The objective of this study was to investigate the effect and possible mechanism of rectally administered low molecular weight heparin (LMWH) on experimental ulcerative colitis. LMWH rectal suppository was prepared and its efficacy was studied by macroscopical and histological scoring systems as well as myeloperoxidase activity. Serum levels, including tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and a link factor of blood coagulation and inflammation factor Xa (FXa) were assayed by enzyme-linked immunosorbent assay. The expression of Musashi-1 (as an intestinal stem cell marker) in the colons was assessed by immunohistochemical analysis. The results showed that LMWH rectal suppository significantly decreased serum levels of TNF-α, IL-6 as well as FXa, while increased the expression of Musashi-1 in colon compared with acetic acid induced ulcerative colitis model group. All these preliminary results indicate LMWH rectal suppository is promising for treatment of ulcerative colitis. 2010 Elsevier Masson SAS. All rights reserved.

The use of novel oral anticoagulants for thromboprophylaxis after elective major orthopedic surgery

PubMed Central

Rachidi, Saleh; Aldin, Ehab Saad; Greenberg, Charles; Sachs, Barton; Streiff, Michael; Zeidan, Amer M

2014-01-01

Venous thromboembolism is a common cause of morbidity and mortality among patients undergoing elective orthopedic surgery. Due to the high incidence of venous thromboembolism in this setting, perioperative anticoagulation is the recommended approach for thromboprophylaxis. Low molecular weight heparin (LMWH), fondaparinux and warfarin are the agents commonly used for thromboprophylaxis. The well-recognized limitations of warfarin and the inconvenience and discomfort associated with the subcutaneous administration of low molecular weight heparin and fondaparinux inspired intense investigation to develop novel oral anticoagulants (NOACs) with more predictable pharmacokinetics, fewer drug interactions and no need for regular laboratory monitoring. Three NOACs have been demonstrated to be effective for thromboprophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in large randomized controlled trials. Here we review the pharmacology of rivaroxaban, dabigatran, and apixaban, summarize the major clinical trials of these agents in thromboprophylaxis after THA and TKA, and discuss the clinical factors to be considered by providers when selecting a NOAC for their patients. PMID:24219550

Oral and parenteral anticoagulants: new kids on the block.

PubMed

Aditya, S

2012-01-01

Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms "anticoagulants", "blood coagulation inhibitors", "anticoagulants and venous thromboembolism", "anticoagulants and atrial fibrillation", and "'antithrombins." Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.

Diagnostic approach and management strategy of childhood stroke.

PubMed

Salih, Mustafa A; Abdel-Gader, Abdel-Galil M

2006-03-01

Prompt recognition and early intervention, with pertinent management and medication, may reduce subsequent neurologic deficits in stroke, which constitutes a devastating event in children. This is due to the tasking and demanding consequences including death or residual neurological deficits, which may last for many decades, in over 60% of survivors. Evidence-based treatment for children with stroke is still lacking, reflecting scarcity in baseline epidemiological data on pediatric stroke, the multitude of underlying risk factors, and the ethical and practical challenges incurred in conducting clinical trials. Based on the experience we gained from a combined prospective and retrospective study on childhood stroke (covering 10 years and 7 months and involving a cohort of 104 Saudi children), a diagnostic algorithm, which outlines the approach to a child with suspected stroke/cerebrovascular lesion, was designed. This algorithm might also be of use for managing other children with stroke from the Arabian Peninsula and Middle Eastern Region with similar demographic, socioeconomic, and ethnic backgrounds. Underlying risk factors, which need special attention, include thrombophilia and hypercoagulable states and sickle cell disease (SCD), which contrary to previous studies from Saudi Arabia, were found to constitute a common risk factor with severe manifestations. Other risk factors include infections (especially neurobrucellosis), cardiac diseases, and hypernatremic dehydration. Recognition of an identifiable syndrome or inherited metabolic cause may unravel an underlying cerebrovascular disease. This is particularly important in this region, given the large pool of autosomal recessive diseases and the high rate of consanguinity. In the evaluation of a suspected case of stroke, important imaging modalities include cranial CT, MRI (including diffusion-weighted images), magnetic resonance angiography (MRA), magnetic resonance venography (MRV) and conventional angiography. Transcranial Doppler sonography of the intracranial vessels and Duplex scan of the neck are valuable modalities for detecting large vessel vasculopathy, which occur in SCD, moyamoya syndrome, arterial dissection, and stenosis. Antithrombotic drugs are increasingly being used in the acute phase of childhood ischemic stroke. These include unfractionated heparin, low-molecular-weight heparins, aspirin or warfarin, or both. Specialized stroke care and follow-up are needed for children with stroke, as well as their families.

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Lung Heparin and Porcine Intestine Heparin.

PubMed

Guan, Yudong; Xu, Xiaohui; Liu, Xinyue; Sheng, Anran; Jin, Lan; Linhardt, Robert J; Chi, Lianli

2016-06-01

Currently porcine intestine is the only approved source for producing pharmaceutical heparin in most countries. Enoxaparin, prepared by benzylation and alkaline depolymerization from porcine intestine heparin, is prevalent in the anticoagulant drug market. It is predicted that porcine intestine heparin-derived enoxaparin (PIE) will encounter shortage, and expanding its production from heparins obtained from other animal tissues may, therefore, be inevitable. Bovine lung heparin is a potential alternative source for producing enoxaparin. Critical processing parameters for producing bovine lung heparin-derived enoxaparin (BLE) are discussed. Three batches of BLEs were prepared and their detailed structures were compared with PIEs using modern analytical techniques, including disaccharide composition, intact chain mapping by liquid chromatography-mass spectrometry and 2-dimensional nuclear magnetic resonance spectroscopy. The results suggested that the differences between PIEs and BLEs mainly result from N-acetylation differences derived from the parent heparins. In addition, bioactivities of BLEs were about 70% of PIEs based on anti-factor IIa and Xa chromogenic assays. We conclude that BLE has the potential to be developed as an analogue of PIE, although some challenges still remain. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12).

PubMed

Ulbricht, David; Oertwig, Kathrin; Arnsburg, Kristin; Saalbach, Anja; Pippel, Jan; Sträter, Norbert; Heiker, John T

2017-01-20

Many members of the serine protease inhibitor (serpin) family are activated by glycosaminoglycans (GAGs). Visceral adipose tissue-derived serpin (vaspin), serpin A12 of the serpin family, and its target protease kallikrein 7 (KLK7) are heparin-binding proteins, and inhibition of KLK7 by vaspin is accelerated by heparin. However, the nature of GAG binding to vaspin is not known. Here, we measured vaspin binding of various glycosaminoglycans and low molecular weight heparins by microscale thermophoresis and analyzed acceleration of protease inhibition by these molecules. In addition, basic residues contributing to heparin binding and heparin activation were identified by a selective labeling approach. Together, these data show that vaspin binds heparin with high affinity (K D = 21 ± 2 nm) and that binding takes place at a basic patch on top of β-sheet A and is different from other heparin-binding serpins. Mutation of basic residues decreased heparin binding and activation of vaspin. Similarly, reactive center loop insertion into sheet A decreased heparin binding because it disturbs the basic cluster. Finally, using vaspin-overexpressing keratinocyte cells, we show that a significant part of secreted vaspin is bound in the extracellular matrix on the cell surface. Together, basic residues of central β-sheet A contribute to heparin binding and activation of vaspin. Thus, binding to GAGs in the extracellular matrix can direct and regulate vaspin interaction with target proteases or other proteins and may play an important role in the various beneficial functions of vaspin in different tissues. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Interaction of antithrombin with sulfated, low molecular weight lignins: opportunities for potent, selective modulation of antithrombin function.

PubMed

Henry, Brian L; Connell, Justin; Liang, Aiye; Krishnasamy, Chandravel; Desai, Umesh R

2009-07-31

Antithrombin, a major regulator of coagulation and angiogenesis, is known to interact with several natural sulfated polysaccharides. Previously, we prepared sulfated low molecular weight variants of natural lignins, called sulfated dehydrogenation polymers (DHPs) (Henry, B. L., Monien, B. H., Bock, P. E., and Desai, U. R. (2007) J. Biol. Chem. 282, 31891-31899), which have now been found to exhibit interesting antithrombin binding properties. Sulfated DHPs represent a library of diverse noncarbohydrate aromatic scaffolds that possess structures completely different from heparin and heparan sulfate. Fluorescence binding studies indicate that sulfated DHPs bind to antithrombin with micromolar affinity under physiological conditions. Salt dependence of binding affinity indicates that the antithrombin-sulfated DHP interaction involves a massive 80-87% non-ionic component to the free energy of binding. Competitive binding studies with heparin pentasaccharide, epicatechin sulfate, and full-length heparin indicate that sulfated DHPs bind to both the pentasaccharide-binding site and extended heparin-binding site of antithrombin. Affinity capillary electrophoresis resolves a limited number of peaks of antithrombin co-complexes suggesting preferential binding of selected DHP structures to the serpin. Computational genetic algorithm-based virtual screening study shows that only one sulfated DHP structure, out of the 11 present in a library of plausible sequences, bound in the heparin-binding site with a high calculated score supporting selectivity of recognition. Enzyme inhibition studies indicate that only one of the three sulfated DHPs studied is a potent inhibitor of free factor VIIa in the presence of antithrombin. Overall, the chemo-enzymatic origin and antithrombin binding properties of sulfated DHPs present novel opportunities for potent and selective modulation of the serpin function, especially for inhibiting the initiation phase of hemostasis.

Interactions between nattokinase and heparin/GAGs.

PubMed

Zhang, Fuming; Zhang, Jianhua; Linhardt, Robert J

2015-12-01

Nattokinase (NK) is a serine protease extracted from a traditional Japanese food called natto. Due to its strong fibrinolytic and thrombolytic activity, NK is regarded as a valuable dietary supplement or nutraceutical for the oral thrombolytic therapy. In addition, NK has been investigated for some other medical applications including treatment of hypertension, Alzheimer's disease, and vitreoretinal disorders. The most widely used clinical anticoagulants are heparin and low molecular weight heparins. The interactions between heparin and proteins modulate diverse patho-physiological processes and heparin modifies the activity of serine proteases. Indeed, heparin plays important roles in almost all of NK's potential therapeutically applications. The current report relies on surface plasmon resonance spectroscopy to examine NK interacting with heparin as well as other glycosaminoglycans (GAGs). These studies showed that NK is a heparin binding protein with an affinity of ~250 nM. Examination with differently sized heparin oligosaccharides indicated that the interaction between NK and heparin is chain-length dependent and the minimum size for heparin binding is a hexasaccharide. Studies using chemically modified heparin showed the 6-O-sulfo as well as the N-sulfo groups but not the 2-O-sulfo groups within heparin, are essential for heparin's interaction with NK. Other GAGs (including HS, DS, and CSE) displayed modest binding affinity to NK. NK also interfered with other heparin-protein interactions, including heparin's interaction with antithrombin and fibroblast growth factors.

Can we produce heparin/heparan sulfate biomimetics using "mother-nature" as the gold standard?

PubMed

Farrugia, Brooke L; Lord, Megan S; Melrose, James; Whitelock, John M

2015-03-05

Heparan sulfate (HS) and heparin are glycosaminoglycans (GAGs) that are heterogeneous in nature, not only due to differing disaccharide combinations, but also their sulfate modifications. HS is well known for its interactions with various growth factors and cytokines; and heparin for its clinical use as an anticoagulant. Due to their potential use in tissue regeneration; and the recent adverse events due to contamination of heparin; there is an increased surge to produce these GAGs on a commercial scale. The production of HS from natural sources is limited so strategies are being explored to be biomimetically produced via chemical; chemoenzymatic synthesis methods and through the recombinant expression of proteoglycans. This review details the most recent advances in the field of HS/heparin synthesis for the production of low molecular weight heparin (LMWH) and as a tool further our understanding of the interactions that occur between GAGs and growth factors and cytokines involved in tissue development and repair.

Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer.

PubMed

Rada, Gabriel; Schünemann, Holger J; Labedi, Nawman; El-Hachem, Pierre; Kairouz, Victor F; Akl, Elie A

2013-02-14

Randomized controlled trials (RCTs) that are inappropriately designed or executed may provide biased findings and mislead clinical practice. In view of recent interest in the treatment and prevention of thrombotic complications in cancer patients we evaluated the characteristics, risk of bias and their time trends in RCTs of anticoagulation in patients with cancer. We conducted a comprehensive search, including a search of four electronic databases (MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL) up to February 2010. We included RCTs in which the intervention and/or comparison consisted of: vitamin K antagonists, unfractionated heparin (UFH), low molecular weight heparin (LMWH), direct thrombin inhibitors or fondaparinux. We performed descriptive analyses and assessed the association between the variables of interest and the year of publication. We included 67 RCTs with 24,071 participants. In twenty one trials (31%) DVT diagnosis was triggered by clinical suspicion; the remaining trials either screened for DVT or were unclear about their approach. 41 (61%), 22 (33%), and 11 (16%) trials respectively reported on major bleeding, minor bleeding, and thrombocytopenia. The percentages of trials satisfying risk of bias criteria were: adequate sequence generation (85%), adequate allocation concealment (61%), participants' blinding (39%), data collectors' blinding (44%), providers' blinding (41%), outcome assessors' blinding (75%), data analysts' blinding (15%), intention to treat analysis (57%), no selective outcome reporting (12%), no stopping early for benefit (97%). The mean follow-up rate was 96%. Adequate allocation concealment and the reporting of intention to treat analysis were the only two quality criteria that improved over time. Many RCTs of anticoagulation in patients with cancer appear to use insufficiently rigorous outcome assessment methods and to have deficiencies in key methodological features. It is not clear whether this reflects a problem in the design, conduct or the reporting of these trials, or both. Future trials should avoid the shortcomings described in this article.

[Treatment of the acute coronary syndrome in Germany: experiences in a German cluster of the GRACE registry].

PubMed

Tebbe, U; Bramlage, P; von Löwis of Menar, P; Lawall, H; Gaudron, P; Lüders, S; Klaus, A; Lengfelder, W; Scholz, K H; Maziejewski, S; Cuneo, A; Hohmann, V; Gulba, D

2007-09-01

The acute coronary syndrome (ACS) remains a major cause of mortality and morbidity in the western world. The Global Registry of Acute Coronary Events (GRACE) documents inpatients with all types of ACS and a follow-up at three months in Germany and worldwide. The data of the German Cluster Detmold were compared with data from the worldwide GRACE registry (31,070 patients). Data from 849 patients with ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) and unstable angina (UA) were collected from October 2001 to September 2005 in eight participating hospitals in the GRACE2 Cluster Detmold. Compared with the worldwide GRACE data the patients in the Cluster Detmold had longer pre-hospital admission times (STEMI patients < 1 h: 13.9 % vs. 17.0 %; p < 0.05); more frequent interventions (PCI 60.1 % vs. 48.7%; p < 0.001) and less thrombolysis (17.9 vs. 42.5%; p < 0.001) in STEMI patients; more frequent use of platelet inhibitors (clopidogrel and ticlopidine, 93.4 % vs. 89.4%; p < 0.001) and unfractionated heparin (69.8 % vs. 36.5; p < 0.001), and less frequent use of low molecular weight heparin (31.1 % vs. 51.2%; p < 0.001); more frequent use of RAS blocking agents (80.2 vs. 66.6, p < 0.001) and beta blockers (87.4 vs. 78.8, p < 0.001) and less frequent use of lipid lowering agents (23.5 vs. 72.5%; p < 0.001). Current management of ACS in Germany closely follows the recommendations of the German society of Cardiology. Differences in practice may account for the observed substantially lower event rates in Germany during hospitalization, but there is still room for improvement in the pre-hospital phase und in the degree to which pharmacotherapy is used for secondary prevention.

Coagulation Profile Changes Due to Thromboprophylaxis and Platelets in Trauma Patients at High-Risk for Venous Thromboembolism.

PubMed

Allen, Casey J; Murray, Clark R; Meizoso, Jonathan P; Ray, Juliet J; Teisch, Laura F; Ruiz, Xiomara D; Hanna, Mena M; Guarch, Gerardo A; Manning, Ronald J; Livingstone, Alan S; Ginzburg, Enrique; Schulman, Carl I; Namias, Nicholas; Proctor, Kenneth G

2015-07-01

We hypothesize there are coagulation profile changes associated both with initiation of thromboporphylaxis (TPX) and with change in platelet levels in trauma patients at high-risk for venous thromboembolism (VTE). A total of 1203 trauma intensive care unit patients were screened with a VTE risk assessment profile. In all, 302 high-risk patients (risk assessment profile score ≥ 10) were consented for weekly thromboelastography. TPX was initiated between initial and follow-up thromboelastography. Seventy-four patients were analyzed. Upon admission, 87 per cent were hypercoagulable, and 81 per cent remained hypercoagulable by Day 7 (P = 0.504). TPX was initiated 3.4 ± 1.4 days after admission; 68 per cent received unfractionated heparin and 32 per cent received low-molecular-weight heparin. The VTE rate was 18 per cent, length of stay 38 (25-37) days, and mortality of 17.6 per cent. In all, 76 per cent had a rapid clotting time at admission versus 39 per cent at Day 7 (P < 0.001); correcting from 7.75 (6.45-8.90) minutes to 10.45 (7.90-15.25) minutes (P < 0.001). At admission, 41 per cent had an elevated maximum clot formation (MCF) and 85 per cent had at Day 7 (P < 0.001); increasing from 61(55-65) mm to 75(69-80) mm (P < 0.001). Platelets positively correlated with MCF at admission (r = 0.308, R(2) = 0.095, P = 0.008) and at Day 7 (r = 0.516, R(2) = 0.266, P < 0.001). Change in platelet levels correlated with change in MCF (r = 0.332, R(2) = 0.110, P = 0.005). In conclusion, hypercoagulability persists despite the use of TPX. Although clotting time normalizes, MCF increases in correlation with platelet levels. As platelet function is a dominant contributor to sustained trauma-evoked hypercoagulability, antiplatelet therapy may be indicated in the management of severely injured trauma patients.

Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials.

PubMed

Wein, Lironne; Wein, Sara; Haas, Steven Joseph; Shaw, James; Krum, Henry

2007-07-23

There is uncertainty regarding which pharmacological agents most effectively prevent venous thromboembolism in hospitalized medical patients. We therefore performed a meta-analysis to determine this. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1950, 1966, and 1800, respectively, through June 30, 2006, for randomized controlled trials that involved medical patients comparing unfractionated heparin (UFH) or low-molecular-weight heparin or heparinoid (LMWH) with a control, LMWH with UFH, or selective factor Xa inhibitors with a comparator. Study selection, validity assessment, and data abstraction were performed by 2 independent reviewers (L.W. and S.W.). Data synthesis was undertaken by 1 blinded investigator (S.J.H.). Thirty-six studies were included. Compared with the control, UFH was associated with a reduced risk of deep venous thrombosis (DVT) (risk ratio [RR], 0.33; 95% confidence interval [CI], 0.26-0.42) and pulmonary embolism (RR, 0.64; 95% CI, 0.50-0.82), as was LMWH (RR, 0.56; 95% CI, 0.45-0.70; and RR, 0.37; 95% CI, 0.21-0.64, respectively). A UFH dosage of 5000 U 3 times daily was more effective in preventing DVT than a UFH dosage of 5000 U twice daily when compared with the control (RR, 0.27; 95% CI, 0.20-0.36; vs RR, 0.52; 95% CI, 0.28-0.96). Neither UFH nor LMWH reduced mortality. When directly compared with UFH, LMWH was associated with a lower risk of DVT (RR, 0.68; 95% CI, 0.52-0.88) and injection site hematoma (RR, 0.47; 95% CI, 0.36-0.62), but no difference was seen between the 2 agents in the risk of bleeding or thrombocytopenia. Both UFH and LMWH reduce venous thromboembolic risk in hospitalized medical patients, but neither agent alters mortality. When directly compared, LMWH is more effective in preventing DVT.

Slow versus fast subcutaneous heparin injections for prevention of bruising and site-pain intensity.

PubMed

Akbari Sari, Ali; Janani, Leila; Mohammady, Mina; Nedjat, Saharnaz

2014-07-18

Heparin is an anticoagulant medication that is normally injected subcutaneously. Subcutaneous administration of heparin may result in complications such as bruising, haematoma and pain at the injection site. One of the factors that may affect pain, haematoma and bruising is injection speed. To assess the effects of the duration (speed) of subcutaneous heparin injection on pain, haematoma and bruising at the injection site in people admitted to hospitals or clinics who require treatment with unfractionated heparin or low molecular weight heparin. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched August 2013) and CENTRAL (2013, Issue 7). We searched MEDLINE, EMBASE, CINAHL and two Persian databases Iranmedex and SID (August 2013). We sought randomised controlled trials (RCTs) comparing the effects of different durations of subcutaneous injections of heparin on pain, bruising and haematoma at the injection site. Two review authors, working independently, extracted data onto a structured form and assessed study quality. We used the criteria recommended by the Cochrane Handbook to assess the quality of included studies. The study outcomes were summarised using quantitative and qualitative methods. One RCT was identified which met the inclusion criteria, involving 50 participants with a mean age of 55.25 (± 12.37) years. In this trial it was not possible to blind the participants and care givers. The method of sequence generation and allocation concealment was not described. The overall quality of the evidence was moderate due to the single small included study. Each participant had two injections, one in the left side and one in right side of the abdomen. One of these was injected slowly (intervention) and the other was injected fast (control). The second injection was 12 hours after the first injection. The duration of fast injection was 10 seconds and the duration of slow injection was 30 seconds. The study reported a significantly lower pain intensity for slow versus fast injection. The mean pain intensity was 13.9 ± 17.1 mm with the slow injection and 20.6 ± 22.3 mm with the fast injection (P < 0.001). In addition the bruising sizes were smaller with slow injections compared to fast injections at 48 hours follow-up (mean bruising size 18.76 ± 9.32 mm(2) with the slow injection and 109.2 ± 468.66 mm(2) with the fast injection, P = 0.033) and 72 hours follow-up (mean bruising size 21.72 ± 76.16 mm(2) with the slow injection and 110.12 ± 472.86 mm(2) with the fast injection, P = 0.025). The incidence of haematoma was not measured as an outcome. There is only limited evidence of any difference in pain intensity and bruising sizes following slow versus fast injections due to the inclusion of only one small unblinded trial. The single included study suggests that slow injection might have slightly lower pain intensity and bruising size at the heparin injection site, but the results should be considered with caution. Until more reliable evidence emerges, slow injection might be the preferred approach.

Interactions between nattokinase and heparin/GAGs

PubMed Central

Zhang, Fuming

2015-01-01

Nattokinase (NK) is a serine protease extracted from a traditional Japanese food called natto. Due to its strong fibrinolytic and thrombolytic activity, NK is regarded as a valuable dietary supplement or nutraceutical for the oral thrombolytic therapy. In addition, NK has been investigated for some other medical applications including treatment of hypertension, Alzheimer’s disease, and vitreoretinal disorders. The most widely used clinical anticoagulants are heparin and low molecular weight heparins. The interactions between heparin and proteins modulate a diverse patho-physiological processes and heparin modifies the activity of serine proteases. Indeed, heparin plays important roles in almost all of NK’s potential therapeutically applications. The current report relies on surface plasmon resonance spectroscopy to examine NK interacting with heparin as well as other glycosaminoglycans (GAGs). These studies showed that NK is a heparin binding protein with an affinity of ~250 nM. Examination with differently sized heparin oligosaccharides indicated that the interaction between NK and heparin is chain-length dependent and the minimum size for heparin binding is a hexasaccharide. Studies using chemically modified heparin showed the 6-O-sulfo as well as the N-sulfo groups but not the 2-O-sulfo groups within heparin, are essential for heparin’s interaction with NK. Other GAGs (including HS, DS, and CSE) displayed modest binding affinity to NK. NK also interfered with other heparin-protein interactions, including heparin’s interaction with antithrombin and fibroblast growth factors. PMID:26412225

[Low molecular weight heparin and non valvular atrial fibrillation].

PubMed

Ederhy, S; Di Angelantonio, E; Meuleman, C; Janower, S; Boccara, F; Cohen, A

2006-12-01

Low molecular weight heparin (LMWH) are obtained through chemical or enzyme depolymerisation of unfractioned heparins (UFH). LMWHs present several advantages over UFH: they exhibit a smaller interindividual variability of the anticoagulant effect, they have a greater bioavailability, a longer plasma half-life and do not require monitoring of the anticoagulant effect. LMWH have restrictive indications in AF patients, cardioversion (II level C and TEE for ACC/AHA/ESC and 2C for ACCP guidelines) or use as a bridge therapy (IIB, level C for ACC/AHA/ESC). The ACE study (Anticoagulation for cardioversion using enoxaparin), showed a reduction, though not statistically significant, of 42% of the composite end point (embolic event, major bleeding and death) 2.8% under enoxaparin vs. 4.8 % under conventional treatment, relative risk 0.58, CI 95% 0.23-1.46). Other studies, using dalteparin, confirmed that an anticoagulant treatment using LMWH followed by warfarin was at least as good as conventional management. ACUTE II (Assessment of cardioversion using transesophageal echochardiography), a randomized multicenter trial, compared the efficacy and tolerance of enoxaparin (1 mg/kg every 12 hours) and UFH in 155 patients eligible for a TEE-guided cardioversion. These patients were administered LMWH or UFH for 24 hours before TEE or cardioversion. There were no significative differences regarding the incidence of the study end points, in particular stroke and bleeding, and no death occurred. HAEST (Heparin in acute embolic stroke trial), a randomized, placebo-controlled, double blind trial failed to show the LMWH superiority over aspirin in patients with acute ischemic stroke and atrial fibrillation. Finally, LMWH have been proposed as a bridge therapy in patients under chronic VKA prior to surgery or invasive procedures. This strategy resulted in a low rate of thromboembolic events and major bleedings.

Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation

PubMed Central

BARAM, D; RASHKOVSKY, M; HERSHKOVIZ, R; DRUCKER, I; RESHEF, T; BEN-SHITRIT, S; MEKORI, Y A

1997-01-01

There has been substantial evidence that suggests that heparin may modulate various aspects of immune function and inflammation in addition to its well known anticoagulant activity. In this regard heparin was found to suppress cell-mediated immune responses or asthmatic reactions to allergen challenge. In the present study we analyse the effects of low molecular weight heparin (LMWH) on mast cell degranulation and cytokine production in vitro and on the elicitation of IgE-mediated mast cell-dependent late cutaneous allergic inflammation in vivo. We have established that LMWH preferentially inhibited tumour necrosis factor-alpha (TNF-α) and IL-4 production without having any significant effect on mast cell degranulation. These effects have been observed in mast cells derived from three different origins that were activated by either immunological or non-immunological stimuli. We have shown that there is inhibition of TNF-α production (and not neutralization of activity), as elimination of the drug after a short preincubation and addition of LMWH to rTNF-α had no effect on TNF-α-mediated cytotoxic activity. These results were also confirmed by ELISA. In vivo, s.c. injection of the LMWH inhibited the leucocyte infiltration associated with the late cutaneous response which followed passive cutaneous anaphylaxis (PCA) reaction, without affecting mast cell numbers or degranulation. These data suggest that LMWH may have an inhibitory role in mast cell-mediated allergic inflammation, and thus might be considered as a possible therapeutic modality. PMID:9409655

Thromboprophylaxis patterns and determinants in critically ill patients: a multicenter audit

PubMed Central

2014-01-01

Introduction Heparin is safe and prevents venous thromboembolism in critical illness. We aimed to determine the guideline concordance for thromboprophylaxis in critically ill patients and its predictors, and to analyze factors associated with the use of low molecular weight heparin (LMWH), as it may be associated with a lower risk of pulmonary embolism and heparin-induced thrombocytopenia without increasing the bleeding risk. Methods We performed a retrospective audit in 28 North American intensive care units (ICUs), including all consecutive medical-surgical patients admitted in November 2011. We documented ICU thromboprophylaxis and reasons for omission. Guideline concordance was determined by adding days in which patients without contraindications received thromboprophylaxis to days in which patients with contraindications did not receive it, divided by the total number of patient-days. We used multilevel logistic regression including time-varying, center and patient-level covariates to determine the predictors of guideline concordance and use of LMWH. Results We enrolled 1,935 patients (62.3 ± 16.7 years, Acute Physiology and Chronic Health Evaluation [APACHE] II score 19.1 ± 8.3). Patients received thromboprophylaxis with unfractionated heparin (UFH) (54.0%) or LMWH (27.6%). Guideline concordance occurred for 95.5% patient-days and was more likely in patients who were sicker (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.17, 1.75 per 10-point increase in APACHE II), heavier (OR 1.32, 95% CI 1.05, 1.65 per 10-m/kg2 increase in body mass index), had cancer (OR 3.22, 95% CI 1.81, 5.72), previous venous thromboembolism (OR 3.94, 95% CI 1.46,10.66), and received mechanical ventilation (OR 1.83, 95% CI 1.32,2.52). Reasons for not receiving thromboprophylaxis were high risk of bleeding (44.5%), current bleeding (16.3%), no reason (12.9%), recent or upcoming invasive procedure (10.2%), nighttime admission or discharge (9.7%), and life-support limitation (6.9%). LMWH was less often administered to sicker patients (OR 0.65, 95% CI 0.48, 0.89 per 10-point increase in APACHE II), surgical patients (OR 0.41, 95% CI 0.24, 0.72), those receiving vasoactive drugs (OR 0.47, 95% CI 0.35, 0.64) or renal replacement therapy (OR 0.10, 95% CI 0.05, 0.23). Conclusions Guideline concordance for thromboprophylaxis was high, but LMWH was less commonly used, especially in patients who were sicker, had surgery, or received vasopressors or renal replacement therapy, representing a potential quality improvement target. PMID:24766968

Comparative effectiveness of venous thromboembolism prophylaxis options for the patient undergoing total hip and knee replacement: a network meta-analysis.

PubMed

Kapoor, A; Ellis, A; Shaffer, N; Gurwitz, J; Chandramohan, A; Saulino, J; Ishak, A; Okubanjo, T; Michota, F; Hylek, E; Trikalinos, T A

2017-02-01

Essentials Despite trial data, guidelines have not endorsed direct oral Xa inhibitors above other options. We provide profiles of venous thromboembolism and hemorrhage risk for 12 options. Direct oral Xa inhibitors had a favorable profile compared with low-molecular-weight heparin. Other options did not have favorable profiles compared with low-molecular-weight heparin. Background There are numerous trials and several meta-analyses comparing venous thromboembolism (VTE) prophylaxis options after total hip and knee replacement (THR and TKR). None have included simultaneous comparison of new with older options. Objective To measure simultaneously the relative risk of VTE and hemorrhage for 12 prophylaxis options. Methods We abstracted VTE and hemorrhage information from randomized controlled trials published between January 1990 and June 2016 comparing 12 prophylaxis options. We then constructed networks to compute the relative risk for each option, relative to once-daily dosing with low-molecular-weight heparin (LMWH) Low. Results Main: Relative to LMWH Low, direct oral Xa inhibitors had the lowest risk of total deep vein thrombosis (DVT)-asymptomatic and symptomatic- (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.35-0.57), translating to 53-139 fewer DVTs per 1000 patients. Vitamin K antagonists (VKAs) titrated to International Normalized Ratio [INR] 2-3 predicted 56% more DVT events (OR, 1.56; 95% CI, 1.14-2.14). Aspirin performed similarly (OR, 0.80; 95% CI, 0.34-1.86), although small numbers prohibit firm conclusions. Direct oral Xa inhibitors did not lead to significantly more bleeding (OR, 1.21; 95% CI, 0.79-1.90). Secondary: Relative to LMWH Low, direct oral Xa inhibitors prevented 4-fold more symptomatic DVTs (OR, 0.25; 95% CI, 0.13-0.47). Conclusions Relative to LMWH Low, direct oral Xa inhibitors had a more favorable profile of VTE and hemorrhage risk, whereas VKAs had a less favorable profile. The profile of other agents was not more or less favorable. Clinicians should consider these profiles when selecting prophylaxis options. © 2016 International Society on Thrombosis and Haemostasis.

Clinical Efficacy of Low Molecular Heparin on Unexplained Recurrent Spontaneous Abortion.

PubMed

Xu, Guang-Li; Hu, Xiao-Fang; Han, Yong-Mei; Wei, Ai-Wu

2018-06-01

To study the clinical effect of low molecular heparin on unexplained recurrent spontaneous abortion (URSA). A total of 120 URSA patients were collected in our hospital from October 2015 to September 2017. They were divided into two groups: control group (n = 60) and observation group (n = 60). The patients in the control group were administered with progesterone and human chorionic gonadotropin, and the observation group with low molecular heparin. Pregnancy outcomes, incidence of complications in pregnancy and adverse drug reactions were compared in the two groups. The pregnancy success rate of patients in the observation group (90.00%) is higher than that in the control group (68.33%) (p < 0.05). The incidence of complications in pregnancy in the observation group (90.00%) is lower than those in the control group (68.33%) (p < 0.05). The incidence of adverse drug reactions between the patients in the observation group (20.00%) and those in the control group (23.33%) showed no significant difference (p > 0.05). Low molecular heparin treatment can improve pregnancy success rate and reduce the incidence of complications in the URSA patients. Low molecular heparin is characterized by safety and reliability and has potential for application in clinic.

Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo

PubMed Central

Mellor, P; Harvey, J R; Murphy, K J; Pye, D; O'Boyle, G; Lennard, T W J; Kirby, J A; Ali, S

2007-01-01

Expression of the chemokine receptor CXCR4 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express CXCL12. In this study, we determined whether this interaction could be disrupted using short-chain length heparin oligosaccharides. Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I125 CXCL12. Heparin dodecasaccharides were found to be the minimal chain length required to efficiently bind CXCL12 (71% inhibition; P<0.001). These oligosaccharides also significantly inhibited CXCL12-induced migration of CXCR4-expressing LMD MDA-MB 231 breast cancer cells. In addition, heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product, Tinzaparin. When given subcutaneously in a SCID mouse model of human breast cancer, heparin dodecasaccharides had no effect on the number of lung metastases, but did however inhibit (P<0.05) tumour growth (lesion area) compared to control groups. In contrast, polymeric heparin significantly inhibited both the number (P<0.001) and area of metastases, suggesting a differing mechanism for the action of polymeric and heparin-derived oligosaccharides in the inhibition of tumour growth and metastases. PMID:17726466

Heparin-induced thrombocytopenia

PubMed Central

Shaikh, Nissar

2011-01-01

In the last 7 decades heparin has remained the most commonly used anticoagulant. Its use is increasing, mainly due to the increase in the number of vascular interventions and aging population. The most feared complication of heparin use is heparin-induced thrombocytopenia (HIT). HIT is a clinicopathologic hypercoagulable, procoagulant prothrombotic condition in patients on heparin therapy, and decrease in platelet count by 50% or to less than 100,000, from 5 to 14 days of therapy. This prothrombotic hypercoagulable state in HIT patient is due to the combined effect of various factors, such as platelet activation, mainly the formation of PF4/heparin/IgG complex, stimulation of the intrinsic factor, and loss of anticoagulant effect of heparin. Diagnosis of HIT is done by clinical condition, heparin use, and timing of thrombocytopenia, and it is confirmed by either serotonin release assay or ELISA assay. Complications of HIT are venous/arterial thrombosis, skin gangrene, and acute platelet activation syndrome. Stopping heparin is the basic initial treatment, and Direct Thrombin Inhibitors (DTI) are medication of choice in these patients. A few routine but essential procedures performed by using heparin are hemodialysis, Percutaneous Coronary Intervention, and Cardiopulmonary Bypass; but it cannot be used if a patient develops HIT. HIT patients with unstable angina, thromboembolism, or indwelling devices, such as valve replacement or intraaortic balloon pump, will require alternative anticoagulation therapy. HIT can be prevented significantly by keeping heparin therapy shorter, avoiding bovine heparin, using low-molecular weight heparin, and stopping heparin use for flush and heparin lock. PMID:21633576

Cellular trafficking of low molecular weight heparin incorporated in layered double hydroxide nanoparticles in rat vascular smooth muscle cells.

PubMed

Gu, Zi; Rolfe, Barbara E; Thomas, Anita C; Campbell, Julie H; Lu, G Q Max; Xu, Zhi P

2011-10-01

This paper reports a clear elucidation of the pathway for the cellular delivery of layered double hydroxide (LDH) nanoparticles intercalated with anti-restenotic low molecular weight heparin (LMWH). Cellular uptake of LMWH-LDH conjugates into cultured rat vascular smooth muscle cells (SMCs) measured via flow cytometry was more than ten times greater than that of LMWH alone. Confocal and transmission electron microscopy showed LMWH-LDH conjugates taken up by endosomes, then released into the cytoplasm. We propose that LMWH-LDH is taken up via a unique 'modified endocytic' pathway, whereby the conjugate is internalized by SMCs in early endosomes, sorted in late endosomes, and quickly released from late endosomes/lysosomes, avoiding degradation. Treatment of cells with LMWH-LDH conjugates suppressed the activation of ERK1/2 in response to foetal calf serum (FCS) for up to 24h, unlike unconjugated LMWH which had no significant effect at 24h. Improved understanding of the intracellular pathway of LMWH-LDH nanohybrids in SMC will allow for refinement of design for LDH nanomedicine applications. Copyright © 2011 Elsevier Ltd. All rights reserved.

Non-obstructive prosthetic aortic valve thrombosis presenting with acute myocardial infarction and stroke in a patient with inadequate low-molecular-weight heparin treatment. The unlucky patient and the (pseudo)prudent physician.

PubMed

Paci, Anna Maria; Lattanzi, Fabio; Cabani, Enrico; Conti, Umberto; De Tommasi, Salvatore Mario

2007-04-01

Non-obstructive prosthetic valve thrombosis is a rare and underestimated complication in patients with left-sided mechanical heart valves. Systemic embolisation, mainly involving the cerebral circulation, often represents the first clinical manifestation. We report a case of multiple, successive embolizations in the coronary and cerebral circulation, presenting with an acute myocardial infarction and stroke in a patient with latent, non-obstructive thrombosis of a mechanical bileaflet aortic valve. Because of scheduled urological surgery, chronic vitamin K antagonist treatment had previously been discontinued and replaced with low-molecular-weight heparin, at inadequate dosage. Following coronary arteriography, brain computed tomography scan and transoesophageal echocardiography, thrombolysis was performed successfully. This case emphasises the utility of performing transoesophageal echocardiography routinely in the presence of ischaemic signs in patients with mechanical heart valves. In patients requiring discontinuation of oral anticoagulant therapy, accurate management and continuous monitoring of alternative medications are needed in order to avoid severe thromboembolic complications.

Low-molecular-weight fucoidan regulates myogenic differentiation through the mitogen-activated protein kinase pathway in C2C12 cells.

PubMed

Kim, Kui-Jin; Lee, Ok-Hwan; Lee, Boo-Yong

2011-12-01

Low-molecular-weight fucoidan (LMWF) has been broadly studied in recent years due to its numerous biological properties. Nevertheless, there have been no reports about the effects of LMWF on myogenic differentiation (MyoD). The objective of the present study was to demonstrate the impact of LMWF on myogenesis in C2C12 cells. The ultimate aim was to establish whether LMWF regulates myogenesis similar to heparin as a partial regulator of myogenesis. LMWF was prepared at a minimal size by ultra-filtration compared with crude fucoidan. We treated C2C12 cells with LMWF and/or heparin during MyoD. The data from the present study are the first to suggest that LMWF suppresses the expression of the myogenic regulatory factors and the myocyte enhancer factors as well as the morphological changes that occur during differentiation. Additionally, the expression of the mitogen-activated protein kinase (MAPK) family was significantly inhibited by LMWF when compared with controls. The LMWF-treated group showed significantly decreased expression of reactive oxygen species (ROS) enzymes compared with control cells. Heparin was used as a positive control because it has been reported to activate MyoD. Taken together, these results suggest that LMWF might regulate MyoD through the MAPK pathway and by regulating ROS activity in C2C12 cells.

Structural and binding studies of SAP-1 protein with heparin.

PubMed

Yadav, Vikash K; Mandal, Rahul S; Puniya, Bhanwar L; Kumar, Rahul; Dey, Sharmistha; Singh, Sarman; Yadav, Savita

2015-03-01

SAP-1 is a low molecular weight cysteine protease inhibitor (CPI) which belongs to type-2 cystatins family. SAP-1 protein purified from human seminal plasma (HuSP) has been shown to inhibit cysteine and serine proteases and exhibit interesting biological properties, including high temperature and pH stability. Heparin is a naturally occurring glycosaminoglycan (with varied chain length) which interacts with a number of proteins and regulates multiple steps in different biological processes. As an anticoagulant, heparin enhances inhibition of thrombin by the serpin antithrombin III. Therefore, we have employed surface plasmon resonance (SPR) to improve our understanding of the binding interaction between heparin and SAP-1 (protease inhibitor). SPR data suggest that SAP-1 binds to heparin with a significant affinity (KD = 158 nm). SPR solution competition studies using heparin oligosaccharides showed that the binding of SAP-1 to heparin is dependent on chain length. Large oligosaccharides show strong binding affinity for SAP-1. Further to get insight into the structural aspect of interactions between SAP-1 and heparin, we used modelled structure of the SAP-1 and docked with heparin and heparin-derived polysaccharides. The results suggest that a positively charged residue lysine plays important role in these interactions. Such information should improve our understanding of how heparin, present in the reproductive tract, regulates cystatins activity. © 2014 John Wiley & Sons A/S.

Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial.

PubMed

Fowler, Robert A; Mittmann, Nicole; Geerts, William H; Heels-Ansdell, Diane; Gould, Michael K; Guyatt, Gordon; Krahn, Murray; Finfer, Simon; Pinto, Ruxandra; Chan, Brian; Ormanidhi, Orges; Arabi, Yaseen; Qushmaq, Ismael; Rocha, Marcelo G; Dodek, Peter; McIntyre, Lauralyn; Hall, Richard; Ferguson, Niall D; Mehta, Sangeeta; Marshall, John C; Doig, Christopher James; Muscedere, John; Jacka, Michael J; Klinger, James R; Vlahakis, Nicholas; Orford, Neil; Seppelt, Ian; Skrobik, Yoanna K; Sud, Sachin; Cade, John F; Cooper, Jamie; Cook, Deborah

2014-12-20

Venous thromboembolism (VTE) is a common complication of critical illness with important clinical consequences. The Prophylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) is a multicenter, blinded, randomized controlled trial comparing the effectiveness of the two most common pharmocoprevention strategies, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) dalteparin, in medical-surgical patients in the intensive care unit (ICU). E-PROTECT is a prospective and concurrent economic evaluation of the PROTECT trial. The primary objective of E-PROTECT is to identify and quantify the total (direct and indirect, variable and fixed) costs associated with the management of critically ill patients participating in the PROTECT trial, and, to combine costs and outcome results to determine the incremental cost-effectiveness of LMWH versus UFH, from the acute healthcare system perspective, over a data-rich time horizon of ICU admission and hospital admission. We derive baseline characteristics and probabilities of in-ICU and in-hospital events from all enrolled patients. Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costs include medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative and non-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirect costs include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incremental effects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primary outcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episode of heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiary outcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimates of incremental cost-effectiveness will be obtained using bootstrapping. This economic evaluation employs a prospective costing methodology concurrent with a randomized controlled blinded clinical trial, with a pre-specified analytic plan, outcome measures, subgroup and sensitivity analyses. This economic evaluation has received only peer-reviewed funding and funders will not play a role in the generation, analysis or decision to submit the manuscripts for publication. Clinicaltrials.gov Identifier: NCT00182143 . Date of registration: 10 September 2005.

Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery.

PubMed

Peng, Yifeng; Tellier, Liane E; Temenoff, Johnna S

2016-08-16

Sustained release of anti-inflammatory agents remains challenging for small molecule drugs due to their low molecular weight and hydrophobicity. Therefore, the goal of this study was to control the release of a small molecule anti-inflammatory agent, crystal violet (CV), from hydrogels fabricated with heparin, a highly sulfated glycosaminoglycan capable of binding positively-charged molecules such as CV. In this system, both electrostatic interactions between heparin and CV and hydrogel degradation were tuned simultaneously by varying the level of heparin sulfation and varying the amount of dithiothreitol within hydrogels, respectively. It was found that heparin sulfation significantly affected CV release, whereby more sulfated heparin hydrogels (Hep and Hep(-N)) released CV with near zero-order release kinetics (R-squared values between 0.96-0.99). Furthermore, CV was released more quickly from fast-degrading hydrogels than slow-degrading hydrogels, providing a method to tune total CV release between 5-15 days while maintaining linear release kinetics. In particular, N-desulfated heparin hydrogels exhibited efficient CV loading (∼90% of originally included CV), near zero-order CV release kinetics, and maintenance of CV bioactivity after release, making this hydrogel formulation a promising CV delivery vehicle for a wide range of inflammatory diseases.

Low-molecular-weight-heparin can benefit women with recurrent pregnancy loss and sole protein S deficiency: a historical control cohort study from Taiwan.

PubMed

Shen, Ming-Ching; Wu, Wan-Ju; Cheng, Po-Jen; Ma, Gwo-Chin; Li, Wen-Chu; Liou, Jui-Der; Chang, Cheng-Shyong; Lin, Wen-Hsiang; Chen, Ming

2016-01-01

Heritable thrombophilias are assumed important etiologies for recurrent pregnancy loss. Unlike in the Caucasian populations, protein S and protein C deficiencies, instead of Factor V Lieden and Prothrombin mutations, are relatively common in the Han Chinese population. In this study we aimed to investigate the therapeutic effect of low molecular weight heparin upon women with recurrent pregnancy loss and documented protein S deficiency. During 2011-2016, 68 women with recurrent pregnancy loss (RPL) and protein S deficiency (both the free antigen and function of protein S were reduced) were initially enrolled. All the women must have experienced at least three recurrent miscarriages. After excluding those carrying balanced translocation, medical condition such as diabetes mellitus, chronic hypertension, and autoimmune disorders (including systemic lupus erythematosus and anti-phospholipid syndrome), coexisting thrombophilias other than persistent protein S deficiency (including transient low protein S level, protein C deficiency, and antithrombin III), only 51 women with RPL and sole protein S deficiency were enrolled. Initially they were prescribed low dose Aspirin (ASA: 100 mg/day) and unfortunately there were still 39 women ended up again with early pregnancy loss (12 livebirths were achieved though). Low-molecular-weight-heparin (LMWH) was given for the 39 women in a dose of 1 mg/Kg every 12 h from the day when the next clinical pregnancy was confirmed to the timing at least 24 h before delivery. The perinatal outcomes were assessed. Of 50 treatment subjects performed for the 39 women (i.e. 11 women enrolled twice for two pregnancies), 46 singletons and one twin achieved livebirths. The successful live-birth rate in the whole series was 94 % (47/50). Nineteen livebirths delivered vaginally whereas 28 delivered by cesarean section. The cesarean delivery rate is thus 59.57 %. Emergent deliveries occurred in 3 but no postpartum hemorrhage had been noted. Our pilot study in Taiwan, an East Asian population, indicated anti-coagulation therapy is of benefit to women with recurrent pregnancy loss who had documented sole protein S deficiency. ISRCTN64574169. Retrospectively registered 29 Jun 2016.

Heparin-associated thrombocytopenia: antibody binding specificity to platelet antigens.

PubMed

Lynch, D M; Howe, S E

1985-11-01

Sera from four patients with heparin-associated thrombocytopenia (HAT) were evaluated by a quantitative enzyme-linked immunosorbent assay (ELISA) to detect heparin-dependent serum platelet-bindable immunoglobulin (S-PBIg) and by Western blotting and immunoprecipitation to investigate the specificity of the antibody binding. All HAT sera showed mildly increased S-PBIg (mean, 7.8 fg per platelet; normal, less than 6.0 fg per platelet) to intact target platelets in the ELISA, which was markedly increased in the presence of heparin (mean, 20.9 fg per platelet). This increase was 20-fold greater than normal control sera, which showed a mean differential increase of only 0.5 fg per platelet. Immunoglobulin binding specificity to platelet antigens was investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis of platelet lysate with transfer of the platelet fractions onto nitrocellulose strips (Western blotting) and subsequent immunoassay using HAT and normal sera. In the presence of heparin, the four HAT patients demonstrated increased binding of immunoglobulin to platelet antigens of apparent molecular weights of 180, 124, and 82 kd. Radiolabeled heparin when incubated with HAT sera, normal sera, or albumin blanks bound to platelet proteins of the same apparent molecular weights. These observations are consistent with current hypotheses suggesting that HAT antibody is directed to heparin-platelet complexes or, alternatively, that heparin induces conformational change of antigenic sites on the platelet membrane.

The anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban or rivaroxaban.

PubMed

Brendel, L C; Dobler, F; Hessling, G; Michel, J; Braun, S L; Steinsiek, A L; Groha, P; Eckl, R; Deisenhofer, I; Hyseni, A; Roest, M; Ott, I; Steppich, B

2017-09-01

Measuring the anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban and rivaroxaban is challenging, since the activated coagulation time (ACT) does not seem to reflect the true anticoagulant activity of these drugs. We therefore evaluated coagulation properties of apixaban and rivaroxaban during RFA by different coagulation assays to better monitor periprocedural hemostasis. The study included 90 patients (61 ± 12 years) with atrial fibrillation who underwent RFA procedures. Patients received 20 mg rivaroxaban (n = 73) once or 5 mg apixaban (n = 17) twice daily 4 weeks prior to the procedure. During RFA, unfractionated heparin i.v. was given to maintain an ACT of 250-300 s. Blood samples were taken before and 10, 60, and 360 min after heparin administration. Heparin displayed a lower anti-Xa activity in rivaroxaban-treated patients compared to apixaban-treated patients. In contrast, D-dimer and prothrombin fragment F1+2 plasma levels indicated a higher activation of the coagulation cascade in apixaban/heparin than in rivaroxaban/heparin patients. This discordant coagulative state measured in vitro had no clinical impact in terms of bleeding or thromboembolic complications. We found different biochemical responses to rivaroxaban/heparin and apixaban/heparin during RFA. Precaution is necessary when monitoring periprocedural hemostasis in DOAC patients to avoid mismanagement.

Low-molecular-weight heparin and intermittent pneumatic compression for thromboprophylaxis in critical patients

PubMed Central

WAN, BING; FU, HAI-YAN; YIN, JIANG-TAO; REN, GUO-QING

2015-01-01

The efficacy and safety of physiotherapeutic prophylaxis for venous thromboembolism in critically ill patients with heparin contraindication remains unclear. In the present study it was hypothesized that physiotherapy prophylaxis with intermittent pneumatic compression (IPC) would be safe and effective for patients unable to receive low-molecular-weight heparin (LMWH). In addition, this study investigated whether a combined therapy of IPC with LMWH would be more effective for the prophylaxis of deep vein thrombosis (DVT) in critical patients. A total of 500 patients were divided into four groups according to the prophylaxis of DVT. The IPC group consisted of 95 patients with heparin contraindication that received IPC treatment; the LMWH group consisted of 185 patients that received an LMWH injection; the LMWH + IPC group consisted of 75 patients that received IPC treatment and LMWH injection; and the control group consisted of 145 patients that received no IPC treatment or injection of LMWH. Each patient was evaluated clinically for development of DVT and the diagnosis was confirmed by Doppler study. Venous thromboembolism was a common complication among the trauma patients with severe injuries. Patients responded positively to the treatment used in the intervention groups. Patients exhibited an improved response to LMWH + ICP compared with IPC or LMWH alone, while no significant difference was detected between the IPC and LMWH groups. These results were applicable to patients that had a Wells score of ≥3; however, no significant differences in DVT incidence were observed among the patients who had a Wells score of <3. In this observational study, LMWH + ICP appeared to be more effective than either treatment alone in treating critically ill trauma patients with severe injuries that are at high risk for VTE and bleeding simultaneously. PMID:26668637

Multifunctional and biologically active matrices from multicomponent polymeric solutions

NASA Technical Reports Server (NTRS)

Kiick, Kristi L. (Inventor); Yamaguchi, Nori (Inventor); Rabolt, John (Inventor); Casper, Cheryl (Inventor)

2012-01-01

A functionalized electrospun matrix for the controlled-release of biologically active agents, such as growth factors, is presented. The functionalized matrix comprises a matrix polymer, a compatibilizing polymer and a biomolecule or other small functioning molecule. In certain aspects the electrospun polymer fibers comprise at least one biologically active molecule functionalized with low molecular weight heparin.

Measuring Anti–Factor Xa Activity to Monitor Low-Molecular-Weight Heparin in Obesity: A Critical Review

PubMed Central

Egan, Gregory; Ensom, Mary H H

2015-01-01

Background: The choice of whether to monitor anti–factor Xa (anti-Xa) activity in patients who are obese and who are receiving low-molecular-weight heparin (LMWH) therapy is controversial. To the authors’ knowledge, no systematic review of monitoring of anti-Xa activity in such patients has been published to date. Objective: To systematically ascertain the utility of monitoring anti-Xa concentrations for LMWH therapy in obese patients. Data Sources: MEDLINE (1946 to September 2014), the Cochrane Database of Systematic Reviews, Embase (1974 to September 2014), PubMed (1947 to September 2014), International Pharmaceutical Abstracts (1970 to September 2014), and Scopus were searched using the terms obesity, morbid obesity, thrombosis, venous thrombosis, embolism, venous thromboembolism, pulmonary embolism, low-molecular weight heparin, enoxaparin, dalteparin, tinzaparin, anti-factor Xa, anti-factor Xa monitoring, anti-factor Xa activity, and anti-factor Xa assay. The reference lists of retrieved articles were also reviewed. Study Selection and Data Extraction: English-language studies describing obese patients treated with LMWH or reporting anti-Xa activity were reviewed using a 9-step decision-making algorithm to determine whether monitoring of LMWH therapy by means of anti-Xa activity in obesity is warranted. Studies published in abstract form were excluded. Data Synthesis: The analysis showed that anti-Xa concentrations are not strongly associated with thrombosis or hemorrhage. In clinical studies of LMWH for thromboprophylaxis in bariatric surgery, orthopedic surgery, general surgery, and medical patients, and for treatment of venous thrombo embolism and acute coronary syndrome, anti-Xa activity can be predicted from dose of LMWH and total body weight; no difference in clinical outcome was found between obese and non-obese participants. Conclusions: Routinely determining anti-Xa concentrations in obese patients to monitor the clinical effectiveness of LMWH is not warranted on the basis of the current evidence. Circumstances where measurement of anti-Xa concentration may help in clinical decision-making in either obese or non-obese patients would be cases where elimination of LMWH is impaired or there is an unexpected clinical response, as well as to confirm compliance with therapy or to identify deviation from predicted pharmacokinetics. PMID:25762818

Incidence and diagnosis of heparin-induced thrombocytopenia (HIT) in patients with traumatic injuries treated with unfractioned or low-molecular-weight heparin: a literature review.

PubMed

Bloemen, A; Testroote, M J G; Janssen-Heijnen, M L G; Janzing, H M J

2012-05-01

The incidence of thromboembolic complications after major traumatic injuries is high (>50%). Thromboprophylaxis, often by low-molecular-weight heparin (LMWH) or unfractioned heparin (UH) is therefore routinely administered. Thromboprophylaxis is also advised after immobilisation for isolated lower leg injuries. Heparin induced thrombocytopenia (HIT) is a rare but very serious immune mediated complication of treatment with LMWH, which can cause potentially fatal thromboembolism. In the general medical and surgical population the incidence of HIT is 0.2%. Little is known about the incidence of HIT and value of screening in trauma patients and in isolated lower extremity injuries. Therefore, we performed a systematic literature review. The online databases Medline and EMBASE were searched independently by two authors. Manuscripts were selected for analysis by quantitative and qualitative selection. After eliminating duplicate articles and irrelevant studies, seven relevant papers reporting on the incidence of HIT in trauma patients were identified and two studies reported the incidence of HIT in patients with lower leg injuries. The selected papers varied in study design: three randomised controlled trials, three cohort studies and one case report were identified. The methodological quality of the studies varied. In a total population of 1920 patients, HIT was identified in seven patients (0.36%). Pooling of data was impossible due to heterogeneity in study design and populations. No HIT was reported in 826 patients with lower extremity injuries, requiring immobilisation. Only a few studies have reported on the incidence of HIT in trauma patients who receive prophylactic LMWH. In the heterogenous populations of the available studies, the incidence of HIT appears to be very low and comparable to other patient populations. There is hardly any literature on the incidence of HIT in patients with isolated lower leg injuries receiving LMWH, but incidence seems to be very low. The incidence of HIT in trauma patients who receive LMWH thromboprophylaxis appears to be low (0.36%). Incidence of HIT in patients with isolated lower leg injuries receiving LMWH seems very low. Monitoring of platelet count could be considered in hospitalised patients with a high risk for development of HIT. A pre-test scoring system may identify these patients. Copyright © 2011. Published by Elsevier Ltd.

Top-down approach for the direct characterization of low molecular weight heparins using LC-FT-MS.

PubMed

Li, Lingyun; Zhang, Fuming; Zaia, Joseph; Linhardt, Robert J

2012-10-16

Low molecular heparins (LMWHs) are structurally complex, heterogeneous, polydisperse, and highly negatively charged mixtures of polysaccharides. The direct characterization of LMWH is a major challenge for currently available analytical technologies. Electrospray ionization (ESI) liquid chromatography-mass spectrometry (LC-MS) is a powerful tool for the characterization complex biological samples in the fields of proteomics, metabolomics, and glycomics. LC-MS has been applied to the analysis of heparin oligosaccharides, separated by size exclusion, reversed phase ion-pairing chromatography, and chip-based amide hydrophilic interaction chromatography (HILIC). However, there have been limited applications of ESI-LC-MS for the direct characterization of intact LMWHs (top-down analysis) due to their structural complexity, low ionization efficiency, and sulfate loss. Here we present a simple and reliable HILIC-Fourier transform (FT)-ESI-MS platform to characterize and compare two currently marketed LMWH products using the top-down approach requiring no special sample preparation steps. This HILIC system relies on cross-linked diol rather than amide chemistry, affording highly resolved chromatographic separations using a relatively high percentage of acetonitrile in the mobile phase, resulting in stable and high efficiency ionization. Bioinformatics software (GlycReSoft 1.0) was used to automatically assign structures within 5-ppm mass accuracy.

LMW Heparin Prevents Increased Kidney Expression of Proinflammatory Mediators in (NZBxNZW)F1 Mice

PubMed Central

Kanapathippillai, Premasany; Rekvig, Ole Petter; Fenton, Kristin Andreassen

2013-01-01

We have previously demonstrated that continuous infusion of low molecular weight (LMW) heparin delays autoantibody production and development of lupus nephritis in (NZBxNZW)F1 (B/W) mice. In this study we investigated the effect of LMW heparin on renal cytokine and chemokine expression and on nucleosome-mediated activation of nucleosome-specific splenocytes. Total mRNA extracted from kidneys of heparin-treated or -untreated B/W mice was analysed by qPCR for the expression of several cytokines, chemokines, and Toll-like receptors. Splenocytes taken from B/W mice were stimulated with nucleosomes with or without the presence of heparin. Splenocyte cell proliferation as thymidine incorporation and the expression of costimulatory molecules and cell activation markers were measured. Heparin treatment of B/W mice reduced the in vivo expression of CCR2, IL1β, and TLR7 compared to untreated B/W mice. Nucleosome-induced cell proliferation of splenocytes was not influenced by heparin. The expression of CD80, CD86, CD69, CD25, CTLA-4, and TLR 2, 7, 8, and 9 was upregulated upon stimulation by nucleosomes, irrespective of whether heparin was added to the cell culture or not. In conclusion, treatment with heparin lowers the kidney expression of proinflammatory mediators in B/W mice but does not affect nucleosomal activation of splenocytes. PMID:24151519

[CBO guideline 'Deep venous thrombosis and pulmonary embolism; revision of the earlier guidelines. Dutch Organization for Quality Assurance in Hospitals].

PubMed

Büller, H R; van der Meer, J; Oudkerk, M

2000-08-05

Diagnosis of clinically suspected deep venous thrombosis is based on a clinical score, serial compression ultrasonography and D-dimer assay. For the diagnosis of pulmonary embolism perfusion scintigraphy, ventilation scintigraphy, echography of the leg veins and pulmonary angiography in that order lead to the lowest mortality, morbidity and costs. Diagnostics with spiral CT followed by pulmonary angiography leads to equal mortality and fewer angiography procedures. Decision rules based on anamnesis, physical examination, blood gas analysis and chest radiograph have proved to be insufficiently reliable. The present D-dimer assays have too little sensitivity and too much variability. Thrombo-prophylaxis with low-molecular-weight heparin is indicated for general surgery, joint replacement of the knee or hip, cranial and spinal surgery, subarachnoid haemorrhage after surgical treatment of an aneurysm, acute myocardial infarction, ischaemic stroke or spinal cord lesion, intensive care patients, patients with acute paralysis due to a neuromuscular disorder, and bedridden patients with a risk factor. Prophylaxis has to be continued as long as the indication exists. In the acute phase of deep venous thrombosis or pulmonary embolism treatment with (low-molecular-weight) heparin in an adequate dose is necessary. When started at the same time as coumarin derivatives the treatment with heparin has to be continued for at least 5 days. The risk of postthrombotic syndrome after deep venous thrombosis will be lowered by carrying compression stockings for at least 2 years after the event.

Antithrombotic therapy in patients with thrombocytopenic cancer: outcomes associated with reduced-dose, low-molecular-weight heparin during hospitalization.

PubMed

Babilonia, Katrina M; Golightly, Larry K; Gutman, Jonathan A; Hassell, Kathryn L; Kaiser, Jeffrey N; Kiser, Tyree H; Klem, Patrick M; Trujillo, Toby C

2014-11-01

Guidelines are discordant concerning management of patients having thrombocytopenia with cancer-associated thrombosis (CAT). Hospitalized adults with CAT and platelets ≤50 × 10(9) cells/L were managed with dalteparin 100 units/kg subcutaneously once daily. Comparator patients with CAT and platelets >50 × 10(9) cells/L were managed with dalteparin 200 units/kg/d. Outcomes of 35 patients with thrombocytopenia (mean platelet count 26 ± 8.3 × 10(9) cells/L) and 58 comparator patients (mean platelet count 155 ± 75 × 10(9) cells/L) were evaluated. In all, 2 (5.7%) patients in the thrombocytopenia group and 1 patient (1.9%) in the comparator group experienced new-onset venous thromboembolism (odds ratio 3.31, 95% confidence interval [CI] 0.29-37.90, P = .556). The incidence of bleeding in patients with thrombocytopenia (8.6%) was similar to that in comparator patients (9.4%; risk ratio 0.94, 95% CI 0.37-2.39, P = .607). In hospitalized patients having thrombocytopenia with CAT, reduced-dose low-molecular-weight heparin was generally efficacious. © The Author(s) 2014.

Cost effectiveness of enoxaparin as prophylaxis against venous thromboembolic complications in acutely ill medical inpatients: modelling study from the hospital perspective in Germany.

PubMed

Schädlich, Peter K; Kentsch, Michael; Weber, Manfred; Kämmerer, Wolfgang; Brecht, Josef Georg; Nadipelli, Vijay; Huppertz, Eduard

2006-01-01

To estimate, from the hospital perspective in Germany, the cost effectiveness of the low-molecular-weight heparin (LMWH) subcutaneous enoxaparin sodium 40 mg once daily (ENOX) relative to no pharmacological prophylaxis (NPP) and relative to subcutaneous unfractionated heparin (UFH) 5,000 IU three times daily (low-dose UFH [LDUFH]). Each is used in addition to elastic bandages/compression stockings and physiotherapy in the prevention of venous thromboembolic events (VTE) in immobilised acutely ill medical inpatients without impaired renal function or extremes of body weight. The incremental cost-effectiveness ratios (ICERs) of the 'additional cost for ENOX per clinical VTE avoided versus NPP' and 'additional cost for ENOX per episode of major bleeding avoided versus LDUFH' were chosen as target variables. The target variables were quantified using a modelling approach based on the decision-tree technique. Resource use during thromboprophylaxis, diagnosis and treatment of VTEs, episode of major bleeding and secondary pneumonia after pulmonary embolism (PE) was collected from a hospital survey. Costs were exclusively those to hospitals incurred by staff expenses, drugs, devices, disposables, laboratory tests and equipment for diagnostic procedures. These costs were determined by multiplying utilised resource items by the price or tariff of each item as of the first quarter of 2003. Safety and efficacy values of the comparators were taken from the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) and the THE-PRINCE (THromboEmbolism-PRevention IN Cardiac or respiratory disease with Enoxaparin) trials and from a meta-analysis. The evaluation encompassed 8 (6-14) days of thromboprophylaxis plus time to treat VTE and episode of major bleeding in hospital. Point estimates of all model parameters were applied exclusively in the base-case analysis. There were incremental costs of euro 1,106 for ENOX per clinical VTE avoided versus NPP (1 euro approximately equals 1.07 US dollars; average of the first quarter of 2003). ENOX dominated LDUFH: cost savings of euro 55,825 were obtained and 7.7 episodes of major bleeding were avoided by ENOX compared with LDUFH, each per 1000 patients. In comprehensive sensitivity analyses, the robustness of the model and its results was shown. Results of this evaluation suggest that, in immobilised acutely ill medical inpatients, ENOX may offer hospitals in Germany a very cost-effective option for thromboprophylaxis compared with NPP and a cost-saving alternative compared with LDUFH.

Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism.

PubMed

Louzada, Martha L; Carrier, Marc; Lazo-Langner, Alejandro; Dao, Vi; Kovacs, Michael J; Ramsay, Timothy O; Rodger, Marc A; Zhang, Jerry; Lee, Agnes Y Y; Meyer, Guy; Wells, Philip S

2012-07-24

Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between -3 and 3 score points. Patients with a score ≤ 0 had low risk (≤ 4.5%) for recurrence and patients with a score >1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Venous Thromboembolism Prevention in Emergency General Surgery: A Review.

PubMed

Murphy, Patrick B; Vogt, Kelly N; Lau, Brandyn D; Aboagye, Jonathan; Parry, Neil G; Streiff, Michael B; Haut, Elliott R

2018-05-01

Venous thromboembolism (VTE) is the most preventable cause of morbidity and mortality in US hospitals, and approximately 2.5% of emergency general surgery (EGS) patients will be diagnosed with a VTE event. Emergency general surgery patients are at increased risk of morbidity and mortality because of the nature of acute surgical conditions and the challenges related to prophylaxis. MEDLINE, Embase, and the Cochrane Database of Collected Reviews were searched from January 1, 1990, through December 31, 2015. Nearly all operatively and nonoperatively treated EGS patients have a moderate to high risk of developing a VTE, and individual risk should be assessed at admission. Pharmacologic prophylaxis in the form of unfractionated or low-molecular-weight heparin should be considered unless an absolute contraindication, such as bleeding, exists. Patients should receive the first dose at admission to the hospital, and administration should continue until discharge without missed doses. Certain patient populations, such as those with malignant tumors, may benefit from prolonged VTE prophylaxis after discharge. Mechanical prophylaxis should be considered in all patients, particularly if pharmacologic prophylaxis is contraindicated. Studies that specifically target improved adherence with VTE prophylaxis in EGS patients suggest that efficacy and quality improvement initiatives should be undertaken from a system and institutional perspective. Operatively and nonoperatively treated EGS patients are at a comparatively high risk of VTE. Despite gaps in existing literature with respect to this increasing patient population, successful best practices can be applied. Best practices include assessment of VTE risk, optimal prophylaxis, and physician, nurse, and patient education regarding the use of mechanical and pharmacologic VTE prophylaxis and institutional policies.

Characterization of currently marketed heparin products: key tests for quality assurance.

PubMed

Keire, David A; Ye, Hongping; Trehy, Michael L; Ye, Wei; Kolinski, Richard E; Westenberger, Benjamin J; Buhse, Lucinda F; Nasr, Moheb; Al-Hakim, Ali

2011-01-01

During the 2007-2008 heparin crisis, it was found that the United States Pharmacopeia (USP) testing monograph for unfractionated heparin sodium (UFH) did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS) in heparin. In response to this concern, new tests and specifications were developed by the Food and Drug Administration (FDA) and USP and put in place to not only detect the contaminant OSCS but also to improve assurance of quality and purity of the drug product. Additional tests were also developed to monitor the heparin supply chain for other possible economically motivated additives or impurities. In 2009, a new USP monograph was put in place that includes 500 MHz (1)H NMR, SAX-HPLC, %galactosamine in total hexosamine, and anticoagulation time assays with purified factor IIa or factor Xa. These tests represent orthogonal approaches for UFH identification, measurement of bioactivity, and for detection of process impurities or contaminants in UFH. The FDA has applied these analytical approaches to the study of UFH active pharmaceutical ingredients in the marketplace. Here, we describe results from a comprehensive survey of UFH collected from seven different sources after the 2009 monograph revision and compare these data with results obtained on other heparin samples collected during the 2007-2008 crisis.

Gel point and fractal microstructure of incipient blood clots are significant new markers of hemostasis for healthy and anticoagulated blood.

PubMed

Evans, Phillip A; Hawkins, Karl; Morris, Roger H K; Thirumalai, Naresh; Munro, Roger; Wakeman, Lisa; Lawrence, Matthew J; Williams, P Rhodri

2010-10-28

Here we report the first application of a fractal analysis of the viscoelastic properties of incipient blood clots. We sought to ascertain whether the incipient clot's fractal dimension, D(f,) could be used as a functional biomarker of hemostasis. The incipient clot is formed at the gel point (GP) of coagulating blood, the GP demarcating a functional change from viscoelastic liquid to a viscoelastic solid. Incipient clots formed in whole healthy blood show a clearly defined value of D(f) within a narrow range that represents an index of clotting in health, where D(f) = 1.74 (± 0.07). A significant relationship is found between the incipient clot formation time, T(GP), and the activated partial thromboplastin time, whereas the association of D(f) with the microstructural characteristics of the incipient clot is supported by its significant correlation with fibrinogen. Our study reveals that unfractionated heparin not only prolongs the onset of clot formation but has a significant effect on its fractal microstructure. A progressive increase in unfractionated heparin concentration results in a linear decrease in D(f) and a corresponding prolongation in T(GP). The results represent a new, quantitative measure of clot quality derived from measurements on whole blood samples.

Effect of thrombocytopenia on outcomes following treatment with either enoxaparin or unfractionated heparin in patients presenting with acute coronary syndromes.

PubMed

Yeh, Robert W; Wiviott, Stephen D; Giugliano, Robert P; Morrow, David A; Shui, Amy; Qin, Jie; Scirica, Benjamin; Bradner, James E; Jang, Ik-Kyung; Gibson, C Michael; Antman, Elliott M

2007-12-15

Thrombocytopenia is associated with an increased risk for adverse cardiac events and bleeding in patients presenting with acute coronary syndromes (ACS) treated with unfractionated heparin (UFH). Enoxaparin has been shown to improve outcomes in ACS; however, its effect on the development of thrombocytopenia in this population is not well documented. This study was conducted to examine the incidence and clinical importance of thrombocytopenia in patients presenting with non-ST-elevation ACS randomized to treatment with enoxaparin or UFH. Thrombocytopenia was defined as a platelet count <100 x 10(9)/L or a >50% decrease from baseline. Thrombocytopenia developed in a total of 93 of 3,910 patients during the follow-up period of 14 days; the incidence was similar between study arms. The development of thrombocytopenia was associated with more frequent death, nonfatal myocardial infarction, and urgent revascularization during the study period (odds ratio 2.96, p = 0.001). This association was independent of assignment to treatment with enoxaparin or UFH (p for interaction = 0.47). Major bleeding was also more common in patients with thrombocytopenia regardless of treatment. In conclusion, thrombocytopenia is a significant correlate of adverse events in patients presenting with non-ST-elevation ACS treated with either enoxaparin or UFH.

Synergism of aspirin and heparin with a low-frequency non-invasive ultrasound system for augmentation of in-vitro clot lysis.

PubMed

Atar, Shaul; Neuman, Yoram; Miyamoto, Takashi; Chen, Ming; Birnbaum, Yochai; Luo, Huai; Kobal, Sergio; Siegel, Robert J

2003-06-01

Aspirin, glycoprotein IIb/IIIa inhibitors and heparin are routinely used in acute coronary syndromes. Previously we showed that there is synergism between ultrasound and heparin and tirofiban in augmenting blood clot disruption. However, there is a little data on a possible synergism of low-frequency ultrasound with aspirin for in-vitro clot dissolution, and especially on the combination of aspirin with heparin and/or glycoprotein IIb/IIIa inhibitors. Human blood clots (n = 320) were incubated for 10 or 20 minutes in saline containing aspirin alone or combined with heparin and/or tirofiban and/or eptifibatide. Clots were randomly treated with low-frequency ultrasound (27.3 kHz) or incubation only. The percent clot weight loss and the incremental effect of ultrasound were calculated. The most significant incremental effect of ultrasound on clot weight reduction was detected with aspirin alone (5.2 +/- 2.3% and 5.2 +/- 2.6% after 10' and 20', p = 0.04 and p = 0.06, respectively) and in combination with heparin (8.8 +/- 2.5% and 11.5 +/- 2.7% after 10' and 20', p = 0.01 and p = 0.0001, respectively). The greatest absolute magnitude of clot weight reduction was observed with ultrasound combined with aspirin and heparin (48.5 +/- 9.5% after 20'). The addition of tirofiban or eptifibatide to aspirin, heparin and ultrasound did not increase clot lysis. However, eptifibatide had significantly better synergism than tirofiban (p = 0.025 and p = 0.015, after 10 and 20 minutes, respectively). Aspirin alone or in combination with heparin results in significant augmentation of clot lysis and is synergistic with application of low-frequency ultrasound for 10 and 20 minutes only. These results may have important implications for a possible use of low-frequency ultrasound in treatment algorithms of acute coronary syndromes.

Successful Deep Inferior Epigastric Perforator Flap Harvest despite Preoperative Therapeutic Subcutaneous Heparin Administration into the Abdominal Pannus.

PubMed

Duncumb, Joseph W; Miyagi, Kana; Forouhi, Parto; Malata, Charles M

2016-01-01

Abdominal free flaps for microsurgical breast reconstruction are most commonly harvested based on the deep inferior epigastric vessels that supply skin and fat via perforators through the rectus muscle and sheath. Intact perforator anatomy and connections are vital for subsequent optimal flap perfusion and avoidance of necrosis, be it partial or total. The intraflap vessels are delicate and easily damaged and it is generally advised that patients should avoid heparin injection into the abdominal pannus preoperatively as this may compromise the vascular perforators through direct needle laceration, pressure from bruising, haematoma formation, or perforator thrombosis secondary to external compression. We report three cases of successful deep inferior epigastric perforator (DIEP) flap harvest despite patients injecting therapeutic doses of low molecular weight heparin into their abdomens for thrombosed central venous lines (portacaths™) used for administering primary chemotherapy in breast cancer.

Successful Deep Inferior Epigastric Perforator Flap Harvest despite Preoperative Therapeutic Subcutaneous Heparin Administration into the Abdominal Pannus

PubMed Central

Miyagi, Kana; Forouhi, Parto

2016-01-01

Abdominal free flaps for microsurgical breast reconstruction are most commonly harvested based on the deep inferior epigastric vessels that supply skin and fat via perforators through the rectus muscle and sheath. Intact perforator anatomy and connections are vital for subsequent optimal flap perfusion and avoidance of necrosis, be it partial or total. The intraflap vessels are delicate and easily damaged and it is generally advised that patients should avoid heparin injection into the abdominal pannus preoperatively as this may compromise the vascular perforators through direct needle laceration, pressure from bruising, haematoma formation, or perforator thrombosis secondary to external compression. We report three cases of successful deep inferior epigastric perforator (DIEP) flap harvest despite patients injecting therapeutic doses of low molecular weight heparin into their abdomens for thrombosed central venous lines (portacaths™) used for administering primary chemotherapy in breast cancer. PMID:27651974

Syncopal episode as the presenting symptom of jugular vein thrombosis in pregnancy: a case report.

PubMed

Merhi, Zaher O; Haberman, Shoshana

2007-06-01

Jugular vein thrombosis has been reported to occur in pregnant women who conceived with assisted reproductive technology (ART). A 28-year-old woman at 17 weeks' gestation presented to the emergency room with a syncopal episode. She reported no arm pain or swelling, no neck pain or swelling, and no dyspnea or difficulty swallowing. Doppler sonography of the neck vasculature revealed acute bilateral internal jugular vein thromboses. Thrombophilia workup was normal. Intravenous anticoagulation with heparin was initiated, and the patient was discharged on low-molecular-weight heparin. Though rare, jugular vein thrombosis should be considered in the differential diagnosis of syncopal episodes even in women who conceive without ART.

Structural characterization of pharmaceutical heparins prepared from different animal tissues.

PubMed

Fu, Li; Li, Guoyun; Yang, Bo; Onishi, Akihiro; Li, Lingyun; Sun, Peilong; Zhang, Fuming; Linhardt, Robert J

2013-05-01

Although most pharmaceutical heparin used today is obtained from porcine intestine, heparin has historically been prepared from bovine lung and ovine intestine. There is some regulatory concern about establishing the species origin of heparin. This concern began with the outbreak of mad cow disease in the 1990s and was exacerbated during the heparin shortage in the 2000s and the heparin contamination crisis of 2007-2008. Three heparins from porcine, ovine, and bovine were characterized through state-of-the-art carbohydrate analysis methods with a view profiling their physicochemical properties. Differences in molecular weight, monosaccharide and disaccharide composition, oligosaccharide sequence, and antithrombin III-binding affinity were observed. These data provide some insight into the variability of heparins obtained from these three species and suggest some analytical approaches that may be useful in confirming the species origin of a heparin active pharmaceutical ingredient. Copyright © 2013 Wiley Periodicals, Inc.

Factors predicting recurrence of chronic subdural haematoma: the influence of intraoperative irrigation and low-molecular-weight heparin thromboprophylaxis.

PubMed

Tahsim-Oglou, Yasemin; Beseoglu, Kerim; Hänggi, Daniel; Stummer, Walter; Steiger, Hans-Jakob

2012-06-01

Burr-hole drainage has become the accepted treatment of choice for chronic subdural haematoma (cSDH), although still burdened with a major recurrence rate. The current analysis was initiated to determine management-related risk factors for recurrence, i.e. postoperative low-molecular-weight heparin thromboprophylaxis, and the importance of rinsing the subdural space. Two-hundred and forty-seven patients with computerised tomography (CT) defined symptomatic cSDH were managed by two burr-hole trepanations and drainage between January 2005 and November 2008. Postoperative thromboprophylaxis with 40 mg enoxaparine daily was given only during the first half of the study period. For the current analysis the amount of rinsing fluid, postoperative low-dose thromboprophylaxis, as well as age and gender, bilaterality, preoperative and postoperative blood coagulation studies, platelet counts and decrease of subdural fluid on early postoperative CT, were recorded and correlated with recurrence. Statistical calculation was done by univariate and multivariate analysis. A total of 62 of 247 patients needed revision surgery for recurrence (25.1 %). Recurrence rates were significantly lower in the patients treated without postoperative enoxaparine (18.84 %) than in the group with postoperative low-dose enoxaparine thromboprophylaxis (32.11 %) and enoxaparine was administered in a higher proportion of the patients suffering recurrence (P = 0.013). A median intraoperative irrigation volume of 863 ml saline was used in the patients suffering recurrence and 1,500 ml in patients without recurrence (P < 0.001). The median age was slightly higher in the patients suffering from recurrence. Male gender predominated in both groups but was slightly more pronounced in the recurrence group. Preoperative and postoperative platelet counts and plasmatic coagulation indices did not differ significantly between the groups. Relative residual subdural fluid collection on early postoperative CT remained larger in patients finally suffering recurrence (P = 0.03). Multivariate analysis confirmed a small amount of rinsing fluid, male gender and the use of enoxaparine as the most important risk factors for recurrence, although that latter factor did not reach statistical significance in the multivariate analysis. The investigation provides evidence that copious intraoperative irrigation and avoidance of postoperative low-molecular-weight heparin thromboprophylaxis may reduce the recurrence rate of cSDH.

Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis.

PubMed

van Rein, N; Biedermann, J S; van der Meer, F J M; Cannegieter, S C; Wiersma, N; Vermaas, H W; Reitsma, P H; Kruip, M J H A; Lijfering, W M

2017-07-01

Essentials Low-molecular-weight-heparins (LMWH) kinetics differ which may result in different bleeding risks. A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding. The absolute major bleeding risk was low among patients registered at the anticoagulation clinic. Once-daily dosing was associated with a lower bleeding risk as compared with twice-daily. Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials. © 2017 International Society on Thrombosis and Haemostasis.

Characterization of a heparin-binding growth factor from adenocarcinoma of the kidney.

PubMed

Mydlo, J H; Heston, W D; Fair, W R

1988-12-01

A polypeptide isolated from tissue extracts of renal adenocarcinoma was mitogenic for BALB/c 3T3 cells and human umbilical vein (HUV) cells in culture. It also demonstrated angiogenic ability using the chorioallantoic membrane bioassay. Using heparin-sepharose affinity chromatography the purified protein eluted with a NaCl concentration between 1.4 and 1.8 M and demonstrated a molecular weight of approximately 17,000 daltons based on SDS polyacrylamide gel electrophoresis. Half maximal stimulation of tritiated thymidine incorporation into BALB/c 3T3 cells was achieved by 1.6 ng./ml. of the heparin binding material. Western blot analysis using antibodies specific to basic fibroblast growth factor (bFGF) only or acidic FGF (aFGF) only demonstrated that the purified protein binds to the former and not the latter. The characteristics of this material, in effect the elution profile off heparin-Sepharose, the molecular weight, angiogenic activity and the results of western blot analysis, suggest that this growth factor is similar to the family of basic fibroblast growth factors.

Safety and efficacy of bridging with low molecular weight heparins: a systematic review and partial meta-analysis.

PubMed

Eijgenraam, Pieter; ten Cate, Hugo; Ten Cate-Hoek, Arina

2013-01-01

Surgical interventions in patients on long term vitamin K antagonist (VKA) treatment create a dilemma; periprocedural interruption of anticoagulation raises the risk of thrombosis, while continuation raises the risk of bleeding. The anticoagulation- free interval is minimized by "bridging" with parenteral anticoagulants. The efficacy and safety of bridging with low molecular weight heparins (LMWH) has however not been unequivocally established. We performed an EMBASE and MEDLINE search for studies that compared bridging anticoagulation with continuation or cessation of VKA without bridging; with thromboembolism (TE) and bleeding as outcomes. We identified 878 articles and finally selected 17. Results of individual studies were pooled. None of the included studies reported significant differences in incidence of TEs between the bridging group and the comparator group; 4 out of 13 studies reported zero TEs. Heparin was identified as a risk factor for bleeding in multivariable adjusted analyses in 3 studies on pacemaker/implantable cardioverter defibrillator (PM/ICD) surgery. In 5 studies (different types of surgery) with unadjusted analyses, bridging was compared to warfarin cessation: 3 studies reported null results for bleeding; 2 studies identified bridging as a risk factor. We pooled a subset of 6 studies regarding postoperative bleeding after PM/ICD surgery and found a relative risk (RR) of 3.03 (95% confidence interval (CI), 1.86-4.95) for bridging compared to continuation of VKA. While the antithrombotic efficacy of bridging with LMWH has not been demonstrated, increased bleeding risk is observed in different types of surgery. PM/ICD surgery can be safely performed on continued VKA.

Safety and efficacy of periprocedural anticoagulation with enoxaparin in patients undergoing peripheral endovascular revascularization.

PubMed

Brodmann, Marianne; Dorr, A; Hafner, F; Gary, T; Froehlich, H; Kvas, E; Deutschmann, H; Pilger, E

2014-07-01

Periprocedural anticoagulation is primarily used in endovascular procedures to prevent acute reocclusion of the target vessel, but periprocedural anticoagulation might also have an impact on long-term outcome. Consecutive bleeding events are feared complications. Despite changes in peripheral endovascular revascularizations (EVRs), the periprocedural management has remained unchanged for years. Unfractionated heparin is still the treatment of choice during and immediately after EVR. We performed a prospective, single-center, open-label phase III study comparing 2 different regimes of enoxaparin peri-interventional to peripheral EVR stratified into low- and high-risk groups according to the acute and long-term reocclusion risk due to their vessel morphology. In both groups, 0.5 mg/kg of enoxaparin as a bolus was administered intravenously 10 to 15 minutes before the start of the procedure. In the low-risk group, 40 mg of enoxaparin were administered once daily for 7 days; whereas in the high-risk group, 1 mg/kg of enoxaparin was administered subcutaneously (sc) 2 times a day for 48 hours after the procedure and afterward 40 mg of enoxaparin was administered sc once daily for 5 days. For the analysis of the per protocol population, 44 patients remained in the low-risk group and 140 in the high-risk group. Concerning the primary safety end point, a total of 25 (13.59%) bleeding events occurred until day 30; 5 (11.36%) of them in the low-risk group and 20 (14.29%) in the high-risk group (P = .809 for low vs high risk). None of the bleeding events observed were major according to Thrombolysis In Myocardial Infarction criteria. Concerning our primary efficacy end point, none of the patients showed an acute reocclusion classified as a significant decrease in ankle-brachial index (ABI) or elevated peak systolic velocity ratio confirmed by duplex sonography until day 30. Concerning the second end point of prevention of chronic reobstruction, at day 180 ABI has decreased in the low-risk group from mean 0.94 at day 30 to mean 0.89 and from 1.28 at day 30 to 0.85 after 6 months in the high-risk group. No significant reobstruction was found in the low-risk group, whereas 5 significant reobstruction events were objectified in the high-risk group, all of them in the femoropopliteal arterial segment at day 180. We conclude that low-molecular-weight heparin either in a low-dose or high-dose regime during a peripheral EVR is safe concerning bleeding complications and acute reobstructions. The long-term follow-up showed no significant difference between our high- and low-risk groups concerning reobstruction. The periprocedural anticoagulation seems to have no influence on the long-term patency rate after peripheral EVR. © The Author(s) 2013.

Binding affinities of vascular endothelial growth factor (VEGF) for heparin-derived oligosaccharides

PubMed Central

Zhao, Wenjing; McCallum, Scott A.; Xiao, Zhongping; Zhang, Fuming; Linhardt, Robert J.

2011-01-01

Heparin and heparan sulphate (HS) exert their wide range of biological activities by interacting with extracellular protein ligands. Among these important protein ligands are various angiogenic growth factors and cytokines. HS-binding to vascular endothelial growth factor (VEGF) regulates multiple aspects of vascular development and function through its specific interaction with HS. Many studies have focused on HS-derived or HS-mimicking structures for the characterization of VEGF165 interaction with HS. Using a heparinase 1-prepared small library of heparin-derived oligosaccharides ranging from hexasaccharide to octadecasaccharide, we systematically investigated the heparin-specific structural features required for VEGF binding. We report the apparent affinities for the association between the heparin-derived oligosaccharides with both VEGF165 and VEGF55, a peptide construct encompassing exclusively the heparin-binding domain of VEGF165. An octasaccharide was the minimum size of oligosaccharide within the library to efficiently bind to both forms of VEGF and that a tetradecasaccharide displayed an effective binding affinity to VEGF165 comparable to unfractionated heparin. The range of relative apparent binding affinities among VEGF and the panel of heparin-derived oligosaccharides demonstrate that VEGF binding affinity likely depends on the specific structural features of these oligosaccharides including their degree of sulphation and sugar ring stereochemistry and conformation. Notably, the unique 3-O-sulpho group found within the specific antithrombin binding site of heparin is not required for VEGF165 binding. These findings afford new insight into the inherent kinetics and affinities for VEGF association with heparin and heparin-derived oligosaccharides with key residue specific modifications and may potentially benefit the future design of oligosaccharide-based anti-angiogenesis drugs. PMID:21658003

Effect of PEG-PDMAEMA Block Copolymer Architecture on Polyelectrolyte Complex Formation with Heparin.

PubMed

Välimäki, Salla; Khakalo, Alexey; Ora, Ari; Johansson, Leena-Sisko; Rojas, Orlando J; Kostiainen, Mauri A

2016-09-12

Heparin is a naturally occurring polyelectrolyte consisting of a sulfated polysaccharide backbone. It is widely used as an anticoagulant during major surgical operations. However, the associated bleeding risks require rapid neutralization after the operation. The only clinically approved antidote for heparin is protamine sulfate, which is, however, ineffective against low molecular weight heparin and can cause severe adverse reactions in patients. In this study, the facile synthesis of cationic-neutral diblock copolymers and their effective heparin binding is presented. Poly(ethylene glycol)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PDMAEMA) block copolymers were synthesized in two steps via atom-transfer radical polymerization (ATRP) using PEG as a macroinitiator. Solution state binding between heparin and a range of PEG-PDMAEMA block copolymers and one homopolymer was studied with dynamic light scattering and methylene blue displacement assay. Also in vitro binding in plasma was studied by utilizing a chromogenic heparin anti-Xa assay. Additionally, quartz crystal microbalance and multiparametric surface plasmon resonance were used to study the surface adsorption kinetics of the polymers on a heparin layer. It was shown that the block copolymers and heparin form electrostatically bound complexes with varying colloidal properties, where the block lengths play a key role in controlling the heparin binding affinity, polyelectrolyte complex size and surface charge. With the optimized polymers (PEG114PDMAEMA52 and PEG114PDMAEMA100), heparin could be neutralized in a dose-dependent manner, and bound efficiently into small neutral complexes, with a hydrodynamic radius less than 100 nm. These complexes had only a limited effect on cell viability. Based on these studies, our approach paves the way for the development of new polymeric heparin binding agents.

Immediate Type Hypersensitivity to Heparins: Two Case Reports and a Review of the Literature.

PubMed

Cesana, Philipp; Scherer, Kathrin; Bircher, Andreas J

2016-01-01

Immediate type hypersensitivity reactions due to heparins are rare, and the exact immunologic pathomechanism has not been identified so far. In our 2 case reports, we describe first a 50-year-old female who received dalteparin (Fragmin®) and developed signs of an immediate type hypersensitivity reaction. The personal history revealed a previous application of dalteparin (Fragmin®). Evaluation with a skin prick test showed positive results for dalteparin. The second case deals with a 73-year-old female with a suspected immediate type reaction after the administration of dalteparin (Fragmin®). A skin prick test was negative but intracutaneous tests showed a positive reaction to the causative agent. Both cases indicated cross-reactivity reactions for low-molecular-weight heparin (LMWH) but not for unfractioned heparin (UFH) or fondaparinux. In conclusion, our case reports including a review of published cases of immediate type hypersensitivity reactions after the application of heparins illustrate this rare complication. Mostly, the causative agent can be identified with a skin test, which is highly suggestive of an IgE-mediated reaction. Therapeutic alternatives for patients with sensitization to an LMWH are UFH and fondaparinux. Both agents have a small risk of cross-reactivity compared to heparins of the same substance class. © 2017 S. Karger AG, Basel.

Affinity of low molecular weight fucoidan for P-selectin triggers its binding to activated human platelets.

PubMed

Bachelet, Laure; Bertholon, Isabelle; Lavigne, Damien; Vassy, Roger; Jandrot-Perrus, Martine; Chaubet, Frédéric; Letourneur, Didier

2009-02-01

P-selectin is an adhesion receptor expressed on activated platelets and endothelial cells. Its natural ligand, P-selectin glycoprotein ligand-1, is expressed on leucocytes and the P-selectin/PSGL-1 interaction is involved in leukocyte rolling. We have compared the interaction of P-selectin with several low molecular weight polysaccharides: fucoidan, heparin and dextran sulfate. Binding assays were obtained from the interaction of the polysaccharides with Sialyl Lewis X and PSGL-1 based constructs onto microtiter plates coated with P-selectin. SELDI TOF mass spectrometry was performed with anionic chips arrays coated with P-selectin in the absence or in the presence of polysaccharides. Kd were obtained from surface plasmon resonance experiments with immobilized P-selectin constructs, polysaccharides being injected in the mobile phase. Human whole blood flow cytometry experiments were performed with fluorescein isothiocyanate labelled polysaccharides with or without platelets activators. The fucoidan prevented P-selectin binding to Sialyl Lewis X with an IC(50) of 20 nM as compared to 400 nM for heparin and <25000 nM for dextran sulfate. It exhibited the highest affinity for immobilized P-selectin with a KD of 1.2 nM, two orders of magnitude greater than the K(D) of the other polysaccharides. Mass spectrometry evidenced the formation of a complex between P-selectin and fucoidan. The intensity of the fucoidan binding to platelets was dependent on the level of platelet activation. Competition between fucoidan and an anti P-selectin antibody demonstrated the specificity of the interaction. Low molecular weight fucoidan is a promising therapeutic agent of natural origin for biomedical applications.

Argatroban for an alternative anticoagulant in HIT during ECMO.

PubMed

Rougé, Alain; Pelen, Felix; Durand, Michel; Schwebel, Carole

2017-01-01

Extracorporeal membrane oxygenation (ECMO) have become more frequently used in daily ICU practice, heparin-induced thrombocytopenia (HIT) is a rare but life-threatening complication while on extracorporeal membrane oxygenation (ECMO). HIT confirmation directly impacts on anticoagulant strategy requiring no delay unfractionated heparin discontinuation to be replaced by alternative systemic anticoagulant treatment. We report two clinical cases of HIT occurring during ECMO in various settings with subsequent recovery with argatroban and provide literature review to help physicians treat HIT during ECMO in clinical daily practice. HIT during ECMO is uncommon, and despite the absence of recommendation, argatroban seems to be an appropriate and safe therapeutic option. Finally, there are not enough arguments favouring routine circuit change in the event of HIT during ECMO.

Inhibition of B16-BL6 melanoma lung colonies by semisynthetic sulfaminoheparosan sulfates from E. coli K5 polysaccharide.

PubMed

Poggi, Andreina; Rossi, Cosmo; Casella, Nicola; Bruno, Cristiana; Sturiale, Luisella; Dossi, Carla; Naggi, Annamaria

2002-08-01

Heparin (H), heparan sulfate (HS), and related glycosaminoglycans can inhibit cancer cell invasion, possibly due to their ability to interact with vascular growth factors, adhesion molecules, endoglycosidases, and signaling proteins, in addition to the well-known effects on the clotting system. We evaluated the antitumor activity of a series of semisynthetic sulfaminoheparosan sulfates (SAHSs) with different degree and distribution of sulfates, obtained by chemical modifications of the E. coli K5 polysaccharide, namely type A, B, and C compounds. B16-BL6 melanoma cells (10 5 cells/mouse) were injected intravenously (i.v.) in a lateral tail vein of C57BL6 mice at a dose of 0.5 mg/ mouse together with test compounds. Tumor lung nodules were significantly reduced as compared with controls only by H (95.5 +/- 1.0% inhibition), SAHS-2 (84.2 +/- 5.0% inhibition), and SAHS-4 (91.1 +/- 4.2% inhibition), among compounds tested. SAHS-2 and SAHS-4 are type B compounds, with a sulfate/carboxylate ratio similar to that of H. A typical mammalian HS showed only 54.8% inhibition. Supersulfated low-molecular-weight heparin and heparan sulfate (ssLMWH and ssLMWHS) showed an activity similar to that of unfractionated compounds. H and SAHS-4 inhibited dose dependently B16-BL6 lung colonies, with IC-50 values of 0.05 and 0.1 mg/mouse, respectively. The relationship with ex vivo anticoagulant potency was evaluated by activated partial thromboplastin time (aPTT) on mouse plasma at different time intervals after i.v. injection (0.1 to 0.5 mg/mouse) of the compound. H showed a dose-dependent anticoagulant activity lasting up to 2 hours, whereas SAHS-4 showed a potent anticoagulant effect only at a dose of 0.5 mg/mouse. Accordingly, H but not SAHS-4 consistently inhibited B16-BL6 lung colonies when given 1 hour before tumor cells. SAHS-4 derivatives, with different size and/or affinity depleted of AT binding sites, showed an inhibitory effect on B16-BL6 melanoma similar to that of SAHS-4, suggesting that the greater antitumor effect of H was not due to AT-mediated inhibition of blood clotting. Interactions with other blood inhibitors, such as heparin cofactor II or tissue factor pathway inhibitory protein cannot be ruled out. The better effect of H may be due to persistence in the circulation and/or ability to inhibit tumor neoangiogenesis.

Distinguishing dissolved organic matter at its origin: size and optical properties of leaf-litter leachates.

PubMed

Cuss, C W; Guéguen, C

2013-09-01

Dissolved organic matter (DOM) was leached from eight distinct samples of leaves taken from six distinct trees (red maple, bur oak at three times of the year, two sugar maple and two white spruce trees from disparate soil types). Multiple samples were taken over 72-96h of leaching. The size and optical properties of leachates were assessed using asymmetrical flow field-flow fractionation (AF4) coupled to diode-array ultraviolet/visible absorbance and excitation-emission matrix fluorescence detectors (EEM). The fluorescence of unfractionated samples was also analyzed. EEMs were analyzed using parallel factor analysis (PARAFAC) and principal component analysis (PCA) of proportional component loadings. Both the unfractionated and AF4-fractionated leachates had distinct size and optical properties. The 95% confidence ranges for molecular weight distributions were determined as: 210-440Da for spruce, 540-920Da for sugar maple, 630-800Da for spring oak leaves, 930-950Da for senescent oak, 1490-1670 for senescent red maple, and 3430-4270Da for oak leaves that were collected from the ground after spring thaw. In most cases the fluorescence properties of leachates were different for individuals from different soil types and across seasons; however, PCA of PARAFAC loadings revealed that the observed distinctiveness was chiefly species-based. Strong correlations were found between the molecular weight distribution of both unfractionated and fractionated leachates and their principal component loadings (R(2)=0.85 and 0.95, respectively). It is concluded that results support a species-based origin for differences in optical properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of unfractionated heparin on endothelial glycocalyx in a septic shock model.

PubMed

Yini, S; Heng, Z; Xin, A; Xiaochun, M

2015-02-01

The constituents of vascular endothelial glycocalyx, such as syndecan-1 and heparan sulphate (HS), can be detected in the plasma of patients and animals with septic shock. However, the dynamics of glycocalyx degradation and its association with inflammation remains largely unknown. In this study, we investigated the association between the biomarkers of acute endothelial glycocalyx degradation and inflammatory factors. We also evaluated the effect of unfractionated heparin (UFH) on glycocalyx shedding in a canine septic shock model. Twenty adult beagle dogs were randomly allocated to one of the following four groups (n = 5): (1) a sham group; (2) a shock group [3.5 × 10(8) colony-forming unit (cfu) Escherichia coli (E. coli)/kg]; (3) a basic therapy group (sensitive antibiotics and 0.9% saline, 10 ml/kg/h); and (4) a heparin group (40 units/kg/h UFH plus basic therapy). After the onset of septic shock, systemic haemodynamic indices were measured. Endothelial glycocalyx degradation markers (i.e., syndecan-1, HS) and inflammatory factors [i.e., interleukin 6 (IL-6), tumour necrosis factor (TNF)-α], platelet count and activated partial thromboplastin time were measured at various time points. A lethal dose of E. coli induced a progressive septic shock model. We observed increased syndecan-1 and HS levels, which correlated with IL-6 and TNF-α in the septic shock model. The glycocalyx shedding was reduced by UFH, which might be regulated by the inhibition of inflammatory factors. A therapeutic dose of UFH can protect glycocalyx from shedding by inhibiting inflammation. Additional studies with larger sample sizes are needed to confirm our conclusions. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Sensitive detection of oversulfated chondroitin sulfate in heparin sodium or crude heparin with a colorimetric microplate based assay.

PubMed

Sommers, Cynthia D; Mans, Daniel J; Mecker, Laura C; Keire, David A

2011-05-01

In this work we describe a 96-well microplate assay for oversulfated chondroitin sulfate A (OSCS) in heparin, based on a water-soluble cationic polythiophene polymer (3-(2-(N-(N'-methylimidazole))ethoxy)-4-methylthiophene (LPTP)) and heparinase digestion of heparin. The assay takes advantage of several unique properties of heparin, OSCS, and LPTP, including OSCS inhibition of heparinase I and II activity, the molecular weight dependence of heparin-LPTP spectral shifts, and the distinct association of heparin fragments and OSCS to LPTP. These factors combine to enable detection of the presence of 0.003% w/w spiked OSCS in 10 μg of heparin sodium active pharmaceutical ingredient (API) using a plate reader and with visual detection to 0.1% levels. The same detection limit for OSCS was observed in the presence of 10% levels of dermatan sulfate (DS) or chondroitin sulfate A (CSA) impurities. In addition, we surveyed a selection of crude heparin samples received by the agency in 2008 and 2009 to determine average and extreme DS, CSA, and galactosamine weight percent levels. In the presence of these impurities and the variable heparin content in the crude heparin samples, spiked OSCS was reliably detected to the 0.1% w/w level using a plate reader. Finally, authentically OSCS contaminated heparin sodium API and crude samples were distinguished visually by color from control samples using the LPTP/heparinase test.

Improving reliability of chemometric models for authentication of species origin of heparin by switching from 1D to 2D NMR experiments.

PubMed

Monakhova, Yulia B; Fareed, Jawed; Yao, Yiming; Diehl, Bernd W K

2018-05-10

Nuclear magnetic resonance (NMR) spectroscopy is regarded as one of the most powerful and versatile analytical approaches to assure the quality of heparin preparations. In particular, it was recently demonstrated that by using 1 H NMR coupled with chemometrics heparin and low molecular weight heparin (LMWH) samples derived from three major animal species (porcine, ovine and bovine) can be differentiated [Y.B. Monakhova et al. J. Pharm. Anal. 149 (2018) 114-119]. In this study, significant improvement of existing chemometric models was achieved by switching to 2D NMR experiments (heteronuclear multiple-quantum correlation (HMQC) and diffusion-ordered spectroscopy (DOSY)). Two representative data sets (sixty-nine heparin and twenty-two LMWH) belonged to different batches and distributed by different commercial companies were investigated. A trend for animal species differentiation was observed in the principal component analysis (PCA) score plot built based on the DOSY data. A superior model was constructed using HMQC experiments, where individual heparin (LMWH) clusters as well as their blends were clearly differentiated. The predictive power of different classification methods as well as unsupervised techniques (independent components analysis, ICA) clearly proved applicability of the model for routine heparin and LMWH analysis. The switch from 1D to 2D NMR techniques provides a wealth of additional information, which is beneficial for multivariate modeling of NMR spectroscopic data for heparin preparations. Copyright © 2018 Elsevier B.V. All rights reserved.

New Insights in Thrombin Inhibition Structure-Activity Relationships by Characterization of Octadecasaccharides from Low Molecular Weight Heparin.

PubMed

Mourier, Pierre A J; Guichard, Olivier Y; Herman, Fréderic; Sizun, Philippe; Viskov, Christian

2017-03-08

Low Molecular Weight Heparins (LMWH) are complex anticoagulant drugs that mainly inhibit the blood coagulation cascade through indirect interaction with antithrombin. While inhibition of the factor Xa is well described, little is known about the polysaccharide structure inhibiting thrombin. In fact, a minimal chain length of 18 saccharides units, including an antithrombin (AT) binding pentasaccharide, is mandatory to form the active ternary complex for LMWH obtained by alkaline β-elimination (e.g., enoxaparin). However, the relationship between structure of octadecasaccharides and their thrombin inhibition has not been yet assessed on natural compounds due to technical hurdles to isolate sufficiently pure material. We report the preparation of five octadecasaccharides by using orthogonal separation methods including size exclusion, AT affinity, ion pairing and strong anion exchange chromatography. Each of these octadecasaccharides possesses two AT binding pentasaccharide sequences located at various positions. After structural elucidation using enzymatic sequencing and NMR, in vitro aFXa and aFIIa were determined. The biological activities reveal the critical role of each pentasaccharide sequence position within the octadecasaccharides and structural requirements to inhibit thrombin. Significant differences in potency, such as the twenty-fold magnitude difference observed between two regioisomers, further highlights the importance of depolymerisation process conditions on LMWH biological activity.

Diagnosis and management of ST elevation myocardial infarction: a review of the recent literature and practice guidelines.

PubMed

Hahn, Sigrid A; Chandler, Charles

2006-01-01

There is a large volume of literature available to guide the peri-infarct management of ST elevation myocardial infarction (STEMI). Most of this literature focuses on improving the availability and efficacy of reperfusion therapy. The purpose of this article is to review contemporary scientific evidence and guideline recommendations regarding the diagnosis and therapy of STEMI. Studies and epidemiological data were identified using Medline, the Cochrane Database, and an Internet search engine. Medline was searched for landmark and recent publications using the following key words: STEMI, guidelines, epidemiology, reperfusion, fibrinolytics, percutaneous coronary intervention (PCI), facilitated PCI, transfer, delay, clopidogrel, glycoprotein IIb/IIIa, low-molecular-weight heparin (LMWH), beta-blockers, nitrates, and angiotensin-converting enzyme (ACE) inhibitors. The data accessed indicate that urgent reperfusion with either fibrinolytics or percutaneous intervention should be considered for every patient having symptoms of myocardial infarction with ST segment elevation or a bundle branch block. The utility of combined mechanical and pharmacological reperfusion is currently under investigation. Ancillary treatments may utilize clopidogrel, glycoprotein IIb/IIIa inhibitors, or low molecular weight heparin, depending on the primary reperfusion strategy used. Comprehensive clinical practice guidelines incorporate much of the available contemporary evidence, and are important resources for the evidence-based management of STEMI.

Thrombin generation in mesalazine refractory ulcerative colitis and the influence of low molecular weight heparin.

PubMed

Vrij, Anton A; Oberndorff-Klein-Woolthuis, Ardi; Dijkstra, Gerard; de Jong, Andrea E; Wagenvoord, Rob; Hemker, Hendrik C; Stockbrügger, Reinhold W

2007-10-01

In ulcerative colitis (UC), a state of hypercoagulation has frequently been observed. Low molecular weight heparin (LMWH) has shown beneficial effects as an adjuvant treatment of steroid refractory UC in open trials. We assessed potential therapeutic effects of the LMWH reviparin in hospitalised patients with mesalazine refractory UC, as well as its influence on haemostasis factors. Twenty-nine patients with mild-to-moderately active UC were included in a double-blind placebo controlled trial. All patients had a flare-up of disease under mesalazine treatment. Reviparin (Clivarin) 3,436 IU anti-Xa/0.6 ml or placebo s.c. was added, and self-administered twice daily for 8 weeks. Patients were monitored for possible adverse events and changes in clinical symptoms. Endoscopical, histological, biochemical and haemostasis parameters were analysed. Tolerability and compliance were excellent and no serious adverse events occurred. No significant differences were observed on the clinical, endoscopical and histological outcome, as compared to placebo. A high intrinsic and extrinsic thrombin potential was found before LMWH therapy. However, the significant reduction in the thrombin generation by LMWH was not related to the reduction in disease activity. The LMWH reviparine reduces thrombin generation in patients with mild-to-moderately active, mesalazine refractory UC, but is not associated with a reduction in disease activity.

A capillary electrophoretic method for fingerprinting low molecular weight heparins.

PubMed

King, J Timothy; Desai, Umesh R

2008-09-15

Clinically used low molecular weight heparins (LMWH) are anticoagulants of choice and are phenomenally complex mixtures of millions of distinct natural and unnatural polymeric sequences. The FDA recommends that each LMWH be considered as an independent drug with its own activity profile, placing significant importance on the biophysical characterization of each intact LMWH. We report a robust protocol for fingerprinting these pharmaceutical agents. Capillary electrophoresis of three LMWHs, enoxaparin, tinzaparin, and a Sigma preparation, under reverse polarity conditions in the presence of selected linear alkyl polyamines gives an electrophoretic pattern that is characteristic of the nature of the starting material. The buffers that best provided optimal resolution without compromising sensitivity and speed of analysis were 50 mM sodium phosphate, pH 2.3, and 100 mM ammonium formate, pH 3.5. Resolution was strongly dependent on the structure of polyamine with pentaethylenehexamine being most effective for enoxaparin and Sigma LMWH. In contrast, tinzaparin could be best resolved with tetraethylenepentamine. Cyclic polyamines were ineffective. Resolution was also dependent on the concentration of resolving agents and displayed a narrow window that provides optimal resolution. These features suggest a strong structural origin of the fingerprint pattern. Overall, the simple protocol will find special use in assessing LMWH quality and batch-to-batch variability.

[Impact of low-molecular-weight heparin practice guidelines in a geriatric hospital].

PubMed

d'Arailh, Lydie; Gaubert-Dahan, Marie-Line; Muller, Florence; Lechowski, Laurent; Teillet, Laurent

2011-06-01

The purpose of this study was to assess the impact of good use of anticoagulants guidelines implementation on low molecular weight heparin (LMWH) prescription in a french geriatric hospital. This interventional "before and after" study was conduced by the same geriatrician on a d-day in 2006 and 2009. Guidelines for anticoagulant's prescription based on selected references in the literature was established by an expert's consensus and implemented in 2008. Data were collected in all departments at the Sainte-Perine geriatric hospital for each patient with an LMWH prescription. Assessment was based on quality judgment criteria (indication, dosage, treatment duration, biological monitoring of LMWH). Data were collected for 72 prescriptions prior to the guidelines implementation and for 54 after. Sex-ratio, mean age and percentage of LMWH prescription did not differ significantly between the two periods. There was a better conformity for LMWH dosage prescription (p = 0.002) and biological monitoring prescription (p = 0.036) after the guidelines implementation. Conformity of LMWH indication and treatment duration were improved but the difference remained not significant (respectively p = 0.49 and p = 0.80). Implementing guidelines for LMWH use in geriatrics can improve quality of prescription. The impact was effective but limited. These guidelines are now in general use in the Sainte-Perine hospital.

Low molecular weight heparin use in unexplained recurrent miscarriage

PubMed Central

Yuksel, Halide; Kayatas, Semra; Boza, Aysen Telce; Api, Murat; Ertekin, A. Aktug; Cam, Cetin

2014-01-01

Objective: The aim of the study was to investigate whether the use of low molecular weight heparin (LMWH) improve live birth rates when compared with control group in patients with unexplained recurrent miscarriages (URM). Methods: In this prospective observational study 150 women with a history of two or more previous unexplained first trimester pregnancy loss who received LMWH; either enoxaparin (n=50), tinzaparin (n=50) or nothing (n=50) were followed for the pregnancy outcome measures. Only the patients who have used standardized dosage of LMWH (4000 IU/day enoxaparin or 3500 IU/day tinzaparin ) were included to the study. The primary end point was the live birth rate and secondary end points were the side effects, late pregnancy complications and neonatal outcome in the study cohorts. Results: Live birth was achieved 85% of the LMWH group and 66% of the control group (p=0.007). According to the subgroup analysis; live birth rates did not differ significantly between the enoxaparin and tinzaparin group (84% and 86%, respectively). Maternal and neonatal side effects were not statistically significant among the study participants. Conclusion: Thromboprophylaxis with LMWH resulted in a improved live-birth rate in patient with 2 or more consecutive unexplained recurrent pregnancy loss. Nevertheless these findings need to be confirmed in larger randomized trials. PMID:25674114

Efficacy and safety of low-molecular-weight heparin in patients with sepsis: a meta-analysis of randomized controlled trials.

PubMed

Fan, Yu; Jiang, Menglin; Gong, Dandan; Zou, Chen

2016-05-16

Low-molecular-weight heparin (LMWH) is part of standard supportive care. We conducted a meta-analysis to investigate the efficacy and safety of LMWH in septic patients. We searched Pubmed, Embase, CKNI and Wanfang database prior to July 2015 for randomized controlled trials investigating treatment with LMWH in septic patients. We identified 11 trials involving 594 septic patients. Meta-analysis showed that LMWH significantly reduced prothrombin time (mean differences [MD] -0.88; 95% CI -1.47 to -0.29), APACHE II score (MD -2.50; 95% CI -3.55 to -1.46), and 28-day mortality (risk ratio [RR] 0.72; 95% CI 0.57-0.91) as well as increased the platelet counts (MD 18.33; 95% CI 0.73-35.93) than the usual treatment. However, LMWH did not reduce D-dimer (MD -0.34; 95% CI -0.85 to 0.18). LMWH also significantly increased the bleeding events (RR 3.82; 95% CI 1.81-8.08). LMWH appears to reduce 28-day mortality and APACHE II score among septic patients. Bleeding complications should be monitored during the LMWH treatment. As for limited data about LMWH and sepsis in the English literature, only trials published in the Chinese were included in the meta-analysis.

Tannins from Hamamelis virginiana bark extract: characterization and improvement of the antiviral efficacy against influenza A virus and human papillomavirus.

PubMed

Theisen, Linda L; Erdelmeier, Clemens A J; Spoden, Gilles A; Boukhallouk, Fatima; Sausy, Aurélie; Florin, Luise; Muller, Claude P

2014-01-01

Antiviral activity has been demonstrated for different tannin-rich plant extracts. Since tannins of different classes and molecular weights are often found together in plant extracts and may differ in their antiviral activity, we have compared the effect against influenza A virus (IAV) of Hamamelis virginiana L. bark extract, fractions enriched in tannins of different molecular weights and individual tannins of defined structures, including pseudotannins. We demonstrate antiviral activity of the bark extract against different IAV strains, including the recently emerged H7N9, and show for the first time that a tannin-rich extract inhibits human papillomavirus (HPV) type 16 infection. As the best performing antiviral candidate, we identified a highly potent fraction against both IAV and HPV, enriched in high molecular weight condensed tannins by ultrafiltration, a simple, reproducible and easily upscalable method. This ultrafiltration concentrate and the bark extract inhibited early and, to a minor extent, later steps in the IAV life cycle and tannin-dependently inhibited HPV attachment. We observed interesting mechanistic differences between tannin structures: High molecular weight tannin containing extracts and tannic acid (1702 g/mol) inhibited both IAV receptor binding and neuraminidase activity. In contrast, low molecular weight compounds (<500 g/mol) such as gallic acid, epigallocatechin gallate or hamamelitannin inhibited neuraminidase but not hemagglutination. Average molecular weight of the compounds seemed to positively correlate with receptor binding (but not neuraminidase) inhibition. In general, neuraminidase inhibition seemed to contribute little to the antiviral activity. Importantly, antiviral use of the ultrafiltration fraction enriched in high molecular weight condensed tannins and, to a lesser extent, the unfractionated bark extract was preferable over individual isolated compounds. These results are of interest for developing and improving plant-based antivirals.

Tannins from Hamamelis virginiana Bark Extract: Characterization and Improvement of the Antiviral Efficacy against Influenza A Virus and Human Papillomavirus

PubMed Central

Theisen, Linda L.; Erdelmeier, Clemens A. J.; Spoden, Gilles A.; Boukhallouk, Fatima; Sausy, Aurélie; Florin, Luise; Muller, Claude P.

2014-01-01

Antiviral activity has been demonstrated for different tannin-rich plant extracts. Since tannins of different classes and molecular weights are often found together in plant extracts and may differ in their antiviral activity, we have compared the effect against influenza A virus (IAV) of Hamamelis virginiana L. bark extract, fractions enriched in tannins of different molecular weights and individual tannins of defined structures, including pseudotannins. We demonstrate antiviral activity of the bark extract against different IAV strains, including the recently emerged H7N9, and show for the first time that a tannin-rich extract inhibits human papillomavirus (HPV) type 16 infection. As the best performing antiviral candidate, we identified a highly potent fraction against both IAV and HPV, enriched in high molecular weight condensed tannins by ultrafiltration, a simple, reproducible and easily upscalable method. This ultrafiltration concentrate and the bark extract inhibited early and, to a minor extent, later steps in the IAV life cycle and tannin-dependently inhibited HPV attachment. We observed interesting mechanistic differences between tannin structures: High molecular weight tannin containing extracts and tannic acid (1702 g/mol) inhibited both IAV receptor binding and neuraminidase activity. In contrast, low molecular weight compounds (<500 g/mol) such as gallic acid, epigallocatechin gallate or hamamelitannin inhibited neuraminidase but not hemagglutination. Average molecular weight of the compounds seemed to positively correlate with receptor binding (but not neuraminidase) inhibition. In general, neuraminidase inhibition seemed to contribute little to the antiviral activity. Importantly, antiviral use of the ultrafiltration fraction enriched in high molecular weight condensed tannins and, to a lesser extent, the unfractionated bark extract was preferable over individual isolated compounds. These results are of interest for developing and improving plant-based antivirals. PMID:24498245

Multifunctional silk-heparin biomaterials for vascular tissue engineering applications

PubMed Central

Seib, F. Philipp; Herklotz, Manuela; Burke, Kelly A.; Maitz, Manfred F.; Werner, Carsten; Kaplan, David L.

2013-01-01

Over the past 30 years, silk has been proposed for numerous biomedical applications that go beyond its traditional use as a suture material. Silk sutures are well tolerated in humans, but the use of silk for vascular engineering applications still requires extensive biocompatibility testing. Some studies have indicated a need to modify silk to yield a hemocompatible surface. This study examined the potential of low molecular weight heparin as a material for refining silk properties by acting as a carrier for vascular endothelial growth factor (VEGF) and improving silk hemocompatibility. Heparinized silk showed a controlled VEGF release over 6 days; the released VEGF was bioactive and supported the growth of human endothelial cells. Silk samples were then assessed using a humanized hemocompatibility system that employs whole blood and endothelial cells. The overall thrombogenic response for silk was very low and similar to the clinical reference material polytetrafluoroethylene. Despite an initial inflammatory response to silk, apparent as complement and leukocyte activation, the endothelium was maintained in a resting, anticoagulant state. The low thrombogenic response and the ability to control VEGF release support the further development of silk for vascular applications. PMID:24099708

Heparin bridge therapy and post-polypectomy bleeding.

PubMed

Kubo, Toshiyuki; Yamashita, Kentaro; Onodera, Kei; Iida, Tomoya; Arimura, Yoshiaki; Nojima, Masanori; Nakase, Hiroshi

2016-12-07

To identify risk factors for post-polypectomy bleeding (PPB), focusing on antithrombotic agents. This was a case-control study based on medical records at a single center. PPB was defined as bleeding that occurred 6 h to 10 d after colonoscopic polypectomy and required endoscopic hemostasis. As risk factors for PPB, patient-related factors including anticoagulants, antiplatelets and heparin bridge therapy as well as polyp- and procedure-related factors were evaluated. All colonoscopic hot polypectomies, endoscopic mucosal resections and endoscopic submucosal dissections performed between January 2011 and December 2014 were reviewed. PPB occurred in 29 (3.7%) of 788 polypectomies performed during the study period. Antiplatelet or anticoagulant agents were prescribed for 210 (26.6%) patients and were ceased before polypectomy except for aspirin and cilostazol in 19 cases. Bridging therapy using intravenous unfractionated heparin was adopted for 73 patients. The univariate analysis revealed that anticoagulants, heparin bridge, and anticoagulants plus heparin bridge were significantly associated with PPB ( P < 0.0001) whereas antiplatelets and antiplatelets plus heparin were not. None of the other factors including age, gender, location, size, shape, number of resected polyps, prophylactic clipping and resection method were correlated with PPB. The multivariate analysis demonstrated that anticoagulants and anticoagulants plus heparin bridge therapy were significant risk factors for PPB ( P < 0.0001). Of the 29 PPB cases, 4 required transfusions and none required surgery. A thromboembolic event occurred in a patient who took anticoagulant. Patients taking anticoagulants have an increased risk of PPB, even if the anticoagulants are interrupted before polypectomy. Heparin-bridge therapy might be responsible for the increased PPB in patients taking anticoagulants.

Vein wall re-endothelialization after deep vein thrombosis is improved with low-molecular-weight heparin.

PubMed

Moaveni, Daria K; Lynch, Erin M; Luke, Cathy; Sood, Vikram; Upchurch, Gilbert R; Wakefield, Thomas W; Henke, Peter K

2008-03-01

Vein wall endothelial turnover after stasis deep vein thrombosis (DVT) has not been well characterized. The purpose of this study was to quantify re-endothelialization after DVT and determine if low-molecular-weight heparin (LMWH) therapy affects this process. Stasis DVT was generated in the rat by inferior vena cava ligation, with harvest at 1, 4, and 14 days. Immunohistologic quantification of vascular smooth muscle cells and luminal endothelialization was estimated by positive staining for alpha-smooth muscle actin and von Willebrand factor, respectively. In separate experiments, rats were treated either before or after DVT with subcutaneous LMWH (3 mg/kg daily) until harvesting at 4 and 14 days. The inferior vena cava was processed for histologic analysis or was processed for organ culture after the thrombus was gently removed. The vein wall was stimulated in vitro with interleukin-1beta (1 ng/mL), and the supernatant was processed at 48 hours for nitric oxide. Cells were processed by real-time polymerase chain reaction for endothelial nitric oxide synthase, inducible nitric oxide synthase, cyclooxygenase-1 and -2, and thrombomodulin at 4 and 14 days, and collagen I and III at 14 days. Comparisons were done with analysis of variance or t test. A P < .05 was significant. Thrombus size peaked at 4 days, whereas luminal re-endothelialization increased over time (1 day, 11% +/- 2%; 4 days, 23% +/- 4%; 14 days, 64% +/- 7% (+) von Willebrand factor staining; P < .01, n = 3 to 4, compared with non-DVT control). Similarly, vascular smooth muscle cell staining was lowest at day 1 and gradually returned to baseline by 14 days. Both before and after DVT, LMWH significantly increased luminal re-endothelialization, without a difference in thrombus size at 4 days, but no significant difference was noted at 14 days despite smaller thrombi with LMWH treatment. Pretreatment with LMWH was associated with increased vascular smooth muscle cell area and recovery of certain inducible endothelial specific genes. No significant difference in nitric oxide levels in the supernatant was found at 4 days. At 14 days, type III collagen was significantly elevated with LMWH treatment. Venous re-endothelialization occurs progressively as the DVT resolves and can be accelerated with LMWH treatment, although this effect appears limited to the early time frame. These findings may have clinical relevance for LMWH timing and treatment compared with mechanical forms of therapy. How the vein wall endothelium responds after deep vein thrombosis (DVT) has not been well documented owing to limited human specimens. This report shows that low-molecular-weight heparin accelerates or protects the endothelium and preserves medial smooth muscle cell integrity after DVT, but that this effect is limited to a relatively early time period. Although most DVT prophylaxis is pharmacologic (a heparin agent), use of nonpharmacologic measures is also common. The use of heparin prophylaxis, compared with after DVT treatment, and the acceleration of post-DVT re-endothelialization require clinical correlation.

Current dosing of low-molecular-weight heparins does not reflect licensed product labels: an international survey

PubMed Central

Barras, Michael A; Kirkpatrick, Carl M J; Green, Bruce

2010-01-01

AIMS Low-molecular-weight heparins (LMWHs) are used globally to treat thromboembolic diseases; however, there is much debate on how to prescribe effectively for patients who have renal impairment and/or obesity. We aimed to investigate the strategies used to dose-individualize LMWH therapy. METHODS We conducted an online survey of selected hospitals in Australia, New Zealand (NZ), United Kingdom (UK) and the United States (US). Outcome measures included: the percentage of hospitals which recommended that LMWHs were prescribed according to the product label (PL), the percentage of hospitals that dose-individualized LMWHs outside the PL based on renal function, body weight and anti-Xa activity and a summary of methods used to dose-individualize therapy. RESULTS A total of 257 surveys were suitable for analysis: 84 (33%) from Australia, 79 (31%) from the UK, 73 (28%) from the US and 21 (8%) from NZ. Formal dosing protocols were used in 207 (81%) hospitals, of which 198 (96%) did not adhere to the PL. Of these 198 hospitals, 175 (87%) preferred to dose-individualize based on renal function, 128 (62%) on body weight and 48 (23%) by monitoring anti-Xa activity. All three of these variables were used in 29 (14%) hospitals, 98 (47%) used two variables and 71 (34%) used only one variable. CONCLUSIONS Dose-individualization strategies for LMWHs, which contravene the PL, were present in 96% of surveyed hospitals. Common individualization methods included dose-capping, use of lean body size descriptors to calculate renal function and the starting dose, followed by post dose anti-Xa monitoring. PMID:20573088

Current dosing of low-molecular-weight heparins does not reflect licensed product labels: an international survey.

PubMed

Barras, Michael A; Kirkpatrick, Carl M J; Green, Bruce

2010-05-01

Low-molecular-weight heparins (LMWHs) are used globally to treat thromboembolic diseases; however, there is much debate on how to prescribe effectively for patients who have renal impairment and/or obesity. We aimed to investigate the strategies used to dose-individualize LMWH therapy. We conducted an online survey of selected hospitals in Australia, New Zealand (NZ), United Kingdom (UK) and the United States (US). Outcome measures included: the percentage of hospitals which recommended that LMWHs were prescribed according to the product label (PL), the percentage of hospitals that dose-individualized LMWHs outside the PL based on renal function, body weight and anti-Xa activity and a summary of methods used to dose-individualize therapy. A total of 257 surveys were suitable for analysis: 84 (33%) from Australia, 79 (31%) from the UK, 73 (28%) from the US and 21 (8%) from NZ. Formal dosing protocols were used in 207 (81%) hospitals, of which 198 (96%) did not adhere to the PL. Of these 198 hospitals, 175 (87%) preferred to dose-individualize based on renal function, 128 (62%) on body weight and 48 (23%) by monitoring anti-Xa activity. All three of these variables were used in 29 (14%) hospitals, 98 (47%) used two variables and 71 (34%) used only one variable. Dose-individualization strategies for LMWHs, which contravene the PL, were present in 96% of surveyed hospitals. Common individualization methods included dose-capping, use of lean body size descriptors to calculate renal function and the starting dose, followed by post dose anti-Xa monitoring.

[Thrombocytopenia induced by type II heparin and myocardial infarct: 2 case reports].

PubMed

Antonijević, Nabojsa; Stanojević, Milica; Perunicić, Jovan; Djokić, Milan; Miković, Danijla; Kovac, Mirjana; Miljić, Predrag; Milosević, Rajko; Terzić, Branka; Vasiljević, Zorana

2004-01-01

Heparin-induced thrombocytopenia (HIT) type II is an acquired thrombophylic state and life-threatening immune complication of a heparin treatment mainly clinically manifested by marked thrombocytopenia, frequently by arterial and venous thrombosis, and sometimes by skin changes. Functional assay as heparin aggregation test and 14C-serotonin release assays are used in diagnostics as well as antigen assays of which detection tests for heparin-platelet factor 4 antibodies are most frequently used. Considering the fact that there is no single reliable assays for HIT II detection available, sometimes it is necessary to combine both of the above-mentioned types of assays. We present the case of a 57-year-old patient with an acute anterior myocardial infarction with cardiac insufficiency of III and IV degree according to Killip, recurrent ventricular fibrillation and diabetes mellitus type II developing thrombocytopenia to 37 x 10(9)/l accompanied with typical skin changes. The diagnosis was confirmed by the heparin aggregation test. The second patient aged 70 undergoing the treatment for anteroseptal myocardial infarction and reinfarction of the inferior wall complicated by a cardiogenic shock and acute right bundle branch block developed thrombocytopenia 59 x 10(9)/l on the third day of the heparin therapy, with the remark that he had received a heparin therapy during the first infarction as well. Antibodies against heparin-platelet factor 4 were detected by particle gel ID-HPF4 immuno-assay. In both patients, the disease had a lethal outcome despite all then available therapeutic measures applied. Further on we discuss advantages of certain types of tests, a therapy doctrine, need for urgent therapeutic measures, inclusive of the administration of antithrombins, avoidance of harmful procedures like low-molecular-weight heparins administration and prophylactic platelet transfusion as well as preventive measures.

Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25.

PubMed

White, Harvey D; Braunwald, Eugene; Murphy, Sabina A; Jacob, Ashok J; Gotcheva, Nina; Polonetsky, Leonid; Antman, Elliott M

2007-05-01

To determine the effects of age on outcomes in patients with STEMI treated with a strategy of enoxaparin (ENOX) vs. unfractionated heparin (UFH). In the ExTRACT-TIMI 25 trial, 20,479 patients with STEMI were randomized in a double-blind fashion to UFH or ENOX. A novel reduced dose of ENOX was administered to patients >or=75 years, and a reduced dose in those with an estimated creatinine clearance of < 30 mL/min. Anti-Xa levels were measured in a subset of patients (n = 73). The exposure to anti-Xa over time was lower in the elderly (AUC(0-12 h) P < 0.0001; AUC(steady-state) P = 0.0046). The relative risk reduction (RR) with ENOX on the primary endpoint, i.e. death or non-fatal recurrent myocardial infarction, was greater in patients < 75 years (20%) than > 75 years (6%), but the absolute benefits were similar. When compared with UFH, ENOX was associated with an RR of 1.67 for major bleeding, but the magnitude of the excess risk tended to be lower (RR = 1.15) in patients >or= 75 years assigned to ENOX. A dose reduction of ENOX in the elderly appears to be helpful in ameliorating bleeding risk. A strategy of ENOX was superior to UFH in both young and elderly patients with STEMI treated with fibrinolysis.

A dose-response study in animals to evaluate the anticoagulant effect of the stage 2 unfractionated heparin USP monograph change.

PubMed

Honchel, R; Carraway, J; Gopee, N; Callicott, R; Chen, J; Patton, R; Xu, Q; Zalkkar, J; Laniyonu, A; Krefting, I; Cato, M; Robie-Suh, K; Rieves, R

2011-08-01

The United States Pharmacopeia (USP) monograph for unfractionated heparin (UFH) was revised in October 2009. This revision was anticipated, based upon in vitro tests, to reduce UFH potency by approximately 10%. To study the potential in vivo consequences of the monograph change, we evaluated activated partial thromboplastin time (aPTT) and activated clotting time (ACT) responses in animals. Female mini-pigs and monkeys (n=8/species) were administered intravenously 60, 54, 48, or 42 U/kg and 50, 45, 40, or 35 U/kg "old" (pre-USP revision) UFH, respectively, in a Williams 4×4 crossover design. Blood samples for aPTT and ACT were collected at 15 min after dosing. The same study design was then repeated using "new" (post-USP revision) UFH. Mean "new" UFH aPTT and ACT values were generally lower than those for "old" UFH although individual animal responses varied considerably. The aPTT and ACT response was generally dose-proportional for both "old" and "new" UFH. These studies indicate that the USP monograph alteration for UFH may result in a modest reduction in the anticoagulant response across a population, but the variability in animal responses underscores the importance of individualization of clinical UFH dosing and the importance of anticoagulant test monitoring. Published by Elsevier Inc.

Risk of thrombosis and thromboembolic prophylaxis in obesity surgery: data analysis from the German Bariatric Surgery Registry.

PubMed

Stroh, C; Michel, N; Luderer, D; Wolff, S; Lange, V; Köckerling, F; Knoll, C; Manger, T

2016-11-01

Evidence-based data on optimal approach for prophylaxis of deep venous thrombosis (VTE) and pulmonary embolism (PE) in bariatric operations is discussed. Using antithrombotic prophylaxis, weight adjusted the risk of VTE and its complications have to be balanced with the increased bleeding risk. Since 2005, the current situation for bariatric surgery has been examined by quality assurance study in Germany. As a prospective multicenter observational study, data on the type, regimen, and time course of VTE prophylaxis were documented. The incidences of clinically diagnosed VTE or PE were derived during the in-hospital course and follow up. Overall, 31,668 primary bariatric procedures were performed between January 2005 and December 2013. Most performed operations were 3999 gastric banding (GB); 13,722 Roux-en-Y-gastric bypass (RYGBP); and 11,840 sleeve gastrectomies (SG). Gender (p = 0.945), surgical procedure (p = 0.666), or administration of thromboembolic prophylaxis (p = 0.272) had no statistical impact on the DVT incidence. By contrast, BMI (p = 0.116) and the duration of thromboembolic prophylaxis (p = 0.127) did impact the frequency of onset of DVT. Age, BMI, male gender, and a previous history of VTE are the most important risk factors. The drug of choice for VTE is heparin. LMWH should be given preference over unfractionated heparins due to their improved pharmacological properties, i.e., better bioavailability and longer half-life as well as ease of use. Despite the low incidence of VTE and PE, there is a lack of evidence. Therefore, prospective randomized studies are necessary to determine the optimal VTE prophylaxis for bariatric surgical patients.

Improved angiogenesis and healing in crush syndrome by fibroblast growth factor-2-containing low-molecular-weight heparin (Fragmin)/protamine nanoparticles.

PubMed

Takikawa, Makoto; Nakamura, Shingo; Ishihara, Masayuki; Takabayashi, Yuki; Fujita, Masanori; Hattori, Hidemi; Kushibiki, Toshihiro; Ishihara, Miya

2015-06-15

We produced fibroblast growth factor (FGF)-2-containing low-molecular-weight heparin (Fragmin)/protamine nanoparticles (FGF-2 + F/P NPs). The purpose of this study was to evaluate the effectiveness of the local administration of FGF-2 + F/P NPs on repairing crush syndrome (CS)-injured lesions after compression release using a nonlethal and reproducible CS injury rat model. The hind limbs of the anesthetized rats were compressed for 6 h using 3.6 kg blocks, as previously described. The effects of administering FGF-2 + F/P NPs (group A), F/P NPs alone (group B), FGF-2 alone (group C), and saline (control; group D) were examined. Motor function, surface blood flow in the hind limbs, and the wet/dry weight ratio in the tibialis anterior muscle were examined for 1-28 d after the compression release. Histologic analyses were also performed. At the middle and late stages (3-28 d after the compression release), group A had higher scores in the motor function, improved blood flow, increased number of blood vessels, and faster recovered muscle tissue, compared with the other groups. There was no significant difference in enhanced edema in the tibialis anterior muscle among all groups. The local administration of FGF-2 + F/P NPs to a CS-injured lesion was effective in repairing damaged muscle tissue after compression release. Copyright © 2015 Elsevier Inc. All rights reserved.

Does intrauterine injection of low-molecular-weight heparin improve the clinical pregnancy rate in intracytoplasmic sperm injection?

PubMed Central

El-Faissal, Yahia; Aboulghar, Mona; Mansour, Ragaa; Serour, Gamal I; Aboulghar, Mohamed

2016-01-01

Objective Heparin can modulate proteins, and influence processes involved in implantation and trophoblastic development. This study aimed to assess the improvement of clinical pregnancy and implantation rates after local intrauterine injection of low-molecular-weight heparin (LMWH) in patients undergoing intracytoplasmic sperm injection (ICSI). Methods A randomised case/control design was followed in women scheduled for ICSI. The study arm was injected with intrauterine LMWH during mock embryo transfer immediately following the ovum pickup procedure, while the control arm was given an intrauterine injection with a similar volume of tissue culture media. Side effects, the clinical pregnancy rate, and the implantation rate were recorded. Results The pregnancy rate was acceptable (33.9%) in the LMWH arm with no significant reported side effects, confirming the safety of the intervention. No statistically significant differences were found in the clinical pregnancy and implantation rates between both groups (p=0.182 and p=0.096, respectively). The odds ratio of being pregnant after intrauterine injection with LMWH compared to the control group was 0.572 (95% confidence interval [CI], 0.27−1.22), while the risk ratio was 0.717 (95% CI, 0.46−1.13; p=0.146). No statistical significance was found between the two groups in other factors affecting implantation, such as day of transfer (p=0.726), number of embryos transferred (p=0.362), or embryo quality. Conclusion Intrauterine injection of LMWH is a safe intervention, but the dose used in this study failed to improve the outcome of ICSI. Based on its safety, further research involving modification of the dosage and/or the timing of administration could result in improved ICSI success rates. PMID:28090465

[Hemorrhage, hemostasis and thrombosis in surgery].

PubMed

Páramo, José A

2009-06-01

Surgery is a leading cause of major hemorrhage as well as of thrombosis unless patients are administered appropriate antithrombotic prophylaxis after their thrombo-hemorrhagic risk has been stratified. Therefore, thorough preoperative evaluation is essential to minimize surgical complications. In cases of incoercible bleeding, drugs such as desmopressin, synthetic antifibrinolytics or recombinant factor VII can be administered. To prevent postoperative thrombosis, low molecular weight heparins or pentasaccharide have been shown to significantly reduce the incidence of thromboembolism.

A Prevention of Pre-eclampsia with the Use of Acetylsalicylic Acid and Low-molecular Weight Heparin - Molecular Mechanisms.

PubMed

Darmochwal-Kolarz, Dorota; Kolarz, Bogdan; Korzeniewski, Michal; Kimber-Trojnar, Zaneta; Patro-Malysza, Jolanta; Mierzynski, Radzisław; Przegalinska-Kałamucka, Monika; Oleszczuk, Jan

Pre-eclampsia appears to be the main cause for the maternal and fetal morbidity and mortality. Pregnant women with pre-eclampsia are more likely to be threatened with conditions which potentially may be lethal, such as: disseminated intravascular coagulation, cerebral hemorrhage, liver and renal failure. Pregnancy complicated with pre-eclampsia is also associated with a greater risk for iatrogenic prematurity, intrauterine growth retardation, premature abruption of placenta, and even intrauterine fetal death. In the majority of cases the reasons for arterial hypertension among pregnant women remain obscure. For the past decades, there were many abortive attempts in the use of some microelements, vitamins or specific diets, such as polyunsaturated fatty acids, for the prophylaxis of pre-eclampsia. Recently, it has been shown that a prevention of pre-eclampsia with the use of a lowmolecular- weight heparins (LMWHs) and acetylsalicylic acid (ASA) could considerably reduce the frequency of preeclampsia. In this review, we present the studies concerning the applications of LMWHs and aspirin in the prophylaxis of pre-eclampsia and some important data about the mechanisms of anti-inflammatory actions of LMWHs and ASA.

Low Molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High Risk of Preeclampsia.

PubMed

McLaughlin, Kelsey; Baczyk, Dora; Potts, Audrey; Hladunewich, Michelle; Parker, John D; Kingdom, John C P

2017-01-01

Low molecular weight heparin (LMWH) has been investigated for the prevention of severe preeclampsia, although the mechanisms of action are unknown. The objective of this study was to investigate the cardiovascular effects of LMWH in pregnant women at high risk of preeclampsia. Pregnant women at high risk of preeclampsia (n=25) and low-risk pregnant controls (n=20) at 22 to 26 weeks' gestation underwent baseline cardiovascular assessments. High-risk women were then randomized to LMWH or saline placebo (30 mg IV bolus and 1 mg/kg subcutaneous dose). Cardiovascular function was assessed 1 and 3 hours post randomization. The in vitro endothelial effects of patient serum and exogenous LMWH on human umbilical venous endothelial cells were determined. High-risk women demonstrated a reduced cardiac output, high resistance hemodynamic profile with impaired radial artery flow-mediated dilation compared with controls. LMWH increased flow-mediated dilation in high-risk women 3 hours after randomization compared with baseline and increased plasma levels of placental growth factor, soluble fms-like tyrosine kinase-1, and myeloperoxidase. Serum from high-risk women impaired endothelial cell angiogenesis and increased PlGF-1 and PlGF-2 transcription compared with serum from low-risk controls. Coexposure of high-risk serum with LMWH improved the in vitro angiogenic response such that it was equivalent to that of low-risk serum and promoted placental growth factor secretion. LMWH improves maternal endothelial function in pregnant women at high risk of developing preeclampsia, possibly mediated through increased placental growth factor bioavailability. © 2016 American Heart Association, Inc.

Quantitative analysis of genomic DNA degradation in whole blood under various storage conditions for molecular diagnostic testing.

PubMed

Permenter, Jessalyn; Ishwar, Arjun; Rounsavall, Angie; Smith, Maddie; Faske, Jennifer; Sailey, Charles J; Alfaro, Maria P

2015-12-01

Proper storage of whole blood is crucial for isolating nucleic acids from leukocytes and to ensure adequate performance of downstream assays in the molecular diagnostic laboratory. Short-term and long-term storage recommendations are lacking for successful isolation of genomic DNA (gDNA). Container type (EDTA or heparin), temperature (4 °C and room temperature) and time (1-130 days) were assessed as criterion for sample acceptance policies. The percentage of integrated area (%Ti) between 150 and 10,000 bp from the 2200 TapeStation electropherogram was calculated to measure gDNA degradation. Refrigerated EDTA samples yielded gDNA with low %Ti (high quality). Heparinized samples stored at room temperature yielded gDNA of worst quality. Downstream analysis demonstrated that the quality of the gDNA correlated with the quality of the data; samples with high %Ti generated significantly lower levels of high molecular weight amplicons. Recommendations from these analyses include storing blood samples intended for nucleic acid isolation in EDTA tubes at 4 °C for long term storage (>10 days). gDNA should be extracted within 3 days when blood is stored at room temperature regardless of the container. Finally, refrigerated heparinized samples should not be stored longer than 9 days if expecting high quality gDNA isolates. Laboratories should consider many factors, in addition to the results obtained herein, to update their policies for sample acceptance for gDNA extraction intended for molecular genetic testing. Copyright © 2015 Elsevier Ltd. All rights reserved.

Further purification of human pituitary-derived chondrocyte growth factor: heparin-binding and cross-reactivity with antiserum to basic FGF.

PubMed

Too, C K; Murphy, P R; Hamel, A M; Friesen, H G

1987-05-14

The previously described human pituitary-derived chondrocyte growth factor (CGF), mitogenic for rabbit fetal chondrocytes, was found to bind to heparin-Sepharose and was eluted with 1.5M NaCl. Further characterization of CGF demonstrated a molecular weight of 18-20 kD and cross-reactivity with antiserum to synthetic bovine basic fibroblast growth factor (FGF1-24). When human pituitaries were homogenized in 0.15 ammonium sulfate (pH 5.5) and the extract chromatographed on heparin-Sepharose, 98% of the mitogenic activity was adsorbed to heparin and eluted with 3M NaCl. These findings indicate that CGF is closely related or identical to basic FGF and that the bulk of mitogenic activity in the human pituitary extracts binds to heparin.

Molecular weight, polydispersity, and spectroscopic properties of aquatic humic substances

USGS Publications Warehouse

Chin, Y.-P.; Aiken, G.; O'Loughlin, E.

1994-01-01

The number- and weight-averaged molecular weights of a number of aquatic fulvic acids, a commercial humic acid, and unfractionated organic matter from four natural water samples were measured by high-pressure size exclusion chromatography (HPSEC). Molecular weights determined in this manner compared favorably with those values reported in the literature. Both recent literature values and our data indicate that these substances are smaller and less polydisperse than previously believed. Moreover, the molecular weights of the organic matter from three of the four natural water samples compared favorably to the fulvic acid samples extracted from similar environments. Bulk spectroscopic properties of the fulvic substances such as molar absorptivity at 280 nm and the E4/E6 ratio were also measured. A strong correlation was observed between molar absorptivity, total aromaticity, and the weight average molecular weights of all the humic substances. This observation suggests that bulk spectroscopic properties can be used to quickly estimate the size of humic substances and their aromatic contents. Both parameters are important with respect to understanding humic substance mobility and their propensity to react with both organic and inorganic pollutants. ?? 1994 American Chemical Society.

Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses.

PubMed

Bleker, Suzanne M; Buchmüller, Andrea; Chauleur, Céline; Ní Áinle, Fionnuala; Donnelly, Jennifer; Verhamme, Peter; Jacobsen, Anne Flem; Ganzevoort, Wessel; Prins, Martin; Beyer-Westendorf, Jan; DeSancho, Maria; Konstantinides, Stavros; Pabinger, Ingrid; Rodger, Marc; Decousus, Hervé; Middeldorp, Saskia

2016-08-01

Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study. The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events. The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of autoclave sterilization on the activity and structure of formulated heparin.

PubMed

Beaudet, Julie M; Weyers, Amanda; Solakyildirim, Kemal; Yang, Bo; Takieddin, Majde; Mousa, Shaker; Zhang, Fuming; Linhardt, Robert J

2011-08-01

The stability of a formulated heparin was examined during its sterilization by autoclaving. A new method to follow loss in heparin binding to the serine protease inhibitor, antithrombin III, and the serine protease, thrombin, was developed using a surface plasmon resonance competitive binding assay. This loss in binding affinity correlated well with loss in antifactor IIa (thrombin) activity as well as antifactor Xa activity as measured using conventional amidolytic assays. Autoclaving also resulted in a modest breakdown of the heparin backbone as confirmed by a slight reduction in number-averaged and weight-averaged molecular weight and an increase in polydispersity. Although no clear changes were observed by nuclear magnetic resonance spectroscopy, disaccharide composition analysis using high-performance liquid chromatography-electrospray ionization-mass spectrometry suggested that loss of selected sulfo groups had taken place. It is this sulfo group loss that probably accounts for a decrease in the binding of autoclaved heparin to antithrombin III and thrombin as well as the observed decrease in its amidolytic activity. Copyright © 2011 Wiley-Liss, Inc.

Mycoplasma pneumonia combined with pulmonary infarction in a child.

PubMed

Zhuo, Zhihong; Li, Fengyan; Chen, Xiaoxin; Jin, Peina; Guo, Qingmin; Wang, Huaili

2015-01-01

We reported a 9-year-old boy with mycoplasma pneumonia who developed pulmonary infarction. The child first had fever and cough, and then had difficult breathing. But, the signs of his lung were not obvious. Mycoplasma antibody IgM was positive. The child was given intravenous azithromycin for anti-infection, and intravenous low molecular weight heparin and oral warfarin for anti-coagulation. Although difficult breathing was relieved, sudden cardiac arrest occurred. His parents requested to give up treatment.

Structural analysis of low molecular weight heparin by ultraperformance size exclusion chromatography/time of flight mass spectrometry and capillary zone electrophoresis.

PubMed

Zhang, Qianqian; Chen, Xi; Zhu, Zhijia; Zhan, Xueqiang; Wu, Yanfang; Song, Lankun; Kang, Jingwu

2013-02-05

Although low molecular weight heparins (LMWHs) have been used as anticoagulant agents for over 2 decades, their structures have not been fully characterized. In this work, we propose a new strategy for the comprehensive structural analysis of LMWHs based on the combination of ultraperformance size exclusion chromatography/electrospray quadruple time-of-flight-mass spectrometry (UPSEC/Q-TOF-MS) and capillary zone electrophoresis (CZE). More than 70 components, including oligosaccharides with special structures such as 1,6-anhydro rings, saturated uronic acid at the nonreducing end and odd-numbered saccharides units were identified with UPSEC/Q-TOF-MS. Furthermore, a more detailed compositional analysis was accomplished by CZE analysis. PEG10000 and MgCl(2) were added to the background electrolyte to separate those saccharides with the nearly same charge-to-mass ratio. Baseline separation and quantification of all the building blocks of the most complex LMWH, namely, enoxaparin, which include 10 disaccharides, 1 trisaccharide, 2 tetrasaccharides, and, of particular importance, 4 1,6-anhyro derivatives, was achieved using CZE for the first time. Additionally, the peaks of oligosaccharides, in the absence of commercially available standards, were assigned on the basis of the linear correlation between the electrophoretic mobilities of oligosaccharides and their charge-to-mass ratios. These two approaches are simple and robust for structural analysis of LMWHs.

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

PubMed Central

Marzec, Ulla M.; Bush, Leslie; Di Cera, Enrico; Fernández, José A.; Berny, Michelle A.; Tucker, Erik I.; McCarty, Owen J. T.; Griffin, John H.; Hanson, Stephen R.

2007-01-01

The anticoagulant and anti-inflammatory enzyme, activated protein C (APC), naturally controls thrombosis without affecting hemostasis. We therefore evaluated whether the integrity of primary hemostasis was preserved during limited pharmacological antithrombotic protein C activator (PCA) treatment in baboons. The double-mutant thrombin (Trp215Ala/Glu217Ala) with less than 1% procoagulant activity was used as a relatively selective PCA and compared with systemic anticoagulation by APC and low-molecular-weight heparin (LMWH) at doses that inhibited fibrin deposition on thrombogenic segments of arteriovenous shunts. As expected, both systemic anticoagulants, APC (0.028 or 0.222 mg/kg for 70 minutes) and LMWH (0.325 to 2.6 mg/kg for 70 minutes), were antithrombotic and prolonged the template bleeding time. In contrast, PCA at doses (0.0021 to 0.0083 mg/kg for 70 minutes) that had antithrombotic effects comparable with LMWH did not demonstrably impair primary hemostasis. PCA bound to platelets and leukocytes, and accumulated in thrombi. APC infusion at higher circulating APC levels was less antithrombotic than PCA infusion at lower circulating APC levels. The observed dissociation of antithrombotic and antihemostatic effects during PCA infusion thus appeared to emulate the physiological regulation of intravascular blood coagulation (thrombosis) by the endogenous protein C system. Our data suggest that limited pharmacological protein C activation might exhibit considerable thrombosis specificity. PMID:17227834

Enhanced effects of low molecular weight heparin intercalated with layered double hydroxide nanoparticles on rat vascular smooth muscle cells.

PubMed

Gu, Zi; Rolfe, Barbara E; Xu, Zhi P; Thomas, Anita C; Campbell, Julie H; Lu, Gao Q M

2010-07-01

Surgical procedures to remove atherosclerotic lesions and restore blood flow also injure the artery wall, promoting vascular smooth muscle cell (SMC) phenotypic change, migration, proliferation, matrix production and ultimately, restenosis of the artery. Hence identification of effective anti-restenotic strategies is a high priority in cardiovascular research, and SMCs are a key target for intervention. This paper presents the in vitro study of layered double hydroxides (LDHs) as drug delivery system for an anti-restenotic drug (low molecular weight heparin, LMWH). The cytotoxicity tests showed that LDH itself had very limited toxicity at concentrations below 50 microg/mL over 6-day incubation. LDH nanoparticles loaded with LMWH (LMWH-LDHs) were prepared and tested on rat vascular SMCs. When conjugated to LDH particles, LMWH enhanced its ability to inhibit SMC proliferation and migration, with greater than above 60% reduction compared with the control (growth medium) over 3 or 7-day incubation. Cellular uptake studies showed that compared with LMWH alone, LMWH-LDH hybrids were internalized by SMCs more rapidly, and uptake was sustained over a longer time, possibly revealing the mechanisms underlying the enhanced biological function of LMWH-LDH. The results suggest the potential of LMWH-LDH as an efficient anti-restenotic drug for clinical application. Copyright 2010 Elsevier Ltd. All rights reserved.

Patient's Compliance on the Use of Extended Low Molecular Weight Heparin Post Major Pelvic Surgeries in Cancer Patients at King Hussein Cancer Center.

PubMed

Baba, M; Al-Masri, M; Salhab, M; El-Ghanem, M

2015-01-01

Effective Venous Thrombo-Embolism (VTE) prophylaxis is used in less than 50% of oncology patients despite its wide availability. Low molecular weight heparin (LMWH) as a daily injection is an essential tool for effective prophylaxis against deep vein thrombosis (DVT). Daily outpatient self-injection by the patients or their family members is common practice. The effectiveness of this measure depends on patient compliance. The purpose of this study is to determine the degree of compliance and the factors that affect compliance to the extended out-patient use of prophylactic LMWH for 1 month after major abdominal/pelvic surgeries in cancer patients at King Hussein Cancer Center (KHCC). Following major abdominal/pelvic surgeries, data on 160 cancer patients at KHCC from January 2007 until July 2012 were collected concerning knowledge of DVT and compliance with prophylactic self-injections by answering a questionnaire. We have achieved a high compliance rate, this was explained by the medical team's role in educating the patients about the risk of VTE and the importance of thromboprophylaxis. The compliance with self-injections was directly associated with younger age, employment and higher degree of education. The high compliance rate outside clinical trials can be achieved through comprehensive patient education by a well-qualified medical team, clarification of the importance of DVT prophylaxis and patients' support.

Vitamin K and cancer.

PubMed

Dahlberg, Sofia; Ede, Jacob; Schött, Ulf

2017-12-01

Subclinical vitamin K deficits refer to carboxylation defects of different types of vitamin K-dependent hepatic and extrahepatic so-called Gla proteins without prolongation of the prothrombin time. This condition has been reported in different clinical situations due to insufficient supply or malabsorption of vitamin K as well as drug interactions. This review discusses the effects of different vitamin K subspecies on tumour growth and the possible anti-tumour effects of increased vitamin K intake. Blocking carboxylation of vitamin K-dependent proteins with warfarin anticoagulation - what are the risks/benefits for carcinogenesis? Previous studies on both heparin and low molecular weight heparin blocking of the vitamin K-dependent factors X and II have shown tumour suppressive effects. Vitamin K has anti-inflammatory effects that could also impact carcinogenesis, but little data exists on this subject.

Heparin bridge therapy and post-polypectomy bleeding

PubMed Central

Kubo, Toshiyuki; Yamashita, Kentaro; Onodera, Kei; Iida, Tomoya; Arimura, Yoshiaki; Nojima, Masanori; Nakase, Hiroshi

2016-01-01

AIM To identify risk factors for post-polypectomy bleeding (PPB), focusing on antithrombotic agents. METHODS This was a case-control study based on medical records at a single center. PPB was defined as bleeding that occurred 6 h to 10 d after colonoscopic polypectomy and required endoscopic hemostasis. As risk factors for PPB, patient-related factors including anticoagulants, antiplatelets and heparin bridge therapy as well as polyp- and procedure-related factors were evaluated. All colonoscopic hot polypectomies, endoscopic mucosal resections and endoscopic submucosal dissections performed between January 2011 and December 2014 were reviewed. RESULTS PPB occurred in 29 (3.7%) of 788 polypectomies performed during the study period. Antiplatelet or anticoagulant agents were prescribed for 210 (26.6%) patients and were ceased before polypectomy except for aspirin and cilostazol in 19 cases. Bridging therapy using intravenous unfractionated heparin was adopted for 73 patients. The univariate analysis revealed that anticoagulants, heparin bridge, and anticoagulants plus heparin bridge were significantly associated with PPB (P < 0.0001) whereas antiplatelets and antiplatelets plus heparin were not. None of the other factors including age, gender, location, size, shape, number of resected polyps, prophylactic clipping and resection method were correlated with PPB. The multivariate analysis demonstrated that anticoagulants and anticoagulants plus heparin bridge therapy were significant risk factors for PPB (P < 0.0001). Of the 29 PPB cases, 4 required transfusions and none required surgery. A thromboembolic event occurred in a patient who took anticoagulant. CONCLUSION Patients taking anticoagulants have an increased risk of PPB, even if the anticoagulants are interrupted before polypectomy. Heparin-bridge therapy might be responsible for the increased PPB in patients taking anticoagulants. PMID:28018108

Deciphering the Role of Sulfonated Unit in Heparin-Mimicking Polymer to Promote Neural Differentiation of Embryonic Stem Cells.

PubMed

Lei, Jiehua; Yuan, Yuqi; Lyu, Zhonglin; Wang, Mengmeng; Liu, Qi; Wang, Hongwei; Yuan, Lin; Chen, Hong

2017-08-30

Glycosaminoglycans (GAGs), especially heparin and heparan sulfate (HS), hold great potential for inducing the neural differentiation of embryonic stem cells (ESCs) and have brought new hope for the treatment of neurological diseases. However, the disadvantages of natural heparin/HS, such as difficulty in isolating them with a sufficient amount, highly heterogeneous structure, and the risk of immune responses, have limited their further therapeutic applications. Thus, there is a great demand for stable, controllable, and well-defined synthetic alternatives of heparin/HS with more effective biological functions. In this study, based upon a previously proposed unit-recombination strategy, several heparin-mimicking polymers were synthesized by integrating glucosamine-like 2-methacrylamido glucopyranose monomers (MAG) with three sulfonated units in different structural forms, and their effects on cell proliferation, the pluripotency, and the differentiation of ESCs were carefully studied. The results showed that all the copolymers had good cytocompatibility and displayed much better bioactivity in promoting the neural differentiation of ESCs as compared to natural heparin; copolymers with different sulfonated units exhibited different levels of promoting ability; among them, copolymer with 3-sulfopropyl acrylate (SPA) as a sulfonated unit was the most potent in promoting the neural differentiation of ESCs; the promoting effect is dependent on the molecular weight and concentration of P(MAG-co-SPA), with the highest levels occurring at the intermediate molecular weight and concentration. These results clearly demonstrated that the sulfonated unit in the copolymers played an important role in determining the promoting effect on ESCs' neural differentiation; SPA was identified as the most potent sulfonated unit for copolymer with the strongest promoting ability. The possible reason for sulfonated unit structure as a vital factor influencing the ability of the copolymers may be attributed to the difference in electrostatic and steric hindrance effect. The synthetic heparin-mimicking polymers obtained here can offer an effective alternative to heparin/HS and have great therapeutic potential for nervous system diseases.

Rationale and design of the HepZero study: a prospective, multicenter, international, open, randomized, controlled clinical study with parallel groups comparing heparin-free dialysis with heparin-coated dialysis membrane (Evodial) versus standard care: study protocol for a randomized controlled trial.

PubMed

Rossignol, Patrick; Dorval, Marc; Fay, Renaud; Ros, Joan Fort; Loughraieb, Nathalie; Moureau, Frédérique; Laville, Maurice

2013-06-01

Anticoagulation for chronic dialysis patients with contraindications to heparin administration is challenging. Current guidelines state that in patients with increased bleeding risks, strategies that can induce systemic anticoagulation should be avoided. Heparin-free dialysis using intermittent saline flushes is widely adopted as the method of choice for patients at risk of bleeding, although on-line blood predilution may also be used. A new dialyzer, Evodial (Gambro, Lund, Sweden), is grafted with unfractionated heparin during the manufacturing process and may allow safe and efficient heparin-free hemodialysis sessions. In the present trial, Evodial was compared to standard care with either saline flushes or blood predilution. The HepZero study is the first international (seven countries), multicenter (10 centers), randomized, controlled, open-label, non-inferiority (and if applicable subsequently, superiority) trial with two parallel groups, comprising 252 end-stage renal disease patients treated by maintenance hemodialysis for at least 3 months and requiring heparin-free dialysis treatments. Patients will be treated during a maximum of three heparin-free dialysis treatments with either saline flushes or blood predilution (control group), or Evodial. The first heparin-free dialysis treatment will be considered successful when there is: no complete occlusion of air traps or dialyzer rendering dialysis impossible; no additional saline flushes to prevent clotting; no change of dialyzer or blood lines because of clotting; and no premature termination (early rinse-back) because of clotting.The primary objectives of the study are to determine the effectiveness of the Evodial dialyzer, compared with standard care in terms of successful treatments during the first heparin-free dialysis. If the non-inferiority of Evodial is demonstrated then the superiority of Evodial over standard care will be tested. The HepZero study results may have major clinical implications for patient care. ClinicalTrials.gov NCT01318486.

Multi-component hybrid hydrogels – understanding the extent of orthogonal assembly and its impact on controlled release† †Electronic supplementary information (ESI) available: Full experimental methods and further data from assays. See DOI: 10.1039/c7sc03301j Click here for additional data file.

PubMed Central

Vieira, Vânia M. P.; Hay, Laura L.

2017-01-01

This paper reports self-assembled multi-component hybrid hydrogels including a range of nanoscale systems and characterizes the extent to which each component maintains its own unique functionality, demonstrating that multi-functionality can be achieved by simply mixing carefully-chosen constituents. Specifically, the individual components are: (i) pH-activated low-molecular-weight gelator (LMWG) 1,3;2,4-dibenzylidenesorbitol-4′,4′′-dicarboxylic acid (DBS–COOH), (ii) thermally-activated polymer gelator (PG) agarose, (iii) anionic biopolymer heparin, and (iv) cationic self-assembled multivalent (SAMul) micelles capable of binding heparin. The LMWG still self-assembles in the presence of PG agarose, is slightly modified on the nanoscale by heparin, but is totally disrupted by the micelles. However, if the SAMul micelles are bound to heparin, DBS–COOH self-assembly is largely unaffected. The LMWG endows hybrid materials with pH-responsive behavior, while the PG provides mechanical robustness. The rate of heparin release can be controlled through network density and composition, with the LMWG and PG behaving differently in this regard, while the presence of the heparin binder completely inhibits heparin release through complexation. This study demonstrates that a multi-component approach can yield exquisite control over self-assembled materials. We reason that controlling orthogonality in such systems will underpin further development of controlled release systems with biomedical applications. PMID:29147525

Wake-Up Right-Sided Hemiparesis and Dysarthria in a Heavy Snorer.

PubMed

Brunetti, Valerio; Ferilli, Michela Ada Noris; Vollono, Catello; Di Franco, Antonino; Della Marca, Giacomo

2018-01-01

A 57-year-old man was referred to the ED for wake-up right-sided hemiparesis, hypoesthesia, dysarthria, and a National Institutes of Health Stroke Scale score of 7. Urgent CT brain scanning showed an ischemic lesion of the left temporal and insular lobes. The patient was admitted to the stroke unit, and acetylsalicylic acid 300 mg and low-molecular-weight heparin 6,000 IU were administered. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Generation of Anaphylatoxins by Human β-Tryptase from C3, C4, and C51

PubMed Central

Fukuoka, Yoshihiro; Xia, Han-Zhang; Sanchez-Muñoz, Laura B.; Dellinger, Anthony L.; Escribano, Luis; Schwartz, Lawrence B.

2009-01-01

Both mast cells and complement participate in innate and acquired immunity. The current study examines whether β-tryptase, the major protease of human mast cells, can directly generate bioactive complement anaphylatoxins. Important variables included pH, monomeric vs tetrameric forms of β-tryptase, and the β-tryptase-activating polyanion. The B12 mAb was used to stabilize β-tryptase in its monomeric form. C3a and C4a were best generated from C3 and C4, respectively, by monomeric β-tryptase in the presence of low molecular weight dextran sulfate or heparin at acidic pH. High molecular weight polyanions increased degradation of these anaphylatoxins. C5a was optimally generated from C5 at acidic pH by β-tryptase monomers in the presence of high molecular weight dextran sulfate and heparin polyanions, but also was produced by β-tryptase tetramers under these conditions. Mass spectrometry verified that the molecular mass of each anaphylatoxin was correct. Both β-tryptase-generated C5a and C3a (but not C4a) were potent activators of human skin mast cells. These complement anaphylatoxins also could be generated by β-tryptase in releasates of activated skin mast cells. Of further biologic interest, β-tryptase also generated C3a from C3 in human plasma at acidic pH. These results suggest β-tryptase might generate complement anaphylatoxins in vivo at sites of inflammation, such as the airway of active asthma patients where the pH is acidic and where elevated levels of β-tryptase and complement anaphylatoxins are detected. PMID:18424754

Assessment of Heparin Anticoagulation Measured Using i-STAT and Hemochron Activated Clotting Time.

PubMed

Maslow, Andrew; Chambers, Alison; Cheves, Tracey; Sweeney, Joseph

2018-01-31

Adequate anticoagulation, measured using activated clotting time (ACT), is important during vascular and cardiac surgeries. Unfractionated heparin is the most common anticoagulant used. The purpose of this analysis was to compare the i-STAT ACT (iACT) to the Hemochron ACT (hACT), both of which were then compared to anti-factor Xa (anti-Xa) assay, a representation of heparin level and activity. Prospective study. Tertiary care cardiovascular center. Eleven consecutive elective adult cardiac surgical patients. Prior to cardiopulmonary bypass, ACTs were measured using i-STAT and Hemochron technologies and compared to each other and to anti-Xa assay prior to and during a cumulative administration of heparin. Data were compared using bias analyses. Heparin (300 U/kg) was administered in quarterly doses. Coagulation labs were collected prior to and 3 minutes after each quarterly dose of heparin. The baseline ACTs for i-STAT and Hemochron were 147 and 142 seconds, respectively. A significant association was found between iACT and hACT (p = 0.002). The iACT measurements underestimated hACT at ACT levels >180 seconds or anti-Xa levels >0.75 U/mL. No significant difference was found between ACT data at anti-Xa levels <0.5 U/mL. There was a good association between the iACT and hACT; however, the 2 tests are not equivalent. Overall, the iACT underestimated the hACT. Agreement between the ACT technologies was good at lower ACTs and anti-Xa levels, but declined with an anti-Xa >0.75 U/mL. Copyright © 2018 Elsevier Inc. All rights reserved.

[Effect of Low Molecular Weight Heparin Calcium Combined Compound Danshen Injection on Perinatal Outcomes of Nephrotic Syndrome Patients with Early Onset Severe Pre-eclampsia].

PubMed

Tong, Chong-xin; Xing, Xiao-fen; Qiao, Shu-hua; Liu, Lin; Shan, Ling

2015-08-01

To observe the effect of low molecular weight heparin calcium (LMWHC) combined Compound Danshen Injection (DI) on nephrotic syndrome patients with early onset severe preeclampsia. Totally 80 nephrotic syndrome patients with early onset severe pre-eclampsia were randomly assigned to four groups voluntarily, i.e., Group A (22 cases, treated by magnesium sulfate), B (19 cases, treated by magnesium sulfate plus LMWHC), C (21 cases, magnesium sulfate plus DI), D (18 cases, magnesium sulfate plus LMWHC and DI). Umbilical arterial S/D ratios, amniotic fluid index (AFI), prolonged gestational age, placenta weight, neonatal weight, and Apgar score were compared among the four groups. Compared with before treatment in the same group, umbilical arterial S/D ratios decreased in the four groups (P <0. 05). AFI decreased in Group A, while it increased in Group B, C, and D (P<0. 05). Compared with Group A at the same time point, umbilical arterial S/D ratios decreased, and AFI increased in Group B, C, and D (P <0. 01 , P <0. 05). Prolonged gestational age and neonatal weight were increased in Group B, C, and D (P <0. 01, P <0. 05). Placenta weight were increased in Group B and D (P <0. 05). Apgar scores at 1 and 5 min were improved in Group D (P <0. 05). Compared with Group B and C at the same time point, umbilical arterial S/D ratios decreased, and AFI increased in Group D (P<0. 05). Compared with Group B, prolonged gestational age and placenta weight were decreased in Group C, but prolonged gestational age and placenta weight were increased in Group D (P <0.05). Compared with Group C, prolonged gestational age, placenta weight, and neonatal weight were increased in Group D (P <0. 05). Treatment of nephrotic syndrome patients with early onset severe pre-eclampsia by LMWHC combined DI could prolong gestational ages, obviously improve prenatal outcomes, with better effect obtained than using any of them alone.

Acute renal infarction from a cardiac thrombus.

PubMed

Nasser, Nicola J; Abadi, Sobhi; Azzam, Zaher S

2007-11-01

A 53-year-old man presented to hospital 2 hours after the abrupt onset of left upper abdominal pain. He was treated with analgesics and discharged after 4 hours of observation, but presented to another hospital 2 hours later with severe left abdominal pain. His past medical history included ischemic dilated cardiomyopathy due to recurrent myocardial infarction. Physical examination, electrocardiography, laboratory investigations, contrast-enhanced computed tomography, and transesophageal echocardiography. Renal artery thromboembolism resulting from dilated cardiomyopathy, severely reduced cardiac function and an intracardiac thrombus. Anticoagulation with unfractionated heparin followed by enoxaparin and warfarin.

Anticoagulation management associated with extracorporeal circulation.

PubMed

Sniecinski, Roman M; Levy, Jerrold H

2015-06-01

The use of extracorporeal circulation requires anticoagulation to maintain blood fluidity throughout the circuit, and to prevent thrombotic complications. Additionally, adequate suppression of hemostatic activation avoids the unnecessary consumption of coagulation factors caused by the contact of blood with foreign surfaces. Cardiopulmonary bypass represents the greatest challenge in this regard, necessitating profound levels of anticoagulation during its conduct, but also quick, efficient reversal of this state once the surgical procedure is completed. Although extracorporeal circulation has been around for more than half a century, many questions remain regarding how to best achieve anticoagulation for it. Although unfractionated heparin is the predominant agent used for cardiopulmonary bypass, the amount required and how best to monitor its effects are still unresolved. This review discusses the use of heparin, novel anticoagulants, and the monitoring of anticoagulation during the conduct of cardiopulmonary bypass. Copyright © 2015 Elsevier Ltd. All rights reserved.

Catheter-related thrombosis: biological and clinical evidence for risk with currently available anticoagulants.

PubMed

Montalescot, Gilles; Walenga, Jeanine M

2009-01-01

Anticoagulants used during percutaneous coronary intervention (PCI) should not only prevent coronary events, but also minimize the risk of periprocedural complications. Current anticoagulation therapies for PCI include unfractionated heparin (UFH), enoxaparin, fondaparinux, and bivalirudin. UFH and enoxaparin have good efficacy and safety profiles in PCI; furthermore, associated periprocedural complications such as catheter thrombosis are rare. Although newer anticoagulants seem safe and effective in patients with acute coronary syndrome, clinical trial data suggest that some pure factor Xa (FXa) inhibitors are associated with increased rates of catheter thrombosis, compared with heparin-based agents. Experimental systems show that polytherapeutic agents, including UFH and enoxaparin, are more effective anticoagulants than certain single-target agents. More studies are needed to assess whether catheter thrombosis is a class-, drug-, or dose-related effect, and how best to prevent it. Future trials should report the rates of periprocedural complications when assessing the safety of novel anticoagulation therapies in PCI.

pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: in vitro and in vivo evaluation.

PubMed

Fan, Bo; Xing, Yang; Zheng, Ying; Sun, Chuan; Liang, Guixian

2016-01-01

The aim of present study was to investigate a pH-responsive and mucoadhesive nanoparticle system for oral bioavailability enhancement of low-molecular weight heparin (LMWH). The thioglycolic acid (TGA) was first covalently attached to chitosan (CS) with 396.97 ± 54.54 μmol thiol groups per gram of polymer and then the nanoparticles were prepared with thiolated chitosan (TCS) and pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) by ionic cross-linking method. The obtained nanoparticles were characterized for the shape, particle size, zeta potential, drug entrapment efficiency and loading capacity. In vitro results revealed the acid stability of pH-responsive nanoparticles, which had a significant control over LMWH release and could effectively protect entrapped drugs in simulated gastric conditions. By the attachment of the thiol ligand, an improvement of permeation-enhancing effect on freshly excised carp intestine (1.86-fold improvement) could be found. The mucoadhesive properties were evaluated using fluorescently labeled TCS or CS nanoparticles. As compared with the controls, a significant improvement of mucoadhesion on rat intestinal mucosa was observed in TCS/HPMCP nanoparticles via confocal laser scanning microscopy. The activated partial thromboplastin time (APTT) was significantly prolonged and an increase in the oral bioavailability of LMWH was turned out to be pronounced after oral delivered LMWH-loaded TCS/HPMCP nanoparticles in rats, which suggested enhanced anticoagulant effects and improved absorption of LMWH. In conclusion, pH-responsive TCS/HPMCP nanoparticles hold promise for oral delivery of LMWH.

Improved Survival of Full-Thickness Skin Graft With Low-Molecular Weight Heparin-Protamine Micro/Nanoparticles Including Platelet-Rich Plasma.

PubMed

Takabayashi, Yuki; Ishihara, Masayuki; Kuwabara, Masahiro; Takikawa, Makoto; Nakamura, Shingo; Hattori, Hidemi; Kiyosawa, Tomoharu

2017-05-01

Activated platelet-rich plasma secrets many growth factors (GFs), and low-molecular weight heparin-protamine micro/nanoparticles (LMWH-P M/NPs) significantly interact with, enhance, and stabilize the secreted GFs. The purpose of this study was to evaluate the effects of LMWH-P M/NPs and GFs (from platelet-rich plasma) on full-thickness skin graft (FTSG). A total of 96 inbred male rats were anesthetized and 4-cm full-thickness skin wound were created on dorsal skin of rats. LMWH-P M/NPs and GFs, LMWH-P M/NPs, GFs and saline (control) were then injected evenly into cutaneous muscles at the wound. The next day, the rats underwent FTSG. On the indicated days after FTSG, blood flow of FTSG site (wound bed and FTSG) was examined by 2-dimensional laser Doppler blood flowmeter. On 10 days, pictures of FTSG site were taken and FTSG survival rate was evaluated. Histologic analyses of skin samples were performed on 4, 7, and 10 days. Treatment of full-thickness skin wound with LMWH-P M/NPs and GFs effectively promoted survival rate of FTSG and blood flow of FTSG site compared with those treated with GFs, LMWH-P M/NPs, and control. LMWH-P M/NPs and GFs also promoted new vessel formation at FTSG site. The prior injection of LMWH-P M/NPs and GFs into wound bed increases FTSG survival rate, and promotes blood flow and angiogenesis at FTSG site.

Treatment of Experimentally Induced Caval Thrombosis With Oral Low Molecular Weight Heparin and Delivery Agent in a Porcine Model of Deep Venous Thrombosis

PubMed Central

Salartash, Khashayar; Lepore, Michael; Gonze, Mark D.; Leone-Bay, Andrea; Baughman, Robert; Charles Sternbergh, W.; Bowen, John C.; Money, Samuel R.

2000-01-01

Objective This experiment evaluated enterally administered low molecular weight heparin (LMWH) combined with sodium N-[10-(2-hydroxybenzoyl)amino] decanoate (SNAD) for the treatment of induced venous thrombosis. Summary Background Data SNAD is a delivery agent that potentiates the gastrointestinal absorption of LMWH. Methods Forty female pigs were equally assigned to four groups: control (saline); enteral LMWH, 2,000 IU/kg; enteral SNAD, 50 mg/kg; and enteral LMWH, 2,000 IU/kg and SNAD, 50 mg/kg. Under fluoroscopic guidance, the infrarenal vena cava was occluded with a balloon catheter. Two milliliters of ethanol was injected into the distal vena cava. The inflated balloon catheter remained in situ for 5 days, at which time animals angiographically exhibiting thrombus were randomly assigned to the four groups. Study medications were dosed at 12-hour intervals by means of a gastrostomy tube placed previously. After 7 days of treatment, thrombus was extracted. A separate group of 10 animals was used to measure plasma antifactor Xa levels for 6 hours after enteral dosing of LMWH/SNAD. Results The amount of residual thrombus after treatment with enteral LMWH/SNAD was significantly decreased. Antifactor Xa levels were significantly elevated in the LMWH/SNAD group versus baseline. Conclusion The combination of enterally administered LMWH and SNAD given for 7 days appeared to decrease caval thrombosis in this model of deep vein thrombosis. Enteral LMWH/SNAD effected an increase in plasma levels of antifactor Xa. PMID:10816621

Development of subcutaneous sustained release nanoparticles encapsulating low molecular weight heparin

PubMed Central

Jogala, Satheesh; Rachamalla, Shyam Sunder; Aukunuru, Jithan

2015-01-01

The objective of the present research work was to prepare and evaluate sustained release subcutaneous (s.c.) nanoparticles of low molecular weight heparin (LMWH). The nanoparticles were prepared by water–in-oil in-water (w/o/w) emulsion and evaporation method using different grades of polylactide co-glycolide (50:50, 85:15), and different concentrations of polyvinyl alcohol (0.1%, 0.5%, 1%) aqueous solution as surfactant. The fabricated nanoparticles were evaluated for size, shape, zeta potential, encapsulation efficiency, in vitro drug release, and in vivo biological activity (anti-factor Xa activity) using the standard kit. The drug and excipient compatibility was analyzed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The formation of nanoparticles was confirmed by scanning electron microscopy; nanoparticles were spherical in shape. The size of prepared nanoparticles was found between 195 nm and 251 nm. The encapsulation efficiency of the nanoparticles was found between 46% and 70%. In vitro drug, release was about 16–38% for 10 days. In vivo drug, release shows the sustained release of drug for 10 days in rats. FTIR studies indicated that there was no loss in chemical integrity of the drug upon fabrication into nanoparticles. DSC and XRD results demonstrated that the drug was changed from the crystalline form to the amorphous form in the formulation during the fabrication process. The results of this study revealed that the s.c. nanoparticles were suitable candidates for sustained delivery of LMWH. PMID:25878975

Early low-anticoagulant desulfated heparin after traumatic brain injury: Reduced brain edema and leukocyte mobilization is associated with improved watermaze learning ability weeks after injury.

PubMed

Nagata, Katsuhiro; Suto, Yujin; Cognetti, John; Browne, Kevin D; Kumasaka, Kenichiro; Johnson, Victoria E; Kaplan, Lewis; Marks, Joshua; Smith, Douglas H; Pascual, Jose L

2018-05-01

Unfractionated heparin administered immediately after traumatic brain injury (TBI) reduces brain leukocyte (LEU) accumulation, and enhances early cognitive recovery, but may increase bleeding after injury. It is unknown how non-anticoagulant heparins, such as 2,3-O desulfated heparin (ODSH), impact post-TBI cerebral inflammation and long-term recovery. We hypothesized that ODSH after TBI reduces LEU-mediated brain inflammation and improves long-term neurologic recovery. CD1 male mice (n = 66) underwent either TBI (controlled cortical impact [CCI]) or sham craniotomy. 2,3-O desulfated heparin (25 mg/kg [25ODSH] or 50 mg/kg [50ODSH]) or saline was administered for 48 hours after TBI in 46 animals. At 48 hours, intravital microscopy visualized rolling LEUs and fluorescent albumin leakage in the pial circulation, and the Garcia Neurologic Test assessed neurologic function. Brain edema (wet/dry ratio) was evaluated post mortem. In a separate group of animals (n = 20), learning/memory ability (% time swimming in the Probe platform quadrant) was assessed by the Morris Water Maze 17 days after TBI. Analysis of variance with Bonferroni correction determined significance (p < 0.05). Compared with CCI (LEU rolling: 32.3 ± 13.7 LEUs/100 μm per minute, cerebrovascular albumin leakage: 57.4 ± 5.6%), both ODSH doses reduced post-TBI pial LEU rolling (25ODSH: 18.5 ± 9.2 LEUs/100 μm per minute, p = 0.036; 50ODSH: 7.8 ± 3.9 LEUs/100 μm per minute, p < 0.001) and cerebrovascular albumin leakage (25ODSH: 37.9 ± 11.7%, p = 0.001, 50ODSH: 32.3 ± 8.7%, p < 0.001). 50ODSH also reduced injured cerebral hemisphere edema (77.7 ± 0.4%) vs. CCI (78.7 ± 0.4 %, p = 0.003). Compared with CCI, both ODSH doses improved Garcia Neurologic Test at 48 hours. Learning/memory ability (% time swimming in target quadrant) was lowest in CCI (5.9 ± 6.4%) and significantly improved in the 25ODSH group (27.5 ± 8.2%, p = 0.025). 2,3-O desulfated heparin after TBI reduces cerebral LEU recruitment, microvascular permeability and edema. 2,3-O desulfated heparin may also improve acute neurologic recovery leading to improved learning/memory ability weeks after injury.

The mechanisms how heparin affects the tumor cell induced VEGF and chemokine release from platelets to attenuate the early metastatic niche formation

PubMed Central

Ponert, Jan Moritz; Schwarz, Svenja; Haschemi, Reza; Müller, Jens; Pötzsch, Bernd; Bendas, Gerd

2018-01-01

Metastasis is responsible for the majority of cancer associated fatalities. Tumor cells leaving the primary tumor and entering the blood flow immediately interact with platelets. Activated platelets contribute in different ways to cancer cell survival and proliferation, e.g. in formation of the early metastatic niche by release of different growth factors and chemokines. Here we show that a direct interaction between platelets and MV3 melanoma or MCF7 breast cancer cells induces platelet activation and a VEGF release in citrated plasma that cannot be further elevated by the coagulation cascade and generated thrombin. In contrast, the release of platelet-derived chemokines CXCL5 and CXCL7 depends on both, a thrombin-mediated platelet activation and a direct interaction between tumor cells and platelets. Preincubation of platelets with therapeutic concentrations of unfractionated heparin reduces the tumor cell initiated VEGF release from platelets. In contrast, tumor cell induced CXCL5 and CXCL7 release from platelets was not impacted by heparin pretreatment in citrated plasma. In defibrinated, recalcified plasma, on the contrary, heparin is able to reduce CXCL5 and CXCL7 release from platelets by thrombin inhibition. Our data indicate that different chemokines and growth factors in diverse platelet granules are released in tightly regulated processes by various trigger mechanisms. We show for the first time that heparin is able to reduce the mediator release induced by different tumor cells both in a contact and coagulation dependent manner. PMID:29346400

Compliance with the 2009 Royal College of Obstetricians and Gynaecologists guidelines for venous thromboembolic disease prophylaxis in pregnancy and postpartum period in Uruguay.

PubMed

Grille, Sofía; Vitureira, Gerardo; Morán, Rosario; Retamosa, Lucía; Alonso, Valeria; Gómez, Luis M; Quartara, Federico; Feldman, Florencia; López, Valentina; Turcatti, Paola; Castro, Viviana; Sosa, Leonardo; Guillermo, Cecilia; Díaz, Lilián; Stevenazzi, Mariana

2018-04-01

: Venous thromboembolism remains as one of the leading causes of maternal death. Prevention of venous thromboembolism in the obstetric population is challenging as recommendations for prophylaxis have low grade of evidence. Risk factors and prophylaxis guidelines have been highlighted by Royal College of Obstetricians and Gynaecologists. In 2014, we developed a written alert following this guidelines to guide thromboprophylaxis. The aim of this study is to assess recommendations compliance. This study was conducted at University-Hospital in Uruguay from January 2014 to December 2016. A total of 1035 women were enrolled and stratified in high, intermediate or low risk based on Royal College of Obstetricians and Gynaecologists guidelines. Thromboprophylaxis was recommended for women at intermediate and high risk. Women were followed up to assess symptomatic thromboembolism or haemorrhagic complications. A total of 309 were pregnant and 731 puerperal. Median age was 24 (19-29) years old. Of them, 3.0% (n = 31) were at high risk and 35.4% (n = 366) at intermediate risk. All high-risk women received prophylaxis with low-molecular-weight heparin. Of the 366 intermediate-risk women, 52.7% received prophylaxis. Venous thromboembolism was developed in only one woman of the intermediate group, who had received prophylaxis. Bleeding complications were not observed. Awareness of the thrombotic risk, as conferred by an easy and suitable risk assessment, has the potential to improve venous thromboembolism prophylaxis in pregnant and puerperal women. We have a good guidelines compliance with the written alert in the high-risk women group. However, we have to improve low-molecular-weight heparin indication in intermediate-risk group, especially in postcaesarean women.

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecular-weight preparations in rhinoconjunctivitis and asthma.

PubMed

Bousquet, J; Maasch, H J; Hejjaoui, A; Skassa-Brociek, W; Wahl, R; Dhivert, H; Michel, F B

1989-10-01

Specific immunotherapy with unmodified formalinized allergoids is effective in grass-pollen allergy, but systemic reactions have been observed. A high-molecular-weight formalinized allergoid (HMW-GOID) was fractionated by gel filtration, retaining molecules of greater than 85,000 daltons in the expectation of improving safety without sacrificing efficacy. HMW-GOID and unfractionated allergoid (GOID) had a similar allergenic activity assessed by RAST inhibition, but the HMW-GOID preparation was 65 times less reactive when it was tested by skin prick test than the GOID preparation. A double-blind, placebo-controlled study was carried out in grass pollen-allergic patients with placebo (14 patients), GOID (15 patients), and HMW-GOID (13 patients). An additional group of 18 patients was treated by a rush schedule with a standardized orchard grass-pollen extract. A similar mean cumulative dose was administered with both allergoids. The fractionated allergoid only elicited minor systemic reactions similar to reactions elicited by placebo, whereas 20% of patients treated by GOID and 5.5% of patients receiving the standardized extract had a severe systemic reaction. For rhinitis, conjunctivitis, and asthma, the HMW-GOID and the standardized extract had a similar efficacy, significantly greater than placebo. GOID was less effective than the other two active treatments but was significantly more effective than placebo treatment for asthma and conjunctivitis.

Male hamster copulatory responses to a high molecular weight fraction of vaginal discharge: effects of vomeronasal organ removal.

PubMed

Clancy, A N; Macrides, F; Singer, A G; Agosta, W C

1984-10-01

The importance of the vomeronasal (accessory olfactory) system for the copulatory responses of male hamsters to a high molecular weight fraction (HMF) of vaginal discharge was assessed in animals that had their vomeronasal organs (VNO) removed. These organs were extirpated bilaterally using an oral approach through the palate so as to eliminate the peripheral afferents to the accessory olfactory bulb (AOB) with minimal or no damage to the main olfactory system. The selective peripheral deafferentation procedure was verified by applying horseradish peroxidase intranasally following intraperitoneal injections of epinephrine to facilitate the vomeronasal pumping mechanism that draws fluids into the VNO. Heavy, bilateral anterograde labeling was evident in the olfactory nerve afferents within the main olfactory bulb of males that had their VNO removed and of animals that received sham surgery. Sham-operated males also had heavy, bilateral labeling in the vomeronasal nerve afferents within the AOB, whereas no such labeling occurred among animals with bilateral removal of the VNO. In sham-operated animals, both the HMF and the unfractionated discharge significantly increased the incidence of intromission attempts toward anesthetized males (surrogate females) whose hindquarters were scented with these stimuli. The unfractionated discharge also produced a significant elevation of overt copulatory behavior in males with selective peripheral deafferentation of the vomeronasal system, whereas the HMF did not facilitate copulatory behavior in these animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Heparin-mimetic polyurethane hydrogels with anticoagulant, tunable mechanical property and controllable drug releasing behavior.

PubMed

Chen, Yuan; Wang, Rui; Wang, Yonghui; Zhao, Weifeng; Sun, Shudong; Zhao, Changsheng

2017-05-01

In the present study, novel heparin-mimetic polyurethane hydrogels were prepared by introducing chemical crosslinked sulfated konjac glucomannan (SKGM). Scanning electron microscopy (SEM) results indicated that the introduction of SKGM and the increase of the molecular weight of diol segments could enlarge the pore sizes of the hydrogels. The swelling behavior corresponded with the SEM results, and the hydrogels could absorb more water after the modification. The modification also led to an improvement in the mechanical property. Meanwhile, the SKGM and the modified polyurethane hydrogels showed excellent hemocompatibility. The thromboplastin time of SKGM could reach up to 182.9s. Gentamycin sulfate (GS) was used as a model drug to be loaded into the hydrogels, and the loading amount was increased ca. 50% after the introduction of SKGM, thus resulting in high bactericidal efficiency. The results indicated that the introduction of SKGM and the alternation in the diol's molecular weight bestowed polyurethane hydrogels with promising properties of integrated blood-compatibility, mechanical properties and drug loading-releasing behavior. Therefore, the heparin-mimetic multifunctional polyurethane hydrogels have great potential to be used in biomedical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics.

PubMed

Shastri, Madhur D; Stewart, Niall; Eapen, Mathew; Peterson, Gregory M; Zaidi, Syed Tabish R; Gueven, Nuri; Sohal, Sukhwinder Singh; Patel, Rahul P

2015-01-01

T-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects. PBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release. Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin. Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases.

Heparin induced alterations in clearance and distribution of blood-borne microparticles following operative trauma.

PubMed

Saba, T M; Antikatzides, T G

1979-04-01

The influence of systemic heparin administration on the vascular clearance and tissue distribution of blood-borne microparticles was evaluated in normal rats and rats after operation (laparotomy plus intestinal manipulation) utilizing an (131)I- colloid which is phagocytized by the reticuloendothelial system (RES). Intravenous heparin administration (100 USP/100g body weight) into normal animals three minutes prior to colloid injection (50 mg/lOOg) induced a significant increase in pulmonary localization of the microparticles as compared to nonheparinized control rats, while hepatic and splenic uptake were decreased. Surgical trauma decreased hepatic RE uptake and increased pulmonary localization of the microparticles when injected systemically at 60 minutes postsurgery. Heparin administration 60 minutes after surgery and three minutes prior to colloid injection, magnified the increased pulmonary localization response with an associated further depression of the RES. The ability of heparin to alter both RE clearance function and lung localization of microparticles was dose dependent and a function of the interval between heparin administration and systemic particulate infusion. Thus, low dose heparin administration was capable of stimulating RE activity while heparin in doses of excess of 50 USP units/lOOg body weight decreased RE function. These findings suggest that the functional state of the hepatic RE system can be greatly affected in a dose-dependent manner by systemic heparin administration which may influence distribution of blood-borne microparticles.

Cerebral Venous Sinus Thrombosis in a Patient with Undiagnosed Factor VII Deficiency.

PubMed

Qadir, Hira; Rashid, Anila; Adil, Salman Naseem

2017-09-01

Factor VII (FVII) deficiency is one of the rare inherited bleeding disorders. Thrombosis has been occasionally described in inherited FVII deficiency. Here, we report a young female with undiagnosed FVII deficiency who presented with cerebral venous sinus thrombosis (CVST). Oral contraceptive pill was found to be prothrombotic risk factor. The CVSToccurred in spite of the congenital FVII deficiency indicating that no definitive antithrombotic protection is assured by this defect. Low molecular weight heparin and anti-Xa assay were found to be safe choice of anticoagulation and monitoring, respectively, in this patient.

A nurse-led ambulatory care pathway for patients with deep venous thrombosis in an acute teaching hospital.

PubMed

Deagle, Jennifer; Allen, James; Mani, Raj

2005-06-01

This article describes the management of deep vein thrombosis (DVT) using an ambulatory nurse-led pathway and the compression technique using duplex ultrasound. This pathway permits the management of the "walking wounded" as well as other patients at varying risks of having DVT and in so doing has changed the approach toward the management of this common clinical event. The success of the described pathway is attributed to the development of low molecular weight heparin and the reliability of diagnostics.

Interaction of fucoidan with proteases and inhibitors of coagulation and fibrinolysis.

PubMed

Minix, R; Doctor, V M

1997-09-01

The interactions of fucoidan with glutamic plasminogen (Glu-Plg), two-chain tissue plasminogen activator (t-PA), LMwt-urokinase, thrombin, and antithrombin III (AT-III) were investigated using fucoidan-sepharose affinity chromatography. The results showed 1) a high degree of affinity between fucoidan-sepharose and Glu-Plg; Lmwt-urokinase and thrombin while t-Pa and AT-III did not bind with fucoidan-sepharose. 2) The double reciprocal plot for the LMwt-urokinase activation of Glu-Plg showed that plasminogen activator inhibitor (PAI-1) inhibited this reaction in a noncompetitive manner and that the presence of fucoidan decreased Km for this interaction by 50% and increased Kcat by 30-fold, 3) The double reciprocal plot for the t-PA activation of Glu-Plg showed that PAI-1 inhibited this reaction in a competitive manner and that fucoidan in conjunction with 6-aminohexanoic acid (6-AH) increased Kcat for this interaction by 5-fold without affecting Km. 4) Fucoidan enhanced the interaction of thrombin with both AT-III and heparin cofactor II (HC-II) and it was more effective than unfractionated heparin of LMwt-heparin in enhancing the interaction of HC-II with thrombin.

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

PubMed Central

Alvarenga, Patricia H.; Xu, Xueqing; Oliveira, Fabiano; Chagas, Andrezza C.; Nascimento, Clarissa R.; Francischetti, Ivo M.B.; Juliano, Maria A.; Juliano, Luiz; Scharfstein, Julio; Valenzuela, Jesus G.; Ribeiro, José M.C.; Andersen, John F.

2014-01-01

Objective Polyphosphate and heparin are anionic polymers released by activated mast cells and platelets that are known to stimulate the contact pathway of coagulation. These polymers promote both the autoactivation of factor XII and the assembly of complexes containing factor XI, prekallikrein, and high-molecular-weight kininogen. We are searching for salivary proteins from blood-feeding insects that counteract the effect of procoagulant and proinflammatory factors in the host, including elements of the contact pathway. Approach and Results Here, we evaluate the ability of the sand fly salivary proteins, PdSP15a and PdSP15b, to inhibit the contact pathway by disrupting binding of its components to anionic polymers. We attempt to demonstrate binding of the proteins to polyphosphate, heparin, and dextran sulfate. We also evaluate the effect of this binding on contact pathway reactions. We also set out to determine the x-ray crystal structure of PdSP15b and examine the determinants of relevant molecular interactions. Both proteins bind polyphosphate, heparin, and dextran sulfate with high affinity. Through this mechanism they inhibit the autoactivation of factor XII and factor XI, the reciprocal activation of factor XII and prekallikrein, the activation of factor XI by thrombin and factor XIIa, the cleavage of high-molecular-weight kininogen in plasma, and plasma extravasation induced by polyphosphate. The crystal structure of PdSP15b contains an amphipathic helix studded with basic side chains that forms the likely interaction surface. Conclusions The results of these studies indicate that the binding of anionic polymers by salivary proteins is used by blood feeders as an antihemostatic/anti-inflammatory mechanism. PMID:24092749

New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events.

PubMed

Mekaj, Ymer H; Mekaj, Agon Y; Duci, Shkelzen B; Miftari, Ermira I

2015-01-01

Despite the discovery and application of many parenteral (unfractionated and low-molecular-weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years. The main objective of this study is to present recent data on non-vitamin K antagonist oral anticoagulants (NOACs) and to analyze their advantages and disadvantages compared with those of VKAs based on a large number of recent studies. NOACs are novel direct-acting medications that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa). Several NOACs, such as dabigatran (a direct inhibitor of FIIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional VKAs, which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required to further assess the efficacy of NOACs.

New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events

PubMed Central

Mekaj, Ymer H; Mekaj, Agon Y; Duci, Shkelzen B; Miftari, Ermira I

2015-01-01

Despite the discovery and application of many parenteral (unfractionated and low-molecular-weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years. The main objective of this study is to present recent data on non-vitamin K antagonist oral anticoagulants (NOACs) and to analyze their advantages and disadvantages compared with those of VKAs based on a large number of recent studies. NOACs are novel direct-acting medications that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa). Several NOACs, such as dabigatran (a direct inhibitor of FIIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional VKAs, which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required to further assess the efficacy of NOACs. PMID:26150723

[Long-term treatment with a low-molecular-weight heparin administered subcutaneously compared with a vitamin K antagonist: subanalysis of patients with cancer].

PubMed

Romera-Villegas, Antonio; Martí Mestre, Xavier; Vila Coll, Ramón; Colomé Nafría, Esteve

2015-01-01

We performed a subanalysis of cancer patients enrolled in a clinical trial that compared long-term (6 months) treatment with a low-molecular-weight heparin (LMWH) administered subcutaneously or with acenocoumarol. The subanalysis assessed whether the characteristics of the tumor had an influence on the clinical response. A randomized open trial included 69 patients with cancer and symptomatic proximal deep vein thrombosis of the lower limbs. The tumor characteristics and treatment type were recorded. The main assessment criterion was the 12-month incidence of recurrent symptomatic venous thromboembolism (VTE). Sixty-one patients (88.4%) were analyzed. At the time of inclusion, the cancer characteristics and treatment were comparable between the 2 groups. Over the course of 12 months, the recurrent VTE was significantly greater in the elderly patients (71.5 ± 6.4 vs. 62.0 ± 15.1; p=.006). The logistic regression analysis showed no association between VTE recurrence and the location or extent of the tumor. However, the use of thrombogenic chemotherapy (p=.045) was independently associated with VTE recurrence, and longterm treatment with tinzaparin was almost a protective factor (p=.15). In this small sample, we observed an association between thrombogenic chemotherapy and recurrent VTE. The tendency towards a reduction in VTE recurrence at 12 months in patients with cancer in the LMWH group could be attributed to the effect of the full LMWH dosage. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Long-term treatment of deep-vein thrombosis with low-molecular-weight heparin: an update of the evidence.

PubMed

Hull, Russell D; Townshend, Grace

2013-07-01

This article reviews updated evidence-based knowledge on long-term treatment of deep-vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs). Eleven trials were identified comparing the two treatments in a broad spectrum of patients with DVT and with >100 study participants. Four comparative trials were identified in patients with cancer and DVT (in whom anticoagulation treatment is more complex and bleeding complications more frequent). In the 11 trials in broad patient populations, LMWHs were as effective as VKAs in preventing recurrent venous thromboembolism (VTE), and there were no consistent differences in the incidence of bleeding complications during long-term treatment. In patients with cancer, VTE recurrence was significantly reduced with LMWH versus VKA in two studies, while major bleeding complications did not differ between groups in any of the four trials. Current evidence-based European and American guidelines recommend LMWH over VKA for the long-term treatment of DVT in patients with cancer. LMWH and VKA are recommended over the new oral anticoagulant drugs, for which there are limited data on use in long-term treatment. Post-thrombotic syndrome (PTS), a common complication of DVT, causes considerable morbidity. Long-term use of tinzaparin reduced the risk of PTS compared with VKA in one trial, and a meta-analysis of nine studies in total demonstrated a consistently favourable effect of LMWHs versus VKA on PTS-related outcomes. Given the limited treatment options available for PTS, this suggests that LMWHs provide a useful therapeutic option in any patient particularly at risk of developing PTS.

Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles

NASA Astrophysics Data System (ADS)

Zhang, Ting; Xiong, Hui; Zohra Dahmani, Fatima; Sun, Li; Li, Yuanke; Yao, Li; Zhou, Jianping; Yao, Jing

2015-04-01

Based on the complementary effects of doxorubicin (DOX), all-trans retinoic acid (ATRA) and low molecular weight heparin (LMWH), the combination therapy of DOX, ATRA and LMWH was expected to exert the enhanced anti-tumor effects and reduce the side effects. In this study, amphiphilic LMWH-ATRA conjugate was synthesized for encapsulating the DOX. In this way, DOX, ATRA and LMWH were assembled into a single nano-system by both chemical and physical modes to obtain a novel anti-tumor targeting drug delivery system that can realize the simultaneous delivery of multiple drugs with different properties to the tumor. LMWH-ATRA nanoparticles exhibited good loading capacities for DOX with excellent physico-chemical properties, good biocompatibility, and good differentiation-inducing activity and antiangiogenic activity. The drug-loading capacity was up to 18.7% with an entrapment efficiency of 78.8%. It was also found that DOX-loaded LMWH-ATRA nanoparticles (DHR nanoparticles) could be efficiently taken up by tumor cells via endocytic pathway, and mainly distributed in cytoplasm at first, then transferred into cell nucleus. Cell viability assays suggested that DHR nanoparticles maintained the cytotoxicity effect of DOX on MCF-7 cells. Moreover, the in vivo imaging analysis indicated that DiR-loaded LMWH-ATRA nanoparticles could target the tumor more effectively as compared to free DiR. Furthermore, DHR nanoparticles possessed much higher anticancer activity and reduced side effects compared to free drugs solution. These results suggested that DHR nanoparticles could be considered as a promising targeted delivery system for combination cancer chemotherapy with lower adverse effects.

Thromboprophylaxis in critically ill children in Spain and Portugal

PubMed Central

Nñnez, A. Rodríguez; Fonte, M.; Faustino, E.V.S.

2015-01-01

Introduction Although critically ill children may be at risk from developing deep venous thrombosis (DVT), data on its incidence and effectiveness of thromboprophylaxis are lacking. Objective To describe the use of thromboprophylaxis in critically ill children in Spain and Portugal, and to compare the results with international data. Material and methods Secondary analysis of the multinational study PROTRACT, carried out in 59 PICUs from 7 developed countries (4 from Portugal and 6 in Spain). Data were collected from patients less than 18 years old, who did not receive therapeutic thromboprophylaxis. Results A total of 308 patients in Spanish and Portuguese (Iberian) PICUS were compared with 2176 admitted to international PICUs. Risk factors such as femoral vein (P = .01), jugular vein central catheter (P < .001), cancer (P = .03), and sepsis (P < .001), were more frequent in Iberian PICUs. The percentage of patients with pharmacological thromboprophylaxis was similar in both groups (15.3% vs. 12.0%). Low molecular weight heparin was used more frequently in Iberian patients (P < .001). In treated children, prior history of thrombosis (P = .02), femoral vein catheter (P < .001), cancer (P = .02) and cranial trauma or craniectomy (P = .006), were more frequent in Iberian PICUs. Mechanical thromboprophylaxis was used in only 6.8% of candidates in Iberian PICUs, compared with 23.8% in the international PICUs (P < .001). Conclusions Despite the presence of risk factors for DVT in many patients, thromboprophylaxis is rarely prescribed, with low molecular weight heparin being the most used drug. Passive thromboprophylaxis use is anecdotal. There should be a consensus on guidelines of thromboprophylaxis in critically ill children. PMID:24907863

Efficacy and safety of rivaroxaban versus low-molecular-weight heparin therapy in patients with lower limb fractures.

PubMed

Long, Anhua; Zhang, Lihai; Zhang, Yingze; Jiang, Baoguo; Mao, Zhi; Li, Hongda; Zhang, Shanbao; Xie, Zongyan; Tang, Peifu

2014-10-01

Thromboprophylaxis with rivaroxaban has proved effective and safe in patients undergoing hip and knee replacement surgery. As it is unclear whether it is also effective and safe in fracture patients, the aim of the present study was to evaluate the efficacy and safety of rivaroxaban in patients with lower limb fractures. We performed a retrospective cohort study of 2,050 consecutive patients treated for lower limb fractures at our trauma center, comparing rates of venous thromboembolism (VTE), bleeding and surgical complications, and the length of hospital stay for 608 patients who received rivaroxaban and 717 who received a low-molecular-weight heparin (LMWH). Rates of symptomatic VTE were 4.9 and 8.6% in the rivaroxaban and LMWH groups, respectively (p = 0.008), and distal VTE rates were 1.8 and 5.7%, respectively (p = 0.036). The incidence of major bleeding events in the rivaroxaban group was also lower than in the LMWH group (0.2 vs 0.6%), but the difference between the groups was not statistically significant. The mean length of hospital stay was significantly shorter in the rivaroxaban group (12.2 vs 13.1 days, respectively; p = 0.016). This retrospective cohort study is the first report documenting the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE by 45% without increasing the risk of bleeding. However, prospective, randomized controlled trials comparing rivaroxaban and LMWH are needed to confirm our findings.

Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: A pilot study.

PubMed

Shute, Janis K; Calzetta, Luigino; Cardaci, Vittorio; di Toro, Stefania; Page, Clive P; Cazzola, Mario

2018-02-01

COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV 1 ) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 μg) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 ± 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cardiac implantable electronic device hematomas: Risk factors and effect of prophylactic pressure bandaging.

PubMed

Koh, Youlin; Bingham, Nicholas E; Law, Natalie; Le, Dustin; Mariani, Justin A

2017-07-01

Cardiac implantable electronic device (CIED) hematomas are associated with many adverse outcomes. We examined the incidence and risk factors associated with hematoma formation post-CIED implantation, and explored the preventative effect of prophylactic pressure bandaging (PPB) in a large tertiary center. 1,091 devices were implanted during October 2011-December 2014. Clinically significant hematomas (CSH) were those that necessitated prolonged admission, including those due to reoperation, and clinically suspicious hematomas were swellings noted by medical/nursing staff. We screened for variables affecting hematoma incidence prior to conducting multivariate logistic regression analyses, one for all hematomas and one for CSH. 61 hematomas were identified (5.6% of patients), with 12 of those clinically significant (1.1% of patients). Factors significantly increasing the odds of developing any hematoma were stage 2 (odds ratio [OR] = 2.93, 95% confidence interval [CI] [1.08-7.94], P = 0.034) and 3 chronic kidney disease (CKD) (OR = 3.39 [1.20-9.56], P = 0.021), unfractionated heparin/therapeutic enoxaparin (OR = 3.15 [1.22-8.14], P = 0.018), and dual antiplatelets-aspirin + clopidogrel (OR = 2.95 [1.14-7.65], P = 0.026) + other combinations. Body Mass index (BMI) 25.0-29.9 (OR 0.52 [0.28-0.98], P = 0.044) and >30 were associated with decreased hematoma risk (OR 0.43 [0.20-0.91], P = 0.028). Factors significant for CSH formation were unfractionated heparin/therapeutic enoxaparin (OR = 9.55 [1.83-49.84], P = 0.007) and aspirin + clopidogrel (OR = 7.19 [1.01-50.91], P = 0.048). PPB nonsignificantly increased the odds of total hematoma development (OR = 1.53 [0.87-2.69], P = 0.135), and reduced CSH (OR = 0.67 [0.18-2.47], P = 0.547). Heparin and dual antiplatelet use remain strong predictors of overall hematoma formation. CKD is a comparatively moderate predictor. BMI > 25 may decrease the risk of hematoma formation. PPB had nonsignificant effects on hematoma development. © 2017 Wiley Periodicals, Inc.

Accuracy, reproducibility and costs of different laboratory assays for the monitoring of unfractionated heparin in clinical practice: a prospective evaluation study and survey among Swiss institutions.

PubMed

Bürki, Susanne; Brand, Béatrice; Escher, Robert; Wuillemin, Walter A; Nagler, Michael

2018-06-09

To investigate the accuracy, reproducibility and costs of different laboratory assays for the monitoring of unfractionated heparin (UFH) in clinical practice and to study test utilisation in Switzerland. Prospective evaluation study and survey among Swiss hospitals and laboratories. Secondary care hospital in rural Switzerland (evaluation study); all Swiss hospitals and laboratories (survey). All consecutive patients, monitored for treatment with UFH during two time periods, were included (May to July 2014 and January to February 2015; n=254). Results of activated partial thromboplastin time (aPTT), thrombin time (TT), prothrombinase-induced clotting time (PiCT) and anti-Xa activity with respect to UFH concentration RESULTS: Spearman's correlation coefficient (r s ) with regard to anti-Xa activity was 0.68 (95% CI 0.60 to 0.75) for aPTT, 0.79 (0.69 to 0.86) for TT and 0.94 (0.93 to 0.95) for PiCT. The correlation (r s ) between anti-Xa activity and heparin concentration as determined by spiking plasma samples was 1.0 (1.0 to 1.0). The coefficient of variation was at most 5% for PiCT and anti-Xa activity (within-run as well as day-to-day variability). The total costs per test in Swiss Francs (SFr) were SFr23.40 for aPTT, SFr33.30 for TT, SFr15.70 for PiCT and SFr24.15 for anti-Xa activity. The various tests were employed in Swiss institutions with the following frequencies: aPTT 53.2%, TT 21.6%, anti-Xa activity 7.2%, PiCT 1.4%; 16.6% of hospitals performed more than one test. The accuracy and reproducibility of PiCT and anti-Xa activity for monitoring of UFH was superior, and analytical costs were equivalent to or lower than aPTT and TT. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Preparation of low molecular weight Sargassum fusiforme polysaccharide and its anticoagulant activity

NASA Astrophysics Data System (ADS)

Sun, Yuhao; Chen, Xiaolin; Liu, Song; Yu, Huahua; Li, Rongfeng; Wang, Xueqin; Qin, Yukun; Li, Pengcheng

2017-10-01

Heparin has been used as an anticoagulant drug for many years, but it has significant side effects. In the search for good substitutes, low molecular weight (MW) polysaccharides from Sargassum fusiforme have been examined and confirmed to possess biological activities. Here, S. fusiforme polysaccharides (SFP) were extracted and subjected to a hydrogen peroxide (H2O2) oxidation method for the preparation of low-MW SFP (LSFP). The effects of temperature, pH, and H2O2 concentration on the degradation process were also examined. Several LSFP of 36, 9, 5.7, and 2.7 kDa were obtained under different conditions, and their anticoagulant activities studied in vitro. The results showed that SFP and LSFP prolonged activated partial thromboplastin (APTT), prothrombin (PT) and thrombin times (TT) significantly, indicating that these low MW polysaccharides possessed anticoagulant activity in the intrinsic, extrinsic, and common coagulation pathways. As these effects were related to the MW of the polysaccharides in APTT and TT but not in PT, the contents of the monosaccharide fucose and sulfate and the polysaccharide MW could have exerted combined effects. The details of this mechanism require further verification.

Subarachnoid Hemorrhage Mimicking Leakage of Contrast Media After Coronary Angiography

PubMed Central

Oh, Min Seok; Kwon, Jee Eun; Kim, Kyung Jun; Jo, Joon Hwan; Min, Yun Ju; Byun, Jun Soo; Kim, Kyung Tae; Kim, Sang Wook

2012-01-01

We report a patient who developed subarachnoid hemorrhage (SAH) just after coronary angiography (CAG) with non-ionic contrast media (CM) and minimal dose of heparin. The 55-year-old man had a history of acute ST elevation myocardial infarction that had been treated with primary percutaneous coronary intervention and was admitted for a follow-up CAG. The CAG was performed by the transradial approach, using 1000 U of unfractionated heparin for the luminal coating and 70 mL of iodixanol. At the end of CAG, he complained of nausea and rapidly became stuporous. Brain CT showed a diffusely increased Hounsfield unit (HU) in the cisternal space, similar to leakage of CM. The maximal HU was 65 in the cisternal space. No vascular malformations were detected on cerebral angiography. The patient partially recovered his mental status and motor weakness after 2 days. Two weeks later, subacute SAH was evident on magnetic resonance imaging. The patient was discharged after 28 days. PMID:22493615

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

PubMed

Gunaratne, Ruwan; Kumar, Shekhar; Frederiksen, James W; Stayrook, Steven; Lohrmann, Jens L; Perry, Kay; Bompiani, Kristin M; Chabata, Charlene V; Thalji, Nabil K; Ho, Michelle D; Arepally, Gowthami; Camire, Rodney M; Krishnaswamy, Sriram; Sullenger, Bruce A

2018-06-04

Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.

Unfractionated heparin-clopidogrel combination in ST-elevation myocardial infarction not receiving reperfusion therapy.

PubMed

Bugiardini, Raffaele; Dorobantu, Maria; Vasiljevic, Zorana; Kedev, Sasko; Knežević, Božidarka; Miličić, Davor; Calmac, Lucian; Trninic, Dijana; Daullxhiu, Irfan; Cenko, Edina; Ricci, Beatrice; Puddu, Paolo Emilio; Manfrini, Olivia; Koller, Akos; Badimon, Lina

2015-07-01

We sought explore the relative benefits of unfractionated heparin (UFH) compared with enoxaparin, alone or in combination with clopidogrel, in ST-segment elevation myocardial infarction (STEMI) patients not undergoing reperfusion therapy. This is a propensity score study from The International Survey on Acute Coronary Syndromes in Transition Countries (ISACS-TC/NCT01218776) on patients admitted between October 2010-June 2013. There were a total of 1175 STEMI patients who did not receive mechanical or pharmacological reperfusion. Of these, 1063 were eligible for the aim of the study, being treated with UFH (522/1175; 44.4%) or enoxaparin (541/1175; 46%). Clopidogrel in combination with UFH or enoxaparin was given to 751 (63.9%) patients. The primary endpoint was in-hospital mortality. Secondary endpoints were intracranial hemorrhages, and clinically relevant bleedings. After adjustment for any confounders, UFH was associated with a lower risk of in-hospital mortality in clopidogrel users (multivariate adjusted regression analysis: odds ratio [OR]: 0.62, 95% Confidence Interval [CI] 0.41-0.94) as compared with clopidogrel non-users (OR: 0.94, 95% CI 0.55-1.60). The observed effect was not associated with combined enoxaparin and clopidogrel therapy. Major bleeding events were comparable in the enoxaparin group and UFH group (0.4% and 1.5% respectively, p = 0.06). The risk of major hemorrhage was nearly similar with combined UFH-clopidogrel therapy (1.4%) as compared with UFH alone (1.9%), p = 0.67. UFH - Clopidogrel combination was associated with a large mortality reduction in STEMI patients not undergoing reperfusion therapy and did not significantly increase the risk of major bleeding. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Three-times-daily subcutaneous unfractionated heparin and neuraxial anesthesia: a retrospective review of 928 cases.

PubMed

Davis, Jennifer J; Bankhead, Byron R; Eckman, Erik J; Wallace, Austin; Strunk, Joseph

2012-01-01

Subcutaneous (SC) unfractionated heparin (UFH) administered 3 times daily (TID) is widely used for venous thromboembolism prophylaxis in the perioperative period. There are no data in the literature regarding the incidence of adverse outcomes with neuraxial analgesia in the setting of this regimen. In this retrospective review, we report the incidence of untoward events related to anticoagulation with SC UFH TID in patients with indwelling epidural catheters. We queried the electronic hospital databases to identify patients receiving thoracic epidural analgesia in conjunction with 5000 U UFH SC TID from July 2008 to October 2010. In this group, we identified the diagnoses of neuraxial hematoma, deep vein thrombosis, or pulmonary embolism and examined measured blood coagulation parameters. In addition, we determined the percentage of patients receiving concomitant therapy with ketorolac. We identified 928 patients who received thoracic epidural analgesia in conjunction with 5000 U UFH SC TID during this period. There were no cases of neuraxial bleeding. Seven patients had a diagnosed deep vein thrombosis or pulmonary embolism. Thirty-four percent (315/928) of patients received ketorolac. The measured activated thromboplastin time was more than 40 seconds (35 seconds being the upper limit of normal) in 115 patients (12%). Given the rare incidence of neuraxial hematoma, statements regarding the appropriateness of epidural analgesia in the setting of TID SC UFH cannot be made from this limited sample size. At present, information regarding epidural hematoma in the setting of a TID SC UFH dosing regimen does not exist in the literature. Our study represents an initial step in the accumulation of data needed to prove or disprove the safety of this practice.

Cost in the use of enoxaparin compared with unfractionated heparin in patients with atrial fibrillation undergoing a transesophageal echocardiography-guided cardioversion (from Assessment of Cardioversion using Transesophageal Echocardiography [ACUTE] II randomized multicenter study).

PubMed

Zhao, Liping; Zhang, Zefeng; Kolm, Paul; Jasper, Susan; Lewis, Cheryl; Klein, Allan; Weintraub, William

2008-02-01

The ACUTE II study demonstrated that transesophageal echocardiographically guided cardioversion with enoxaparin in patients with atrial fibrillation was associated with shorter initial hospital stay, more normal sinus rhythm at 5 weeks, and no significant differences in stroke, bleeding, or death compared with unfractionated heparin (UFH). The present study evaluated resource use and costs in enoxaparin (n=76) and UFH (n=79) during 5-week follow-up. Resources included initial and subsequent hospitalizations, study drugs, outpatient services, and emergency room visits. Two costing approaches were employed for the hospitalization costing. The first approach was based on the UB-92 formulation of hospital bill and diagnosis-related group. The second approach was based on UB-92 and imputation using multivariable linear regression. Costs for outpatient and emergency room visits were determined from the Medicare fee schedule. Sensitivity analysis was performed to assess the robustness of the results. A bootstrap resample approach was used to obtain the confidence interval (CI) for the cost differences. Costs of initial and subsequent hospitalizations, outpatient procedures, and emergency room visits were lower in the enoxaparin group. Average total costs remained significantly lower for the enoxaparin group for the 2 costing approaches ($5,800 vs $8,167, difference $2,367, 95% CI 855 to 4,388, for the first approach; $7,942 vs $10,076, difference $2,134, 95% CI 437 to 4,207, for the second approach). Sensitivity analysis showed that cost differences between strategies are robust to variation of drug costs. In conclusion, the use of enoxaparin as a bridging therapy is a cost-saving strategy (similar clinical outcomes and lower costs) for atrial fibrillation.

Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis.

PubMed

Castellucci, Lana A; Cameron, Chris; Le Gal, Grégoire; Rodger, Marc A; Coyle, Doug; Wells, Philip S; Clifford, Tammy; Gandara, Esteban; Wells, George; Carrier, Marc

2014-09-17

Many anticoagulant strategies are available for the treatment of acute venous thromboembolism, yet little guidance exists regarding which drug is most effective and safe. To summarize and compare the efficacy and safety outcomes associated with 8 anticoagulation options (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux in combination with vitamin K antagonists); LMWH with dabigatran or edoxaban; rivaroxaban; apixaban; and LMWH alone) for treatment of venous thromboembolism. A systematic literature search was conducted using MEDLINE, EMBASE, and the evidence-based medicine reviews from inception through February 28, 2014. Eligible studies were randomized trials reporting rates of recurrent venous thromboembolism and major bleeding in patients with acute venous thromboembolism. Of the 1197 studies identified, 45 trials including 44,989 patients were included in the analyses. Two reviewers independently extracted trial-level data including number of patients, duration of follow-up, and outcomes. The data were pooled using network meta-analysis. The primary clinical and safety outcomes were recurrent venous thromboembolism and major bleeding, respectively. Compared with the LMWH-vitamin K antagonist combination, a treatment strategy using the UFH-vitamin K antagonist combination was associated with an increased risk of recurrent venous thromboembolism (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15-1.79). The proportion of patients experiencing recurrent venous thromboembolism during 3 months of treatment were 1.84% (95% CrI, 1.33%-2.51%) for the UFH-vitamin K antagonist combination and 1.30% (95% CrI, 1.02%-1.62%) for the LMWH-vitamin K antagonist combination. Rivaroxaban (HR, 0.55; 95% CrI, 0.35-0.89) and apixaban (HR, 0.31; 95% CrI, 0.15-0.62) were associated with a lower risk of bleeding than was the LMWH-vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49% (95% CrI, 0.29%-0.85%) for rivaroxaban, 0.28% (95% CrI, 0.14%-0.50%) for apixaban, and 0.89% (95% CrI, 0.66%-1.16%) for the LMWH-vitamin K antagonist combination. Using meta-analytic pooling, there were no statistically significant differences for efficacy and safety associated with most treatment strategies used to treat acute venous thromboembolism compared with the LMWH-vitamin K antagonist combination. However, findings suggest that the UFH-vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.

Cancer-associated thrombosis: prevention and treatment

PubMed Central

Brose, K.M.J.; Lee, A.Y.Y.

2008-01-01

Patients with cancer are at high risk to develop venous thromboembolism, and they are also more likely to develop complications from anticoagulant treatment. Because little research has focused on the oncology population to date, the optimal methods of prophylaxis and treatment remain uncertain in some clinical situations. Currently, low molecular weight heparin and warfarin are the most frequently used pharmacologic agents; however, they have their limitations. Other therapeutic options, such as inferior caval filters, are poorly studied and remain controversial. A summary of the most recent evidence on the prevention and treatment of venous thromboembolism in cancer patients is presented here. PMID:18231650

Enoxaparin can be used safely in patients with severe thrombocytopenia due to intensive chemotherapy regimens.

PubMed

Herishanu, Yair; Misgav, Mudi; Kirgner, Ilya; Ben-Tal, Ofira; Eldor, Amiram; Naparstek, Ella

2004-07-01

Treatment with intensive chemotherapy regimens is frequently complicated by severe thrombocytopenia. During the period of severe thrombocytopenia, anticoagulant treatment is not uncommonly indicated for thromboembolic events or thromboprophylaxis in these patients. We report 10 hematological patients treated with intensive chemotherapy protocols that were anticoagulated with enoxaparin for catheter related central venous thrombosis and thromboprophylaxis. During the period of severe thrombocytopenia the dosages of enoxaparin were reduced and no major bleeding occurred. Based on our experience we suggest that reduced dosages of low molecular weight heparins may be used relatively safely during transient severe thrombocytopenia.

Short-Term Heparin Kinetics during Catheter Ablation of Atrial Fibrillation.

PubMed

Gabus, Vincent; Rollin, Anne; Maury, Philippe; Forclaz, Andrei; Pascale, Patrizio; Dhutia, Harshil; Bisch, Laurence; Pruvot, Etienne

2015-10-01

Percutaneous catheter ablation of atrial fibrillation (CA-AF) is a treatment option for symptomatic drug-refractory atrial fibrillation (AF). CA-AF carries a risk for thromboembolic complications that has been minimized by the use of intraprocedural intravenous unfractionated heparin (UFH). The optimal administration of UFH as well as its kinetics are not well established and need to be precisely determined. A total 102 of consecutive patients suffering from symptomatic drug-refractory AF underwent CA-AF. The mean age was 61 ± 10 years old. After transseptal puncture of the fossa ovalis, weight-adjusted UFH bolus (100 U/kg) was infused. A significant increase in activated clotting time (ACT) was observed from an average value of 100 ± 27 seconds at baseline, to 355 ± 94 seconds at 10 min (T10), to 375 ± 90 seconds at 20 min (T20). Twenty-four patients failed to reach the targeted ACT value of ≥300 seconds at T10 and more than half of these remained with subtherapeutic ACT values at T20. This subset of patients showed similar clinical characteristics and amount of UFH but were more frequently prescribed preprocedural vitamin K1 than the rest of the study population. In a typical intervention setting, UFH displays unexpected slow anticoagulation kinetics in a significant proportion of procedures up to 20 minutes after infusion. These findings support the infusion of UFH before transseptal puncture or any left-sided catheterization with early ACT measurements to identify patients with delayed kinetics. They are in line with recent guidelines to perform CA-AF under therapeutic anticoagulation. © 2015 Wiley Periodicals, Inc.

The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction.

PubMed

Groom, Katie M; David, Anna L

2018-02-01

Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction. Copyright © 2017 Elsevier Inc. All rights reserved.

Patient compliance with extended low molecular weight heparin injections following hip and knee arthroplasty.

PubMed

Deakin, Dan E; Mishreki, Andrew; Aslam, Nadim; Docker, Charles

2010-01-01

The use of extended duration thromboprophylaxis following hip and knee arthroplasty is becoming widespread. The aim of our study was to determine patient compliance with extended duration thromboprophylaxis using low molecular weight (LMWH) injections following hip and knee arthroplasty. 42 consecutive patients undergoing hip and knee arthroplasty were prospectively contacted during their fifth post operative week. A fully anonymised questionnaire was completed by each patient. All patients responded. One was excluded having been prescribed warfarin for pre existing atrial fibrillation. Twenty nine (71%) patients were discharged with the intention of self administering LMWH injections. Eight (20%) and four (9%) patients were discharged with the intention of administration by a relative or district nurse respectively. No patient required the person administering the injections to be changed after discharge from hospital. 90% (n=37) of patients reported not missing any doses. 10% (n=2) of patients missed one dose and 10% (n=2) missed two doses. Patient compliance with extended duration thromboprophylaxis using LMWH injections is extremely high. Oral thromboprophylaxis may be useful in the minority of patients requiring daily visits by a nurse to administer injections.

The AN69 ST haemodialysis membrane under conditions of two different extracorporeal circuit rinse protocols a comparison of thrombogenicity parameters.

PubMed

Richtrova, Pavlina; Opatrny, Karel; Vit, Ladislav; Sefrna, Frantisek; Perlik, Radek

2007-10-01

Thrombogenicity is an important parameter of haemodialysis (HD) membrane biocompatibility. The surface of the polyacrylonitrile AN69 ST membrane is coated with a polyethylenimine. This modification allows heparin adsorption. The binding of heparin to the membrane surface occurs during priming of the extracorporeal circuit (ECC) by rinsing it with saline and heparin. Our aims were to assess and compare the thrombogenicity of the AN69 ST membrane under conditions of two extracorporeal circuit (ECC) rinse protocols-with and without unfractionated heparin (UFH). In a prospective, crossover and randomized study, we examined 10 patients during HD after ECC preparation with either rinse protocols. Prior to HD and at 15, 60 and 240 min, we determined plasma levels of the thrombin-antithrombin complexes (TAT), platelet factor 4 (PF4), heparin concentration (antiXa) and thrombocyte count. Systemic anticoagulation was performed using UFH. During HD after ECC rinse without UFH, there was a significantly earlier and more marked increase in TAT compared with UFH-containing rinse (P <0.05). Using Spearman coefficient, we demonstrated a significant correlation between TAT and antiXa at 60 min (r = -0.534) and 240 min (r = -0.538). A comparison of the TAT/antiXa ratios between rinses at 60 min revealed a significantly higher increase in TAT following UFH-free rinse (P <0.05). There was no difference in PF4 between the rinses. Platelet count did not change significantly during HD using either rinse protocol. Based on plasma TAT levels, ECC priming with an UFH-containing solution reduces the thrombogenicity of the AN69 ST membrane. There is no significant difference between both types of priming concerning PF4 and thrombocyte count.

Evaluation of the anticoagulant potential of polysaccharide-rich fractions extracted from macroalgae.

PubMed

Adrien, Amandine; Dufour, Delphine; Baudouin, Stanislas; Maugard, Thierry; Bridiau, Nicolas

2017-09-01

The aim of this study was to evaluate the potential anticoagulant activity of sulphated polysaccharide-containing extracts of six french edible marine macroalgae. Aqueous extracts of brown (Himanthalia elongata, Laminaria digitata, Ascophyllum nodosum, Fucus vesiculosus), green (Ulva lactuca) and red (Chondrus crispus) macroalgae were prepared and their biochemical properties were determined, including major biomolecules, sulphate and ash contents. The anticoagulant activity of each extract was investigated using different scales from the specific antithrombin-dependent pathway (anti-Xa and anti-IIa) to the intrinsic and/or common (Activated Partial Thromboplastin Time, APTT), extrinsic (Prothrombin Time, PT) or common (Thrombin Time, TT) anticoagulant pathways, and compared with those of commercial anticoagulants, heparin and Lovenox®. Laminaria digitata, Fucus vesiculosus and Chondrus crispus extracts showed a significant APTT anticoagulant capacity, only 5-fold lower than that of Lovenox®, which is a pure low molecular weight heparin used as an anticoagulant agent to prevent pulmonary embolism in patients undergoing surgery.

Rivaroxaban: An Affordable and Effective Alternative in Cancer-Related Thrombosis?

PubMed Central

Hoff, Paulo Marcelo Gehm; Braghiroli, Maria Ignez; Paterlini, Ana Carolina Carvalho Rocha; Souza, Karla Teixeira; Faria, Luiza Dib Batista Bugiato; Ferreira, Fernando Sergio Blumm; Machado, Karime Kalil; Fernandes, Gustavo dos Santos

2017-01-01

Background Venous thromboembolic events (VTEs) are common and potentially fatal complications in cancer patients, and they are responsible for the second most common cause of death. Low molecular weight heparin (LMWH) is the gold-standard treatment, but the costs involved limit its use, especially in developing countries. Recently, the oral anticoagulant rivaroxaban, which directly inhibits factor Xa, was approved for VTE treatment. Methods We conducted a retrospective analysis from January 2009 to February 2014 with patients who had cancer and VTE who were receiving rivaroxaban. We compared the efficacy, safety, and cost of rivaroxaban and low molecular weight heparin (LMWH) alone or followed by vitamin K antagonists. Results Forty-one patients were identified, with a median age of 62.5 years. The most frequent tumor histology was adenocarcinoma (78%), which was most often found in the colon (26.8%). Most participants had advanced disease and an implanted central venous catheter. Patients’ VTE risk-assessment scores were low (12.5%), intermediate (50%), and high (35.5%). Pulmonary thromboembolism was reported in 41.4% of patients, but inferior limb thrombosis was reported only in 14.6%; 43.9% of patients received enoxaparin before starting rivaroxaban. Rivaroxaban was used for a median time of 5.5 months. Nonmajor bleeding was reported in 12.2% of patients, and rethrombosis was reported in 12.2%. In our study, rivaroxaban was as safe and effective as enoxaparin/vitamin K antagonists (P = .54 and P = .25, respectively) or LMWH (P = .46 and P = .29, respectively). Conclusion Although our study was a retrospective analysis, our results suggest that in this cohort of oncologic patients, rivaroxaban was safe and effective. Its oral route and lower cost make it an attractive alternative to LMWH, improving management of patients with cancer in low-income countries. Additional studies are necessary to confirm our data. PMID:28717737

Oral heparin delivery: design and in vivo evaluation of a stomach-targeted mucoadhesive delivery system.

PubMed

Schmitz, Thierry; Leitner, Verena M; Bernkop-Schnürch, Andreas

2005-05-01

Low molecular weight heparin (LMWH) is an agent of choice in the anti-coagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, the therapeutic use is partially limited due to a poor oral bioavailability. It was therefore the aim of this study to design and evaluate a highly efficient stomach-targeted oral delivery system for LMWH. In order to appraise the influence of the molecular weight on the oral bioavailability, mini-tablets comprising 3 kDa (279 IU) and 6 kDa (300 IU) LMWH, respectively, were generated and tested in vivo in rats. The potential of the test formulations based on thiolated polycarbophil, was evaluated in comparison to hydroxyethylcellulose (HEC) as control carrier matrix. The plasma levels of LMWH after oral versus subcutaneous administration were determined in order to calculate the relative bioavailability. With the delivery system containing 3 kDa LMWH (279 IU) a relative bioavailability of 19.1% was achieved, offering a significantly (p < 0.05) better bioavailability than the control system displaying a relative bioavailability of 8.1% The 6 kDa LMWH (300 IU) formulation displayed a relative bioavailability of 10.7% in contrast to the control displaying a relative bioavailability of 2.1%. In conclusion, these results suggest that mucoadhesive thiolated polymers are a promising tool for the non-invasive stomach-targeted systemic delivery of LMWH as model for a hydrophilic macromolecular polysaccharide. Copyright 2005 Wiley-Liss, Inc

Evaluation of self-dissolving needles containing low molecular weight heparin (LMWH) in rats.

PubMed

Ito, Yukako; Murakami, Aiko; Maeda, Tomohiro; Sugioka, Nobuyuki; Takada, Kanji

2008-02-12

Feasibility study of self-dissolving needles containing polysaccharide was performed. Low molecular weight heparin (LMWH) was used as a representative polysaccharide. Using chondroitin, dextran and dextrin as the base, self-dissolving needles (SDN) were prepared. The obtained SDNs were evaluated in rat absorption experiment, where pharmacological availability (PA) was calculated by comparing the plasma anti-Xa activity vs. time curves between SDNs and i.v. solution. After the insertion of SDNs to rats skin where the doses of LMWH were 25, 50 and 100 IU/kg, plasma samples were collected for 6h and anti-Xa activity was measured as the pharmacological index of LMWH. The anti-Xa level was maintained above 0.2 IU/ml, the therapeutic level, for about 2h at a dose of 100 IU/kg. Almost the same PAs of LMWH were obtained with dextran and dextrin SDNs, 97.7% and 102.3%, though lower PA was obtained with chondroitin SDN, 81.5%. In vitro dissolution experiment showed that LMWH was released from dextran, dextrin and chondroitin SDNs within 10 min. The T(50%)s were 0.84+/-0.06 min for dextran SDN, 1.07+/-0.12 min for chondroitin SDN and 2.11+/-0.31 min for dextrin SDN, respectively. Plasma anti-Xa activity vs. time profiles showed good dose-dependency in the 25-100 IU/kg range and high PAs were obtained, 90.0% for 25 IU/kg, 95.4% for 50 IU/kg and 97.7% for 100 IU/kg from dextran SDNs. Stability experiment was performed with dextran SDNs for 3 months. Above 97% of LMWH were remained in SDNs under three different conditions, -80, 4 and 40 degrees C. These results suggest the usefulness of SDN to polysaccharide drug.

Low-molecular weight heparin protamine complex augmented the potential of adipose-derived stromal cells to ameliorate limb ischemia.

PubMed

Kishimoto, Satoko; Inoue, Ken-Ichi; Nakamura, Shingo; Hattori, Hidemi; Ishihara, Masayuki; Sakuma, Masashi; Toyoda, Shigeru; Iwaguro, Hideki; Taguchi, Isao; Inoue, Teruo; Yoshida, Ken-Ichiro

2016-06-01

Heparin/protamine micro/nanoparticles (LH/P-MPs) were recently developed as low-molecular weight, biodegradable carriers for adipose-derived stromal cells (ADSCs). These particles can be used for a locally delivered stem cell therapy that promotes angiogenesis. LH/P-MPs bind to the cell surface of ADSCs and promote cell-to-cell interaction and aggregation of ADSCs. Cultured ADSC/LH/P-MP aggregates remain viable. Here, we examined the ability of these aggregates to rescue limb loss in a mouse model of hindlimb ischemia. Unilateral hindlimb ischemia was induced in adult male BALB/c mice by ligation of the iliac artery and hindlimb vein. For allotransplantation of ADSCs from the same inbred strain, we injected ADSC alone or ADSC/LH/P-MP aggregates or control medium (sham-treated) directly into the ischemic muscles. Ischemic limb blood perfusion, vessel density, and vessel area were recorded. The extent of ischemic limb necrosis or limb loss was assessed on postoperative days 2, 7, and 14. Compared with the sham-treatment control, treatment with ADSCs alone showed modest effects on blood perfusion recovery and increased the number of α-SMA-positive vessels. Response to ADSC/LH/P-MP aggregates was significantly greater than ADSCs alone for every endpoint. ADSC/LH/P-MP aggregates more effectively prevented the loss of ischemic hindlimbs than ADSCs alone or the sham-treatment. The LH/P-MPs augmented the effects of ADSCs on angiogenesis and reversal of limb ischemia. Use of ADSC/LH/P-MP aggregates offers a novel and convenient treatment method and potentially represents a promising new therapeutic approach to inducing angiogenesis in ischemic diseases. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The safety of low molecular-weight heparin after blunt liver and spleen injuries.

PubMed

Rostas, Jack W; Manley, Justin; Gonzalez, Richard P; Brevard, Sidney B; Ahmed, Naveed; Frotan, Mohammad Amin; Mitchell, Ellen; Simmons, Jon D

2015-07-01

Anticoagulation is routinely administered to all trauma patients owing to the high incidence of venous thromboembolism (VTE). However, the timing of administration of anticoagulation is not clearly defined when patients have blunt spleen or liver injuries because of the perceived risk of hemorrhage with early administration. A retrospective chart review was performed of all blunt trauma patients who sustained blunt liver and/or spleen injuries during the 5-year period from 2007 to 2011. Data were collected for all patients managed with nonoperative therapy for these injuries while also receiving routine prophylactic anticoagulation with low molecular-weight heparin. Patients were categorized based on the initiation of enoxaparin therapy after injury: early (<48 hours), intermediate (48 to 72 hours), and late (>72 hours). Primary and secondary outcomes were designated as need for operative or radiologic intervention secondary to spleen or liver hemorrhage, number of transfusions, and incidence of VTE. Three hundred and twenty-eight patients were included. There were no enoxaparin-related hemorrhagic complications or hemorrhage necessitating operative intervention. Patients in the early, intermediate, and late groups received an average of .9, .93, and 1.55 units of blood, respectively. There was 1 pulmonary embolism in the early group, and there were 6 VTE complications in the late group (3 deep venous thromboses and 3 pulmonary embolisms). There are currently no standards for the initiation of prophylactic anticoagulation in trauma patients with blunt liver and spleen injuries. Early administration may be safe and reduce the incidence of thrombotic complications in patients with blunt spleen and liver injuries. Prospective studies in this area are warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

Safety and Efficacy of Novel Oral Anticoagulants vs Low Molecular Weight Heparin for Thromboprophylaxis in Large-Volume Liposuction and Body Contouring Procedures.

PubMed

Morales, Rolando; Ruff, Eric; Patronella, Christopher; Mentz, Henry; Newall, Germán; Hustak, Kristi L; Fortes, Paul; Bush, Amelia

2016-04-01

Preventing venous thromboembolism (VTE) remains an important topic in the plastic surgery community. However, there is little consensus regarding appropriate VTE prophylaxis for patients undergoing common body contouring procedures. This study compared the use of two novel oral anticoagulants (Rivaroxaban and Apixiban) vs low molecular weight heparin (LMWH) for postoperative chemical prophylaxis in body contouring plastic surgery procedures. A single center retrospective chart review of 1572 patients who underwent body contouring plastic surgery procedures from January 2012 to February 2015 was performed. Major complications associated with chemical prophylaxis were reviewed including hematomas requiring surgical evacuation, acute blood loss anemia requiring transfusions, and thrombotic or hemorrhagic events. Drug-related adverse events occurred in 1.27% (n = 20) of patients. The complications encountered by the 454 patients on LMWH consisted of 0.88% (n = 4) with hematomas requiring surgical evacuation, 0.44% (n = 2) with decreased hemoglobin requiring transfusions, and 0.22% (n = 1) with a deep vein thrombosis (DVT). The complications encountered by 703 patients on with Rivaroxaban consisted of 1.3% (n = 9) with hematomas requiring surgical evacuation, 0.43% (n = 3) with decreased hemoglobin requiring transfusions, and 0.1% (n = 1) with a DVT and pulmonary embolism. The complications encountered by 415 patients on with Apixaban consisted of 0.48% (n = 2) with a DVT. Novel oral anticoagulants (Rivaroxaban and Apixiban) are comparable to LMWH for chemical prophylaxis after body contouring procedures with similar rates of drug-related complications. Further investigation is warranted with more clinical cases in order to recommend the use of this medication for routine postoperative chemical prophylaxis after body contouring procedures. 3 Therapeutic. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Post-pregnancy aspirin resistance appears not to be related with recurrent hypertensive disorders of pregnancy.

PubMed

Abheiden, Carolien N H; Fuijkschot, Wessel W; Arduç, Arda; van Diemen, Jeske J K; Harmsze, Ankie M; de Boer, Marjon A; Thijs, Abel; de Vries, Johanna I P

2017-03-01

The FRUIT-RCT concluded that low-molecular-weight heparin added to aspirin compared to treatment with aspirin alone is beneficial in the prevention of early-onset hypertensive disorders of pregnancy (HD) in women with inheritable thrombophilia and prior HD and/or a small-for-gestational age (SGA) infant leading to delivery before 34 weeks gestation. The aim of this study is to answer the question whether aspirin resistance is associated with recurrent HD. Women with and without recurrent HD matched for age, study arm, and chronic hypertension were invited for this follow-up study 6-16 years after they participated in the FRUIT-RCT. Aspirin resistance was tested after 10days of aspirin intake using three complementary tests: PFA-200, VerifyNow ® and serum thromboxane B 2 (TXB 2 ). An independent t-test, Mann-Whitney U test, Fisher's Exact test and Chi 2 test were used for the statistical analyses. Thirteen of 24 women with recurrent HD and 16 of 24 women without recurrent HD participated. The prevalence of laboratory aspirin resistance was 34.5% according to the PFA-200, 3.4% according to the VerifyNow ® and 24.1% according to TXB 2 . The prevalence of aspirin resistance by any test was 51.7%. Aspirin resistance per individual test did not differ between women with and without recurrent HD. Aspirin resistance measured by any test occurred more frequently in women without recurrent HD (p<0.01), irrespective of low-molecular-weight heparin. No relation could be demonstrated between recurrent HD and aspirin resistance per test, measured up to 16 years after pregnancy. On the contrary, complementary aspirin resistance measurements were encountered more frequently in women without recurrent HD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Low-Molecular-Weight Heparin and the Relative Risk of Surgical Site Bleeding Complications: Results of a Systematic Review and Meta-Analysis of Randomized Controlled Trials of Venous Thromboprophylaxis in Patients After Total Joint Arthroplasty.

PubMed

Suen, Kary; Westh, Roger N; Churilov, Leonid; Hardidge, Andrew J

2017-09-01

Venous thromboembolism causes significant morbidity and mortality in patients after total joint arthroplasty. Although network meta-analyses have demonstrated a benefit of various thromboprophylactic agents, there remains a concern in the surgical community regarding the resulting wound complications. There is currently no systematic review of the surgical site bleeding complications of thromboprophylactic agents. The aim of this study was to systematically review the surgical site bleeding outcomes of venous thromboembolism prophylaxis in this population. A systematic review and meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized controlled trials comparing more than one of low-molecular-weight heparin (LMWH), warfarin, rivaroxaban, apixaban, dabigatran, aspirin, or no pharmacologic treatment in patients after total hip or knee arthroplasty were selected for inclusion. Five meta-analyses were performed to compare LMWH with control, warfarin, apixaban, rivaroxaban, and dabigatran. Forty-five randomized controlled trials of 56,730 patients were included. LMWH had a significantly increased relative risk of surgical site bleeding in comparison with control (relative risk, 2.32; 95% confidence interval, 1.40-3.85) and warfarin (1.54; 1.23-1.94). The relative risk of LMWH trended higher than apixaban (1.27; 1.00-1.63) and was similar to rivaroxaban (0.95; 0.74-1.23). Only 1 study reported the risk of surgical site bleeding in LMWH vs dabigatran (5.97; 2.08-17.11). LMWH increased the risk of surgical site bleeding compared with control, warfarin. and dabigatran and trended toward an increased risk compared with apixaban. The risk of surgical site bleeding was similar with LMWH and rivaroxaban. Copyright © 2017 Elsevier Inc. All rights reserved.

[Prevention of venous thromboembolic disease in the critical patient: an assessment of clinical practice in the Community of Madrid].

PubMed

García-Olivares, P; Guerrero, J E; Tomey, M J; Hernangómez, A M; Stanescu, D O

2014-01-01

To analyze measures referred to venous thromboembolic prophylaxis in critically ill patients. An epidemiological, cross-sectional (prevalence cut), multicenter study was performed using an electronic survey. Comparison of results with quality indexes of the Spanish Society of Intensive Care Medicine, the American College of Chest Physician guidelines and international studies. Intensive Care Units (ICUs) in the Community of Madrid (Spain). All patients admitted to the ICU on the day of the survey. General aspects of venous thromboembolic prophylaxis and protocols used (risk stratification and ultrasound screening). A descriptive analysis was performed, continuous data being expressed as the mean or median, and categorical data as percentages. A total of 234 patients in 18 ICUs were included. Eighteen percent (42/234) received no prophylaxis, and 55% had no contraindication to pharmacological prophylaxis. Of the 192 patients receiving prophylaxis, 84% received pharmacological prophylaxis, 14% mechanical prophylaxis and 2% combined prophylaxis. Low molecular weight heparin was the only pharmacological prophylaxis used, with a majority use of enoxaparin (17 of 18 ICUs). In patients with mechanical prophylaxis (31/192), antiembolic stockings were the most commonly used option (58%). Pharmacological prophylaxis contraindications were reported in 20% of the patients (46/234), the most frequent cause being thrombocytopenia (28% of the cases). Fifty percent of the ICUs used no specific venous thromboembolic prophylaxis protocol. Pharmacological prophylaxis with low molecular weight heparin was the most frequently used venous thromboembolic prophylactic measure. In patients with contraindications to pharmacological prophylaxis, mechanical measures were little used. The use of combined prophylaxis was anecdotal. Many of our ICUs lack specific prophylaxis protocols. Copyright © 2013 Elsevier España, S.L. and SEMICYUC. All rights reserved.

Diagnostic and management of spontaneous rectus sheath hematoma.

PubMed

Smithson, Alex; Ruiz, Jessica; Perello, Rafael; Valverde, Marta; Ramos, Javier; Garzo, Luïsa

2013-09-01

Spontaneous rectus sheath hematoma is an uncommon and often misdiagnosed cause of abdominal pain. The aim of this study is to describe our experience in their management. Retrospective analysis of the characteristics and outcomes of the spontaneous rectus sheath hematomas diagnosed over the last 12years was conducted. 24 patients were included (66% women; mean age: 74years; range: 54-87). All cases presented predisposing factors mainly anticoagulant therapy in 21 (87.5%) patients, hypertension in 19 (79.1%) and abdominal surgery in 12 (50%) cases. Eighteen (75%) referred triggering factors like coughing being the most common one, present in 17 (70.8%) patients. The main clinical findings were abdominal pain in 21 (87.5%) cases and the existence of an abdominal mass in 20 (83.3%). The diagnosis was confirmed by abdominal ultrasonography and/or computerized tomography in 23 (95.8%) patients. Nineteen cases (79.1%) responded to conservative management while 5 (20.8%) required interventional treatment, which consisted in an arteriography with selective embolization of the epigastric arteries in all cases. Four (80%) of the patients needing interventional treatment were receiving low molecular weight heparin. Nine (37.5%) patients developed hypovolemic shock and 1 (4%) died. Spontaneous rectus sheath hematomas should be considered in the differential diagnosis of abdominal pain, particularly in elderly women under anticoagulant therapy with onset of symptoms after a bout of cough. Most cases respond to conservative management, although those related to low molecular weight heparin might require interventional treatment; arteriography with selective embolization of the epigastric arteries is the first therapeutic option. Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

[Thromboprophylaxis in critically ill children in Spain and Portugal].

PubMed

Rodríguez Núñez, A; Fonte, M; Faustino, E V S

2015-03-01

Although critically ill children may be at risk from developing deep venous thrombosis (DVT), data on its incidence and effectiveness of thromboprophylaxis are lacking. To describe the use of thromboprophylaxis in critically ill children in Spain and Portugal, and to compare the results with international data. Secondary analysis of the multinational study PROTRACT, carried out in 59 PICUs from 7 developed countries (4 from Portugal and 6 in Spain). Data were collected from patients less than 18 years old, who did not receive therapeutic thromboprophylaxis. A total of 308 patients in Spanish and Portuguese (Iberian) PICUS were compared with 2176 admitted to international PICUs. Risk factors such as femoral vein (P=.01), jugular vein central catheter (P<.001), cancer (P=.03), and sepsis (P<.001), were more frequent in Iberian PICUs. The percentage of patients with pharmacological thromboprophylaxis was similar in both groups (15.3% vs. 12.0%). Low molecular weight heparin was used more frequently in Iberian patients (P<.001). In treated children, prior history of thrombosis (P=.02), femoral vein catheter (P<.001), cancer (P=.02) and cranial trauma or craniectomy (P=.006), were more frequent in Iberian PICUs. Mechanical thromboprophylaxis was used in only 6.8% of candidates in Iberian PICUs, compared with 23.8% in the international PICUs (P<.001). Despite the presence of risk factors for DVT in many patients, thromboprophylaxis is rarely prescribed, with low molecular weight heparin being the most used drug. Passive thromboprophylaxis use is anecdotal. There should be a consensus on guidelines of thromboprophylaxis in critically ill children. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

New oral anticoagulants in patients with cancer: current state of evidence.

PubMed

Sardar, Partha; Chatterjee, Saurav; Herzog, Eyal; Pekler, Gerald; Mushiyev, Savi; Pastori, Luciano J; Visco, Ferdinand; Aronow, Wilbert S

2015-01-01

Effectiveness of new oral anticoagulants (NOAC) in patients with cancer is not clearly defined. There remain concerns of doubtful benefit and chances of potential harm with newer agents. In this meta-analysis, we evaluated the efficacy and safety of NOAC in patients with cancer. PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 01, 2001 through February 28, 2013. Randomized controlled trials reporting efficacy and safety data of NOACs (rivaroxaban, dabigatran, and apixaban) with control (low-molecular-weight heparin/vitamin K antagonists/placebo) for patients with cancer were included. Primary efficacy outcome was venous thromboembolism (VTE) or VTE-related death, and primary safety outcome was clinically relevant bleeding. We used random-effects models. Six trials randomized 19,832 patients, and 1197 patients had cancer. Risk of VTE or VTE-related death was not significantly different with NOAC versus control [odds ratio (OR), 0.80; 95% confidence interval (CI), 0.39-1.65] in patients with cancer. Separate analysis for individual effects showed similar results for rivaroxaban (OR, 1.08; 95% CI, 0.60-1.94) and dabigatran (OR, 0.91; 95% CI, 0.21-3.91). Clinically relevant bleeding was not higher with NOAC compared with control (OR, 1.49; 95% CI, 0.82-2.71); individual effect of rivaroxaban showed similar results. No statistically significant difference of efficacy and safety with NOAC was found between patients with and without cancer. Rivaroxaban might be equally effective and safe as vitamin K antagonist in patients with cancer. Dabigatran is as effective as comparator; however, safety profile of dabigatran is unknown. Randomized trials of new anticoagulants specific to the cancer population are necessary, and NOAC also need to be evaluated against low-molecular-weight heparin.

The oxidative mechanism of heparin interferes with radical production by glucose and reduces the degree of glycooxidative modifications on human serum albumin.

PubMed

Finotti, P; Pagetta, A; Ashton, T

2001-04-01

Among substances which may prove useful in preventing or reducing the progression of glycooxidative modifications of proteins, heparin plays a unique role. To elucidate the mechanism whereby heparin may favourably influence the protein structure during glycation, human serum albumin (HSA) was glycated with both 25 and 50 mM glucose in the absence and presence of 12 microg.mL(-1) low-molecular-mass heparin. Glycation caused: (a) modifications of fluorescence emission and excitation spectra consistent with the covalent attachment of glucose to protein; (b) a significant increase in the esterase activity of HSA on p-nitrophenyl acetate; (c) a reduced susceptibility to tryptic digestion and (d) enhanced formation of high-molecular mass aggregates of HSA. These alterations were accompanied by oxidative reactions, as the EPR spectra showed a clear-cut radical signal, dependent on glucose concentration, further confirmed by measurement of the carbonyl content of HSA, as an indirect proof of oxidative damage. In the presence of heparin all the above alterations, especially at 25 mM glucose, turned out to be antagonized. The effects of heparin were dependent on its specific binding to HSA, which triggered an oxidative mechanism strikingly different from that caused by glucose. In the presence of heparin, only the radical species catalyzed by heparin was detected across all samples of glycated HSA, irrespective of glucose concentration. In addition, at 25 mM glucose, enhancement of the oxidative capacity of heparin was also observed. The results demonstrate that the oxidative mechanism sustained by heparin mediates biological effects that may be beneficial in reducing the extent of glycooxidative damage on HSA.

Widespread IgE-mediated hypersensitivity in the Sudan to the 'green nimitti' midge, Cladotanytarsus lewisi (Diptera: Chironomidae) II. Identification of a major allergen.

PubMed Central

Gad El Rab, M O; Thatcher, D R; Kay, A B

1980-01-01

A major allergen has been identified in an aqueous extract of the 'green nimitti' midge, Cladotanytarsus lewisi (Diptera: Chironomidae). Following chromatography on Sephadex G-100 allergenic activity, as assessed by skin ('prick') testing, eluted as two closely related peaks (pools I and II) at about 50% bed volume. When these pools were applied separately to columns of CM-cellulose, activity in each eluted with 0 . 05 M NaCl. Isoelectric focusing of the unfractionated allergen gave a single peak of activity at pI 4 . 3. By SDS--PAGE, biological activity in the whole 'green nimitti' extract and the material eluting from both pools I and II of the Sephadex G-100 column migrated to the same positions and were associated with a molecular size of 15,000--20,000 daltons. Skin test reactivity of the unfractionated material and the Sephadex G-100 pool I and II eluates were all destroyed following incubation with trypsin, chymotrypsin, thermolysin and neuraminidase. These experiments indicate that a major allergen derived from the 'green nimitti' midge, a cause of widespread and severe immediate-type allergy in the Sudan, is an acidic glycoprotein of 15,000--20,000 molecular weight. Images Fig. 3 PMID:7438559

Intravenous heparin dosing strategy in hospitalized patients with atrial dysrhythmias.

PubMed

Roswell, Robert O; Greet, Brian; Shah, Sunny; Bernard, Samuel; Milin, Alexandra; Lobach, Iryna; Guo, Yu; Radford, Martha J; Berger, Jeffrey S

2016-08-01

Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding.

Molecular dynamics-based model of VEGF-A and its heparin interactions.

PubMed

Uciechowska-Kaczmarzyk, Urszula; Babik, Sándor; Zsila, Ferenc; Bojarski, Krzysztof Kamil; Beke-Somfai, Tamás; Samsonov, Sergey A

2018-06-01

We present a computational model of the Vascular Endothelial Growth Factor (VEGF), an important regulator of blood vessels formation, which function is affected by its heparin interactions. Although structures of a receptor binding (RBD) and a heparin binding domain (HBD) of VEGF are known, there are structural data neither on the 12 amino acids interdomain linker nor on its complexes with heparin. We apply molecular docking and molecular dynamics techniques combined with circular dichroism spectroscopy to model the full structure of the dimeric VEGF and to propose putative molecular mechanisms underlying the function of VEGF/VEGF receptors/heparin system. We show that both the conformational flexibility of the linker and the formation of HBD-heparin-HBD sandwich-like structures regulate the mutual disposition of HBDs and so affect the VEGF-mediated signalling. Copyright © 2018 Elsevier Inc. All rights reserved.

Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial.

PubMed

Lewis, Edmund J; Lewis, Julia B; Greene, Tom; Hunsicker, Lawrence G; Berl, Tomas; Pohl, Marc A; de Zeeuw, Dick; Heerspink, Hiddo Lambers; Rohde, Richard D; Atkins, Robert C; Reutens, Anne T; Packham, David K; Raz, Itamar

2011-11-01

Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes. We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy. Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required. The study drug was sulodexide, 200 mg/d. The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >25%) or 50% decrease in baseline ACR. In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 ± 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups. We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract. Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria. Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Dual antiplatelet treatment in patients candidates for abdominal surgery.

PubMed

Illuminati, Giulio; Ceccanei, Gianluca; Pacilè, Maria A; Pizzardi, Giulia; Palumbo, Piergaspare; Vietri, Francesco

2013-01-01

With the increasing diffusion of percutaneous interventions (PCI), surgeons are often faced with the problem of operating on patients under dual antiplatelet treatment. Replacing dual antiplatelet regiment with low molecular weight heparin may expose to the abrupt thrombosis of coronary stent and massive myocardial infarction. The purpose of this study was to test the hypothesis that abdominal operations can be safely performed under dual antiplatelet treatment. Eleven patients underwent 5 colectomies, 3 nefrectomies, 2 gastrectomies and 1 hysterectomy under aspirin and plavix without any significant perioperative hemorrhage. These preliminary results show that abdominal operations can be safely performed under dual antiplatelet regimen. Abdominal surgery, Dual antiplatelet treatment.

Management of cancer-associated thrombosis in people with advanced disease.

PubMed

Noble, Simon; Johnson, Miriam J

2012-06-01

The management of venous thromboembolism in the cancer population is clearly established. Low molecular weight heparin has a greater efficacy than warfarin in the treatment of cancer-associated thrombosis and is recommended as the preferred therapy. However, the evidence informing these recommendations excluded patients with poor prognosis or performance status, thrombocytopenia, bleeding or brain metastases. Furthermore, there is limited data on the management of venous thromboembolism resistant to anticoagulation, a phenomenon frequently encountered in the advanced cancer population. This paper will review the management of cancer-associated thrombosis with a particular focus on challenging clinical situations faced by palliative care teams looking after patients with advanced disease.

Nebulized heparin and N-acetylcysteine for smoke inhalational injury: A case report.

PubMed

Ashraf, Umair; Bajantri, Bharat; Roa-Gomez, Gabriella; Venkatram, Sindhaghatta; Cantin, Amanda; Diaz-Fuentes, Gilda

2018-05-01

Every year, ∼40,000 people suffer burn-related injuries in the United States. Despite recent advances, the odds of dying from exposure to fire, flames, or smoke are one in ∼1500. Smoke inhalation causes injury to the airways via a complex physiological process, and the treatment is mainly supportive. Many recent interventions aim to decrease the formation of fibrin casts, the main cause of airway damage in these patients. Among these, treatment with a combination of nebulized heparin and N-acetylcysteine (NAC) has shown benefit. We describe the case of a 58-year-old man who presented after smoke inhalation during a fire. Soot was found in the nostrils when he was admitted to our hospital, and after he began coughing up carbonaceous material, he was electively intubated and placed on volume assist control ventilation. Bronchoscopy on the first day of intensive care confirmed the injury from smoke inhalation and revealed mucosal edema and soot involving the tracheobronchial tree. Inhaled unfractionated heparin of 10,000 IU in 3 mL of 0.9% normal saline alternating every 2 hours with 3 mL of 20% NAC was started 48 hours after admission and continued for 7 days. Bronchoscopy on the fifth day of intensive care showed significant improvement in airway edema and a resolution of soot. On the basis of our experience with this case and limited literature, we posit that nebulized heparin and NAC may be of benefit in patients with inhalational smoke-induced lung injury and mild-to-severe lung injury scores.

Tissue factor-expressing monocytes inhibit fibrinolysis through a TAFI-mediated mechanism, and make clots resistant to heparins

PubMed Central

Semeraro, Fabrizio; Ammollo, Concetta T.; Semeraro, Nicola; Colucci, Mario

2009-01-01

Background Thrombin is the main activator of the fibrinolysis inhibitor TAFI (thrombin activatable fibrinolysis inhibitor) and heightened clotting activation is believed to impair fibrinolysis through the increase of thrombin activatable fibrinolysis inhibitor activation. However, the enhancement of thrombin generation by soluble tissue factor was reported to have no effect on plasma fibrinolysis and it is not known whether the same is true for cell-associated tissue factor. The aim of this study was to evaluate the effect of tissue factor-expressing monocytes on plasma fibrinolysis in vitro. Design and Methods Tissue factor expression by human blood mononuclear cells (MNC) and monocytes was induced by LPS stimulation. Fibrinolysis was spectrophotometrically evaluated by measuring the lysis time of plasma clots containing LPS-stimulated or control cells and a low concentration of exogenous tissue plasminogen activator. Results LPS-stimulated MNC (LPS-MNC) prolonged fibrinolysis time as compared to unstimulated MNC (C-MNC) in contact-inhibited but not in normal citrated plasma. A significantly prolonged lysis time was observed using as few as 30 activated cells/μL. Fibrinolysis was also impaired when clots were generated on adherent LPS-stimulated monocytes. The antifibrinolytic effect of LPS-MNC or LPS-monocytes was abolished by an anti-tissue factor antibody, by an antibody preventing thrombin-mediated thrombin activatable fibrinolysis inhibitor activation, and by a TAFIa inhibitor (PTCI). Assays of thrombin and TAFIa in contact-inhibited plasma confirmed the greater generation of these enzymes in the presence of LPS-MNC. Finally, the profibrinolytic effect of unfractionated heparin and enoxaparin was markedly lower (~50%) in the presence of LPS-MNC than in the presence of a thromboplastin preparation displaying an identical tissue factor activity. Conclusions Our data indicate that LPS-stimulated monocytes inhibit fibrinolysis through a tissue factor-mediated enhancement of thrombin activatable fibrinolysis inhibitor activation and make clots resistant to the profibrinolytic activity of heparins, thus providing an additional mechanism whereby tissue factor-expressing monocytes/macrophages may favor fibrin accumulation and diminish the antithrombotic efficacy of heparins. PMID:19377079

Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial.

PubMed

Dangas, George D; Lefèvre, Thierry; Kupatt, Christian; Tchetche, Didier; Schäfer, Ulrich; Dumonteil, Nicolas; Webb, John G; Colombo, Antonio; Windecker, Stephan; Ten Berg, Jurriën M; Hildick-Smith, David; Mehran, Roxana; Boekstegers, Peter; Linke, Axel; Tron, Christophe; Van Belle, Eric; Asgar, Anita W; Fach, Andreas; Jeger, Raban; Sardella, Gennaro; Hink, Hans Ulrich; Husser, Oliver; Grube, Eberhard; Deliargyris, Efthymios N; Lechthaler, Ilknur; Bernstein, Debra; Wijngaard, Peter; Anthopoulos, Prodromos; Hengstenberg, Christian

2015-12-29

Anticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting. The goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR. A total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding. Anticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: -1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant. In this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-limb immobilization.

PubMed

Zee, Aniek Ag; van Lieshout, Kelly; van der Heide, Maaike; Janssen, Loes; Janzing, Heinrich Mj

2017-08-06

Immobilization of the lower limb is a risk factor for venous thromboembolism (VTE). Low molecular weight heparins (LMWHs) are anticoagulants, which might be used in adult patients with lower-limb immobilization to prevent deep venous thrombosis (DVT) and its complications. This is an update of the review first published in 2008. To assess the effectiveness of low molecular weight heparin for the prevention of venous thromboembolism in patients with lower-limb immobilization in an ambulatory setting. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register, CENTRAL, and three trials registers (April 2017). Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that described thromboprophylaxis by means of LMWH compared with no prophylaxis or placebo in adult patients with lower-limb immobilization. Immobilization was by means of a plaster cast or brace. Two review authors independently selected trials, assessed risk of bias and extracted data. The review authors contacted the trial authors for additional information if required. Statistical analysis was carried out using Review Manager 5. We included eight RCTs that fulfilled our criteria, with a total of 3680 participants. The quality of evidence, according GRADE, varied by outcome and ranged from low to moderate. We found an incidence of DVT ranging from 4.3% to 40% in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least one week, and who received no prophylaxis, or placebo. This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization, with event rates ranging from 0% to 37% (odds ratio (OR) 0.45, 95% confidence interval (CI) 0.33 to 0.61; with minimal evidence of heterogeneity: I² = 26%, P = 0.23; seven studies; 1676 participants, moderate-quality evidence). Comparable results were seen in the following groups of participants: patients with below-knee casts, conservatively treated patients (non-operated patients), operated patients, patients with fractures, patients with soft-tissue injuries, and patients with distal or proximal thrombosis. No clear differences were found between the LMWH and control groups for pulmonary embolism (OR 0.50, 95% CI 0.17 to 1.47; with no evidence of heterogeneity: I² = 0%, P = 0.56; five studies, 2517 participants; low-quality evidence). The studies also showed less symptomatic VTE in the LMWH groups compared with the control groups (OR 0.40, 95% CI 0.21 to 0.76; with minimal evidence of heterogeneity: I² = 16%, P = 0.31; six studies; 2924 participants; low-quality evidence). One death was reported in the included studies, but no deaths due to pulmonary embolism were reported. Complications of major adverse events were rare, with minor bleeding the main adverse events reported. Moderate-quality evidence showed that the use of LMWH in outpatients reduced DVT when immobilization of the lower limb was required, when compared with no prophylaxis or placebo. The quality of the evidence was reduced to moderate because of risk of selection and attrition bias in the included studies. Low-quality evidence showed no clear differences in PE between the LMWH and control groups, but less symptomatic VTE in the LMWH groups. The quality of the evidence was downgraded due to risk of bias and imprecision.

Structure-function relations of heparin-mimetic sulfated xylan oligosaccharides: inhibition of human immunodeficiency virus-1 infectivity in vitro.

PubMed

Stone, A L; Melton, D J; Lewis, M S

1998-07-01

Heparins/heparan sulfates modulate the function of proteins and cell membranes in numerous biological systems including normal and disease processes in humans. Heparin has been used for many years as an anticoagulant, and anticoagulant heparin-mimetics were developed several decades ago by chemical sulfation of non-mammalian polysaccharides, e.g., an antithrombotic sulfated xylan. This pharmaceutical, which comprises a mixture of sulfated oligoxylans, also mimics most other biological actions of natural heparins in vitro, including inhibition of the human immunodeficiency virus, but the molecular basis for these actions has been unclear. Here, numerous Components of the sulfated oligoxylan mixture were isolated and when bioassayed in the case of anti-HIV-1 infectivity revealed that a structural specificity underlines the capacity of sulfated xylan to inhibit HIV-1, rather than a non-specific mechanism. Components were isolated by chromatographic fractionation through Bio-Gel P10 in 0.5 M ammonium bicarbonate. This fractionation revealed an elution range associated with apparent molecular weights of approximately 22000 to <1500 relative to standard heparin and heparan sulfates and newly prepared sulfated oligosaccharide standards. Components were characterized by metachromatic absorption spectroscopy, ultracentrifugation, GlcA analysis, and potency against HIV-1 infectivity, both in the tetrazolium cytotoxicity assay and in syncytium-forming assays, in CD4-lymphocytes. Structural specificity was indicated by the differential potencies exhibited by the Components: Highest activity (cytotoxicity) was exhibited by Components in the chromatographic region > or = approximately 5500 in mass (50% effective (inhibitory) concentration = 0.5-0.7 microg ml(-1) in the first fractionation series, and 0.1-0.5 microg ml(-1) in a second series). The potency declined sharply below approximately 5400 in mass, but with an exception; a second structure exhibiting relatively high potency eluted among low-mass oligosaccharides which had an average size of approximately a nonomer. Components displayed differential potencies also against the syncytium-forming infectivity of HIV-1. The high potency against syncytium-formation was retained by Components down to a minimum size of about 4500 in mass, smaller than the > or = approximately 5400 required above. One in ten of the beta1,4-linked xyloses in the native xylan are substituted with a monomeric alpha1,2 DGlcA branch. We have speculated that pharmaceutical actions of sulfated xylan might be related to structures involving the alpha-D linked substituents and this was examined using a space-filling model of a sulfated octaxylan and by analyses of Components for GlcA content. Understanding structure/function relations in the heparin-like actions of these agents would be of general significance for the careful examination of their potential clinical usefulness in many human processes modulated by heparins, including AIDS.

Heparin-induced thrombocytopenia (HIT) in pediatric cardiac surgery: an emerging cause of morbidity and mortality.

PubMed

Alsoufi, Bahaaldin; Boshkov, Lynn K; Kirby, Aileen; Ibsen, Laura; Dower, Nancy; Shen, Irving; Ungerleider, Ross

2004-01-01

Unfractionated heparin (UFH) is immunogenic, and heparin-dependent antibodies can be demonstrated 5 to 10 days postoperatively in 25% to 50% of adult postcardiac surgery patients. In a minority of these cases (1% to 3% if UFH is continued longer than 1 week) these antibodies strongly activate platelets, causing thrombocytopenia and massive thrombin generation (HIT syndrome). HIT is an intensely procoagulant disorder, and in adult cardiac surgery patients carries both significant thrombotic morbidity (38% to 81%) and mortality (28%). Despite the ubiquitous use of UFH in pediatric intensive care units, and the repeated and sustained exposures to UFH in neonates and young children with congenital heart disease, HIT has been infrequently recognized and reported in this patient population. However, emerging experience at our institution and elsewhere suggests that HIT is significantly under-recognized in pediatric congenital heart disease patients, and may in fact have an incidence and associated thrombotic morbidity and mortality in this patient group comparable to that seen in adult cardiac surgery patients. This article will review HIT in pediatric patients with congenital heart disease and emphasize the special challenges posed in clinical recognition, laboratory diagnosis, and treatment of HIT in this patient group. We will also outline our experience with the off-label use of the direct thrombin inhibitor, argatroban, in pediatric patients with HIT.

A practical approach to the prevention of miscarriage: part 5--antiphospholipid syndrome as a cause of spontaneous abortion.

PubMed

Check, J H

2011-01-01

To describe the diagnosis and treatment of antiphospholipid syndrome as it relates to spontaneous abortion. The relative importance of performing tests of antiphospholipid antibodies that prolong the partial thromboplastin time and other autoantibodies against phospholipids measured by ELISA are discussed. The most important diagnostic tests are the lupus anticoagulant, anticardiolipin antibody and antiphosphatidyl serine. Low molecular weight heparin and low dose aspirin are the two most important therapies. Women with recurrent miscarriages or even an unexplained miscarriage especially after ten weeks (but sometimes even early first trimester) or a history of thrombosis or intrauterine growth restriction and maybe preeclampsia are candidates for anticoagulant therapy, especially with the presence of significant levels of the lupus anticoagulant or anticardiolipin or antiphosphatidyl serine antibodies (> 40 pl units/ml).

[How to provide practical treatment for ambulatory patients with deep venous thrombosis].

PubMed

Achkar, A; Samama, M M

1999-02-01

Much interest has been focused on low molecular weight heparins (LMWH), light weight fragments of standard heparin, for the management of deep vein thrombosis (DVT) without pulmonary embolism (PE). LMWHs offer several advantages: predictable anticoagulant activity, better bioavailability, longer half-life, better patient and caretaker comfort, safety and efficacy at least comparable to continuous intravenous heparin. Ambulatory treatment is quite attractive and a large number of patients with DVT are now being managed as outpatients. There are however certain precautions which must be taken to avoid unsatisfactory anticoagulation and subsequent consequences which have nevertheless been shown to be exceptional in well-designed and well-conducted trials excluding patients with high risk for hemorrhage and based on attentive medical control. The purpose of this review is to propose clear and simple protocols for everyday practice aimed at a global diagnostic and therapeutic management of venous thromboembolism. The review of the literature draws attention to the need for confirmation of the clinical suspicion of DVT, practical application of the anticoagulant treatment, and the importance of the etiology search in order to avoid missing a congenital or acquired state of thrombophilia or an occult cancer revealed by DVT. Half of all cases of thrombosis are caused by these two etiologies. In addition, with the development of noninvasive methods for diagnosing DVT, the efficacy of clear therapeutic regimens and the simplification of coagulation tests warrant outpatient management in many cases of DVT in compliance with certain rules of good clinical practice: confirmation of the diagnosis and regular treatment controls. An essential element is the close collaboration between the patient, the physician, the nursing staff, the laboratory and the pharmacist.

Safety of Endovascular Intervention for Stroke on Therapeutic Anticoagulation: Multicenter Cohort Study and Meta-Analysis.

PubMed

Kurowski, Donna; Jonczak, Karin; Shah, Qaisar; Yaghi, Shadi; Marshall, Randolph S; Ahmad, Haroon; McKinney, James; Torres, Jose; Ishida, Koto; Cucchiara, Brett

2017-05-01

Intravenous (IV) tissue plasminogen activator (tPA) is contraindicated in therapeutically anti-coagulated patients. Such patients may be considered for endovascular intervention. However, there are limited data on its safety. We performed a multicenter retrospective study of patients undergoing endovascular intervention for acute ischemic stroke while on therapeutic anticoagulation. We compared the observed rate of National Institute of Neurological Disorders and Stroke defined symptomatic intracerebral hemorrhage (sICH) with risk-adjusted historical control rates of sICH after IV tPA using weighted averages of the hemorrhage after thrombolysis (HAT) and Multicenter Stroke Survey (MSS) prediction scores. We also performed a metaanalysis of studies assessing risk of sICH with endovascular intervention in patients on anticoagulation. Of 94 cases, mean age was 73 years and median National Institutes of Health Stroke Scale was 19. Anticoagulation consisted of warfarin (n = 51), dabigatran (n = 6), rivaroxaban (n = 13), apixaban (n = 1), IV heparin (n = 19), low molecular weight heparin (n = 3), and combined warfarin and IV heparin (n = 3). sICH was seen in 7 patients (7%, 95% confidence interval 4-15), all on warfarin. Predicted sICH rates for the cohort based on HAT and MSS scoring were 12% and 7%, respectively. Meta-analysis of 6 studies showed no significant difference in sICH between patients undergoing endovascular intervention on anticoagulation and comparator groups. Endovascular intervention in subjects on therapeutic anticoagulation appears reasonably safe, with a sICH rate similar to patients not on anticoagulation receiving IV tPA. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Rivaroxaban in the treatment of venous thromboembolism and the prevention of recurrences: a practical approach.

PubMed

Arcelus, Juan I; Domènech, Pere; Fernández-Capitan, Ma Del Carmen; Guijarro, Ricardo; Jiménez, David; Jiménez, Sonia; Lozano, Francisco S; Monreal, Manel; Nieto, José A; Páramo, José A

2015-05-01

Anticoagulation therapy is the standard treatment of patients with symptomatic venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. Until recently, treatment of VTE was based on parenteral or low-molecular-weight heparin for initial therapy (5-10 days) and oral vitamin K antagonists for long-term therapy. Those treatments have some limitations, including parenteral administration (heparins), the need for frequent monitoring and dose adjustments, interactions with several medications, and dietary restrictions (vitamin K antagonists). Rivaroxaban is a new oral direct factor Xa inhibitor with a wide therapeutic window, predictable anticoagulant effect, no food interactions, and few drug interactions. Consequently, no periodic monitoring of anticoagulation is needed, and fixed doses can be prescribed. EINSTEIN program demonstrated that rivaroxaban was as effective as and significantly safer than standard therapy for treatment of VTE. Rivaroxaban was recently authorized so doubts exist about how to use it in daily clinical practice. This document aims to clarify common questions formulated by clinicians regarding the use of this new drug. © The Author(s) 2014.

Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT-TIMI 25 analysis.

PubMed

Giraldez, Roberto R; Nicolau, José Carlos; Corbalan, Ramon; Gurfinkel, Enrique P; Juarez, Ursulo; Lopez-Sendon, Jose; Parkhomenko, Alexander; Molhoek, Peter; Mohanavelu, Satishkumar; Morrow, David A; Antman, Elliott M

2007-07-01

We compared outcomes of ST-elevation myocardial infarction (STEMI) patients randomized to a strategy of either enoxaparin or unfractionated heparin (UFH) to support fibrinolysis. In the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial, 20,479 patients undergoing fibrinolysis for STEMI with a fibrin-specific agent (N = 16,283) or streptokinase (SK) (N = 4139) were randomized to enoxaparin throughout their hospitalization or UFH for at least 48 h. The primary end point of death or nonfatal recurrent MI through 30 days occurred in 12.0% of patients in the UFH and 9.8% in the enoxaparin groups when treated with fibrin-specific lytics [odds ratio(adjusted) (OR(adj)) 0.78; 95% CI 0.70-0.87; P < 0.001] and 11.8 vs. 10.2%, respectively, when treated with SK (OR(adj) 0.83; 95% CI 0.66-1.04; P = 0.10; P(interaction) = 0.58). Major bleeding rates including intracranial hemorrhage within the fibrin-specific cohort were 1.2 and 2.0% in the UFH and enoxaparin groups, respectively (P < 0.001) and 2.0% in UFH and 2.4% in enoxaparin patients in the SK cohort (P = 0.16). Interaction tests between antithrombin- and lytic-type were non-significant (P = 0.20). Death, nonfatal MI, or major bleeding was significantly reduced with enoxaparin in the fibrin-specific cohort (OR(adj) 0.82; 95% CI 0.74-0.91; P < 0.001) and favoured enoxaparin in the SK cohort (OR(adj) 0.89; 95% CI 0.72-1.10; P = 0.29; P(interaction) = 0.53). The benefits of an enoxaparin strategy over UFH were observed in both SK and fibrin-specific-treated STEMI patients. Therefore, an enoxaparin strategy is preferred over UFH to support fibrinolysis for STEMI regardless of lytic agent.

The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

PubMed

Ansell, Jack; Hirsh, Jack; Poller, Leon; Bussey, Henry; Jacobson, Alan; Hylek, Elaine

2004-09-01

This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. The article describes the antithrombotic effect of VKAs, the monitoring of anticoagulation intensity, the clinical applications of VKA therapy, and the optimal therapeutic range of VKAs, and provides specific management recommendations. Grade 1 recommendations are strong, and indicate that the benefits do, or do not, outweigh the risks, burdens, and costs. Grade 2 suggests that individual patient's values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this article are the following: for dosing of VKAs, we suggest the initiation of oral anticoagulation therapy with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 2B). In the elderly and in other patient subgroups with an elevated bleeding risk, we suggest a starting dose at < or = 5 mg (Grade 2C). We recommend basing subsequent doses after the initial two or three doses on the results of INR monitoring (Grade 1C). The article also includes several specific recommendations for the management of patients with INRs above the therapeutic range and for patients requiring invasive procedures. For example, in patients with mild to moderately elevated INRs without major bleeding, we suggest that when vitamin K is to be given it be administered orally rather than subcutaneously (Grade 1A). For the management of patients with a low risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before they undergo surgery (Grade 2C). For patients with a high risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before surgery, to allow the INR to return to normal, and beginning therapy with full-dose unfractionated heparin or full-dose low-molecular-weight heparin as the INR falls (Grade 2C). In patients undergoing dental procedures, we suggest the use of tranexamic acid mouthwash (Grade 2B) or epsilon amino caproic acid mouthwash without interrupting anticoagulant therapy (Grade 2B) if there is a concern for local bleeding. For most patients who have a lupus inhibitor, we suggest a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 2B]. In patients with recurrent thromboembolic events with a therapeutic INR or other additional risk factors, we suggest a target INR of 3.0 (range, 2.5 to 3.5) [Grade 2C]. As models of anticoagulation monitoring and management, we recommend that clinicians incorporate patient education, systematic INR testing, tracking, and follow-up, and good communication with patients concerning results and dosing decisions (Grade 1C+).

Influence of Layer-by-Layer Polyelectrolyte Deposition and EDC/NHS Activated Heparin Immobilization onto Silk Fibroin Fabric

PubMed Central

Elahi, M. Fazley; Guan, Guoping; Wang, Lu; King, Martin W.

2014-01-01

To enhance the hemocompatibility of silk fibroin fabric as biomedical material, polyelectrolytes architectures have been assembled through the layer-by-layer (LbL) technique on silk fibroin fabric (SFF). In particular, 1.5 and 2.5 bilayer of oppositely charged polyelectrolytes were assembled onto SFF using poly(allylamine hydrochloride) (PAH) as polycationic polymer and poly(acrylic acid) (PAA) as polyanionic polymer with PAH topmost. Low molecular weight heparin (LMWH) activated with 1-ethyl-3-(dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) was then immobilized on its surface. Alcian Blue staining, toluidine blue assay and X-ray photoelectron spectroscopy (XPS) confirmed the presence of heparin on modified SFF surfaces. The surface morphology of the modified silk fibroin fabric surfaces was characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM), and obtained increased roughness. Negligible hemolytic effect and a higher concentration of free hemoglobin by a kinetic clotting time test ensured the improved biological performance of the modified fibroin fabric. Overall, the deposition of 2.5 bilayer was found effective in terms of biological and surface properties of the modified fibroin fabric compared to 1.5 bilayer self-assembly technique. Therefore, this novel approach to surface modification may demonstrate long term patency in future in vivo animal trials of small diameter silk fibroin vascular grafts. PMID:28788601

Effects of Sildenafil Citrate and Heparin Treatments on Placental Cell Morphology in a Murine Model of Pregnancy Loss.

PubMed

Luna, Rayana Leal; Vasconcelos, Anne Gabrielle; Nunes, Ana Karolina Santana; de Oliveira, Wilma Helena; Barbosa, Karla Patricia de Sousa; Peixoto, Christina Alves

2016-01-01

Lipopolysaccharide (LPS) injections during pregnancy are well established as models for pregnancy complications, including fetal growth restriction (FGR), thrombophilia, preterm labor and abortion. Indeed, inflammation, as induced by LPS injection has been described as a pivotal factor in cases of miscarriage related to placental tissue damage. The phosphodiesterase-5 inhibitor sildenafil (Viagra®) is currently used to treat FGR cases in women, while low-molecular weight heparin (Fragmin®) is a standard treatment for recurrent miscarriage (RM). However, the pathways and cellular dynamics involved in RM are not completely understood. The aim of this study was to evaluate the protective effect of sildenafil and dalteparin in a mouse model of LPS-induced abortion. Histopathology, ultrastructural analysis and immunofluorescence for P-selectin were studied in two different placental cell types: trophoblast cells and labyrinth endothelial cells. Treatment with sildenafil either alone or in combination with heparin showed the best response against LPS-induced injury during pregnancy. In conclusion, our results support the use of these drugs as future therapeutic agents that may protect the placenta against inflammatory injury in RM events. Analyses of the ultrastructure and placental immunophysiology are important to understand the mechanism underlying RM. These findings may spark future studies and aid in the development of new therapies in cases of RM. © 2016 S. Karger AG, Basel.

Fondaparinux in the initial and long-term treatment of venous thromboembolism.

PubMed

Pesavento, Raffaele; Amitrano, Maria; Trujillo-Santos, Javier; Di Micco, Pierpaolo; Mangiacapra, Sara; López-Jiménez, Luciano; Falgá, Conxita; García-Bragado, Fernando; Piovella, Chiara; Prandoni, Paolo; Monreal, Manuel

2015-02-01

Even in the absence of evidence on its long-term efficacy and safety, a number of patients with venous thromboembolism (VTE) receive long-term therapy with fondaparinux alone in everyday practice. We used the Registro Informatizado de Enfermedad Tromboembólica (RIETE) registry to compare the rate of VTE recurrences and major bleeding at 10 and 90 days in patients with and without cancer. For long-term therapy, fondaparinux was compared with vitamin K antagonists (VKA) in patients without cancer and with low-molecular-weight heparin (LMWH) in those with cancer. Of 47,378 patients recruited, 46,513 were initially treated with heparin, 865 with fondaparinux. Then, 263 patients (78 with cancer) were treated for at least 3 months with fondaparinux. After propensity-score matching, there were no differences between patients receiving initial therapy with heparin or fondaparinux. Among patients with cancer, there were no differences between fondaparinux and LMWH. Among patients without cancer, the long-term use of fondaparinux was associated with an increased risk of major bleeding (3.24 % vs. 0.95 %, p<0.05). An unexpected high rate of major bleeding was observed in non-cancer patients treated with long-term fondaparinux. Our small sample does not allow to derive relevant conclusions on the use of fondaparinux in cancer patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor.

PubMed

Bolnick, Alan D; Bolnick, Jay M; Kohan-Ghadr, Hamid-Reza; Kilburn, Brian A; Pasalodos, Omar J; Singhal, Pankaj K; Dai, Jing; Diamond, Michael P; Armant, D Randall; Drewlo, Sascha

2017-06-01

Does low molecular weight heparin (LMWH) require heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) signaling to induce extravillous trophoblast differentiation and decrease apoptosis during oxidative stress? LMWH increased HBEGF expression and secretion, and HBEGF signaling was required to stimulate trophoblast extravillous differentiation, increase invasion in vitro and reduce trophoblast apoptosis during oxidative stress. Abnormal trophoblast differentiation and survival contribute to placental insufficiency syndromes, including preeclampsia and intrauterine growth restriction. Preeclampsia often manifests as a pro-thrombotic state, with unsuccessful transformation of the spiral arteries that reduces oxygen supply and can produce placental infarction. LMWH improves placental function by increasing blood flow. Recent data suggest that the actions of LMWH transcend its anti-coagulative properties, but the molecular mechanism is unknown. There is evidence that LMWH alters the expression of human HBEGF in trophoblast cells, which regulates human trophoblast pathophysiology. HBEGF, itself, is capable of increasing trophoblast survival and invasiveness. First-trimester placental explants and the HTR-8/SVneo cell line, established using extravillous trophoblast outgrowths from first-trimester villous explants, were treated in vitro with LMWH to examine the effects on HBEGF signaling and trophoblast function under normal physiological and pathological conditions. A highly specific antagonist of HBEGF and other inhibitors of HBEGF downstream signaling were used to determine the relationship between LMWH treatment and HBEGF. Placental tissues (n = 5) were obtained with IRB approval and patient consent from first-trimester terminations. Placental explants and HTR-8/SVneo cells were cultured on plastic or Matrigel™ and treated with a therapeutic dose of LMWH (Enoxaparin; 10 IU/ml), with or without CRM197, pan Erb-B2 Receptor Tyrosine Kinase (ERBB) inhibitor, anti-ERBB1 or ERBB4 blocking antibodies, or pretreatment of cells with heparitinase I. Extravillous differentiation was assessed by immunocytochemistry to determine the relative levels of integrins α6β4 and α1β1. Trophoblast invasiveness was assessed in villous explants by measuring outgrowth from villous tips cultured on Matrigel, and by invasion assays with HTR-8/SVneo cells cultured on Matrigel-coated transwell insert. Placental explants and HTR-8/SVneo cells were exposed to oxidative stress in a hypoxia-reoxygenation (H-R) model, measuring cell death by TUNEL assay, caspase 3 cleavage, and BCL-2α expression. LMWH induced extravillous differentiation, according to trophoblast invasion assays and integrin (α6β4-α1β1) switching. Treatment with LMWH rescued cytotrophoblasts and HTR-8/SVneo cells from apoptosis during exposure to reoxygenation injury, based on TUNEL, caspase 3 cleavage and BCL-2α expression. Experiments using CRM197, ERBB1 and ERBB4 blocking antibodies, pan-ERBB inhibitor and removal of cell surface heparin demonstrated that the effects of LMWH on trophoblast invasion and survival were dependent upon HBEGF signaling. N/A. The primary limitation of this study was the use of only in vitro experiments. Patient demographics from elective terminations were not available. These data provide new insights into the non-coagulation-related aspects of perinatal LMWH treatment in the management of placental insufficiency disorders. This research was supported by grants from the National Institutes of Health (HD071408 and HL128628), the March of Dimes, and the W. K. Kellogg Foundation. There were no conflicts or competing interests. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis.

PubMed

Glas, Gerie J; Serpa Neto, Ary; Horn, Janneke; Cochran, Amalia; Dixon, Barry; Elamin, Elamin M; Faraklas, Iris; Dissanaike, Sharmila; Miller, Andrew C; Schultz, Marcus J

2016-12-01

Pulmonary coagulopathy is a characteristic feature of lung injury including ventilator-induced lung injury. The aim of this individual patient data meta-analysis is to assess the effects of nebulized anticoagulants on outcome of ventilated intensive care unit (ICU) patients. A systematic search of PubMed (1966-2014), Scopus, EMBASE, and Web of Science was conducted to identify relevant publications. Studies evaluating nebulization of anticoagulants in ventilated patients were screened for inclusion, and corresponding authors of included studies were contacted to provide individual patient data. The primary endpoint was the number of ventilator-free days and alive at day 28. Secondary endpoints included hospital mortality, ICU- and hospital-free days at day 28, and lung injury scores at day seven. We constructed a propensity score-matched cohort for comparisons between patients treated with nebulized anticoagulants and controls. Data from five studies (one randomized controlled trial, one open label study, and three studies using historical controls) were included in the meta-analysis, compassing 286 patients. In all studies unfractionated heparin was used as anticoagulant. The number of ventilator-free days and alive at day 28 was higher in patients treated with nebulized heparin compared to patients in the control group (14 [IQR 0-23] vs. 6 [IQR 0-22]), though the difference did not reach statistical significance (P = 0.459). The number of ICU-free days and alive at day 28 was significantly higher, and the lung injury scores at day seven were significantly lower in patients treated with nebulized heparin. In the propensity score-matched analysis, there were no differences in any of the endpoints. This individual patient data meta-analysis provides no convincing evidence for benefit of heparin nebulization in intubated and ventilated ICU patients. The small patient numbers and methodological shortcomings of included studies underline the need for high-quality well-powered randomized controlled trials.

The non-anticoagulant heparin-like K5 polysaccharide derivative K5-N,OSepi attenuates myocardial ischaemia/reperfusion injury

PubMed Central

Collino, Massimo; Pini, Alessandro; Mastroianni, Rosanna; Benetti, Elisa; Lanzi, Cecilia; Bani, Daniele; Chini, Jacopo; Manoni, Marco; Fantozzi, Roberto; Masini, Emanuela

2012-01-01

Heparin and low molecular weight heparins have been demonstrated to reduce myocardial ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhagic and thrombotic complications. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility of producing heparin-like compounds with low anticoagulant activity and strong anti-inflammatory effects. Using a rat model of regional myocardial I/R, we investigated the effects of an epimerized N-,O-sulphated K5 polysaccharide derivative, K5-N,OSepi, on infarct size and histological signs of myocardial injury caused by 30 min. ligature of the left anterior descending coronary artery followed by 1 or 24 h reperfusion. K5-N,OSepi (0.1–1 mg/kg given i.v. 15 min. before reperfusion) significantly reduced the extent of myocardial damage in a dose-dependent manner. Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by K5-N,OSepi. In left ventricular samples, I/R induced mast cell degranulation and a robust increase in lipid peroxidation, free radical-induced DNA damage and calcium overload. Markers of neutrophil infiltration and activation were also induced by I/R in rat hearts, specifically myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, prostaglandin-E2 and tumour-necrosis-factor-α production. The robust increase in oxidative stress and inflammatory markers was blunted by K5-N,OSepi, in a dose-dependent manner, with maximum at 1 mg/kg. Furthermore, K5-N,OSepi administration attenuated the increase in caspase 3 activity, Bid and Bax activation and ameliorated the decrease in expression of Bcl-2 within the ischaemic myocardium. In conclusion, we demonstrate that the cardioprotective effect of the non-anticoagulant K5 derivative K5-N,OSepi is secondary to a combination of anti-apoptotic and anti-inflammatory effects. PMID:22248092

Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes.

PubMed

Pinto, Duane S; Stone, Gregg W; Shi, Chunxue; Dunn, Elizabeth S; Reynolds, Matthew R; York, Meghan; Walczak, Joshua; Berezin, Ronna H; Mehran, Roxana; McLaurin, Brent T; Cox, David A; Ohman, E Magnus; Lincoff, A Michael; Cohen, David J

2008-11-25

The aim of this study was to determine the economic impact of several anticoagulation strategies for moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients managed invasively. The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial demonstrated that bivalirudin monotherapy yields similar rates of ischemic complications and less bleeding than regimens incorporating glycoprotein IIb/IIIa receptor inhibitors (GPI) for moderate- and high-risk NSTE-ACS. In ACUITY, 7,851 U.S. patients were randomized to: 1) heparin (unfractionated or enoxaparin) + GPI; 2) bivalirudin + GPI; or 3) bivalirudin monotherapy. Patients assigned to GPI were also randomized to upstream GPI before catheterization or selective GPI only with percutaneous coronary intervention. Resource use data were collected prospectively through 30-day follow-up. Costs were estimated with standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule. At 30 days, ischemic events were similar for all groups. Major bleeding was reduced with bivalirudin monotherapy compared with heparin + GPI or bivalirudin + GPI (p < 0.001). Length of stay was lowest with bivalirudin monotherapy or bivalirudin + catheterization laboratory GPI (p = 0.02). Despite higher drug costs, aggregate hospital stay costs were lowest with bivalirudin monotherapy (mean difference range: $184 to $1,081, p < 0.001 for overall comparison) and at 30 days (mean difference range: $123 to $938, p = 0.005). Regression modeling demonstrated that hospital savings were primarily due to less major and minor bleeding with bivalirudin ($8,658/event and $2,282/event, respectively). Among U.S. patients in the ACUITY trial, bivalirudin monotherapy compared with heparin + GPI resulted in similar protection from ischemic events, reduced bleeding, and shorter length of stay. Despite higher drug costs, aggregate hospital and 30-day costs were lowest with bivalirudin monotherapy. Thus bivalirudin monotherapy seems to be an economically attractive alternative to heparin + GPI for patients with moderate- and high-risk NSTE-ACS. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

Anticoagulants (extended duration) for prevention of venous thromboembolism following total hip or knee replacement or hip fracture repair.

PubMed

Forster, Rachel; Stewart, Marlene

2016-03-30

The optimal duration of thromboprophylaxis after total hip or knee replacement, or hip fracture repair remains controversial. It is common practice to administer prophylaxis using low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) until discharge from hospital, usually seven to 14 days after surgery. International guidelines recommend extending thromboprophylaxis for up to 35 days following major orthopaedic surgery but the recommendation is weak due to moderate quality evidence. In addition, recent oral anticoagulants that exert effect by direct inhibition of thrombin or activated factor X lack the need for monitoring and have few known drug interactions. Interest in this topic remains high. To assess the effects of extended-duration anticoagulant thromboprophylaxis for the prevention of venous thromboembolism (VTE) in people undergoing elective hip or knee replacement surgery, or hip fracture repair. The Cochrane Vascular Information Specialist searched the Specialised Register (last searched May 2015) and CENTRAL (2015, Issue 4). Clinical trials databases were searched for ongoing or unpublished studies. Randomised controlled trials assessing extended-duration thromboprophylaxis (five to seven weeks) using accepted prophylactic doses of LMWH, UFH, vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) compared with short-duration thromboprophylaxis (seven to 14 days) followed by placebo, no treatment or similar extended-duration thromboprophylaxis with LMWH, UFH, VKA or DOACs in participants undergoing hip or knee replacement or hip fracture repair. We independently selected trials and extracted data. Disagreements were resolved by discussion. We performed fixed-effect model meta-analyses with odds ratios (ORs) and 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity. We included 16 studies (24,930 participants); six compared heparin with placebo, one compared VKA with placebo, two compared DOAC with placebo, one compared VKA with heparin, five compared DOAC with heparin and one compared anticoagulants chosen at investigators' discretion with placebo. Three trials included participants undergoing knee replacement. No studies assessed hip fracture repair.Trials were generally of good methodological quality. The main reason for unclear risk of bias was insufficient reporting. The quality of evidence according to GRADE was generally moderate, as some comparisons included a single study, low number of events or heterogeneity between studies leading to wide CIs.We showed no difference between extended-duration heparin and placebo in symptomatic VTE (OR 0.59, 95% CI 0.35 to 1.01; 2329 participants; 5 studies; high quality evidence), symptomatic deep vein thrombosis (DVT) (OR 0.73, 95% CI 0.39 to 1.38; 2019 participants; 4 studies; moderate quality evidence), symptomatic pulmonary embolism (PE) (OR 0.61, 95% CI 0.16 to 2.33; 1595 participants; 3 studies; low quality evidence) and major bleeding (OR 0.59, 95% CI 0.14 to 2.46; 2500 participants; 5 studies; moderate quality evidence). Minor bleeding was increased in the heparin group (OR 2.01, 95% CI 1.43 to 2.81; 2500 participants; 5 studies; high quality evidence). Clinically relevant non-major bleeding was not reported.We showed no difference between extended-duration VKA and placebo (one study, 360 participants) for symptomatic VTE (OR 0.10, 95% CI 0.01 to 1.94; moderate quality evidence), symptomatic DVT (OR 0.13, 95% CI 0.01 to 2.62; moderate quality evidence), symptomatic PE (OR 0.32, 95% CI 0.01 to 7.84; moderate quality evidence) and major bleeding (OR 2.89, 95% CI 0.12 to 71.31; low quality evidence). Clinically relevant non-major bleeding and minor bleeding were not reported.Extended-duration DOAC showed reduced symptomatic VTE (OR 0.20, 95% CI 0.06 to 0.68; 2419 participants; 1 study; moderate quality evidence) and symptomatic DVT (OR 0.18, 95% CI 0.04 to 0.81; 2459 participants; 2 studies; high quality evidence) compared to placebo. No differences were found for symptomatic PE (OR 0.25, 95% CI 0.03 to 2.25; 1733 participants; 1 study; low quality evidence), major bleeding (OR 1.00, 95% CI 0.06 to 16.02; 2457 participants; 1 study; low quality evidence), clinically relevant non-major bleeding (OR 1.22, 95% CI 0.76 to 1.95; 2457 participants; 1 study; moderate quality evidence) and minor bleeding (OR 1.18, 95% CI 0.74 to 1.88; 2457 participants; 1 study; moderate quality evidence).We showed no difference between extended-duration anticoagulants chosen at investigators' discretion and placebo (one study, 557 participants, low quality evidence) for symptomatic VTE (OR 0.50, 95% CI 0.09 to 2.74), symptomatic DVT (OR 0.33, 95% CI 0.03 to 3.21), symptomatic PE (OR 1.00, 95% CI 0.06 to 16.13), and major bleeding (OR 5.05, 95% CI 0.24 to 105.76). Clinically relevant non-major bleeding and minor bleeding were not reported.We showed no difference between extended-duration VKA and heparin (one study, low quality evidence) for symptomatic VTE (OR 1.64, 95% CI 0.85 to 3.16; 1279 participants), symptomatic DVT (OR 1.36, 95% CI 0.69 to 2.68; 1279 participants), symptomatic PE (OR 9.16, 95% CI 0.49 to 170.42; 1279 participants), major bleeding (OR 3.87, 95% CI 1.91 to 7.85; 1272 participants) and minor bleeding (OR 1.33, 95% CI 0.64 to 2.76; 1279 participants). Clinically relevant non-major bleeding was not reported.We showed no difference between extended-duration DOAC and heparin for symptomatic VTE (OR 0.70, 95% CI 0.28 to 1.70; 15,977 participants; 5 studies; low quality evidence), symptomatic DVT (OR 0.60, 95% CI 0.11 to 3.27; 15,977 participants; 5 studies; low quality evidence), symptomatic PE (OR 0.91, 95% CI 0.43 to 1.94; 14,731 participants; 5 studies; moderate quality evidence), major bleeding (OR 1.11, 95% CI 0.79 to 1.54; 16,199 participants; 5 studies; high quality evidence), clinically relevant non-major bleeding (OR 1.08, 95% CI 0.90 to 1.28; 15,241 participants; 4 studies; high quality evidence) and minor bleeding (OR 0.95, 95% CI 0.82 to 1.10; 11,766 participants; 4 studies; high quality evidence). Moderate quality evidence suggests extended-duration anticoagulants to prevent VTE should be considered for people undergoing hip replacement surgery, although the benefit should be weighed against the increased risk of minor bleeding. Further studies are needed to better understand the association between VTE and extended-duration oral anticoagulants in relation to knee replacement and hip fracture repair, as well as outcomes such as distal and proximal DVT, reoperation, wound infection and healing.

Method for the isolation of biologically active monomeric immunoglobulin A from a plasma fraction.

PubMed

Leibl, H; Tomasits, R; Wolf, H M; Eibl, M M; Mannhalter, J W

1996-04-12

A purification method for immunoglobulin A (IgA) yielding monomeric IgA with a purity of over 97% has been developed. This procedure uses ethanol-precipitated plasma (Cohn fraction III precipitate) as the starting material and includes heparin-Sepharose adsorption, dextran sulfate and ammonium sulfate precipitation, hydroxyapatite chromatography, batch adsorption by an anion-exchange matrix and gel permeation. Additional protein G Sepharose treatment leads to an IgA preparation of greater than 99% purity. The isolated IgA presented with an IgA subclass distribution, equivalent to IgA in unfractionated plasma, and was biologically active, as was shown by its ability to down-modulate Haemophilus influenzae-b-induced IL-6 secretion of human monocytes.

Thrombophilia-Related Complications in the Treatment of a Left Atrial Appendage Thrombus: A Case Report

PubMed Central

Parato, Vito Maurizio; Scarano, Michele; Labanti, Benedetto

2014-01-01

Trans-esophageal echocardiography (TEE) revealed a left atrial appendage (LAA) thrombus in an 84-year-old woman with nonvalvular atrial fibrillation not known before our evaluation. In her medical history, there were hypertension, dyslipidemia and a previous pulmonary embolism. She was taking warfarin at time of our evaluation and presented signs and symptoms of heart failure. Together with heart failure treatment, intravenous anticoagulation with unfractionated heparin was initiated. Treatment was complicated by additional right lower limb embolic event and the LAA thrombus remained unchanged. Testing revealed heterozygosity for both the factor V Leiden and the methylenetetrahydrofolate reductase C677T mutations inducing resistance to activated protein C. The patient refused transcatheter closure of the left atrial appendage. PMID:28465906

Resistance of uterine radial artery blood flow was correlated with peripheral blood NK cell fraction and improved with low molecular weight heparin therapy in women with unexplained recurrent pregnancy loss.

PubMed

Koo, Hwa Seon; Kwak-Kim, Joanne; Yi, Hyun Jeong; Ahn, Hyun Kyong; Park, Chan Woo; Cha, Sun Hwa; Kang, Inn Soo; Yang, Kwang Moon

2015-02-01

To investigate whether peripheral blood natural killer (pbNK) cell levels are associated with uterine blood flow, and low molecular weight heparin (LMWH) treatment is effective to improve uterine blood flow in women with decreased uterine blood flow and unexplained recurrent pregnancy loss (RPL). This was a prospective controlled study. Study population included 33 pregnant women (between 5 and 7 weeks gestation) with ≥ 2 RPL and controls were 47 healthy pregnant women. pbNK cell fractions (CD3(-)/56(+)/16(+)) of peripheral blood mononuclear cells were measured by flow cytometry. Uterine color-pulsed Doppler ultrasound was performed to evaluate uterine radial artery resistance index (URa-RI). In RPL women with elevated URa-RI (≥ 0.5), LMWH (ranges 40-60 mg/day) was administered subcutaneously daily and URa-RI was reassessed 1 week later. Pregnancy outcome was analyzed at 12 weeks gestation. URa-RI was significantly higher in pregnant women with RPL than controls (0.60 ± 0.14 versus 0.54 ± 0.12, P = 0.039). In pregnant women with RPL, pbNK cell fractions displayed a positive correlation with URa-RI (Pearson's r = 0.429, P = 0.013). URa-RI was significantly decreased 1 week after LMWH treatment as compared to that of pretreatment (pretreatment RI: 0.65 ± 0.11 versus post-treatment RI: 0.56 ± 0.13, P = 0.011). Pregnancy outcome of RPL women with LMWH treatment was not different from that of pregnant controls (73.3% versus 85.0%, P = NS). Increased pbNK cells are associated with decreased uterine radial artery blood flow. LMWH treatment effectively decreases URa-RI with improved pregnancy outcome in women with RPLs and elevated URa-RI. A larger scale study is needed to verify these findings. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Impact of apixaban vs low molecular weight heparin/vitamin k antagonist on hospital resource use in patients with venous thromboembolism.

PubMed

Browne, C; Lanitis, T; Hamilton, M; Li, X; Horbyluk, R; Mardekian, J; Kongnakorn, T; Cohen, A

2017-01-01

The clinical and economic benefits associated with apixaban treatment have been established in clinical trials and published economic evaluations. The benefits associated with apixaban could extend to improving hospital efficiencies, potentially influencing hospital resource use, and bed days. The objective of this study is to estimate the impact of 6-month treatment with apixaban vs low molecular weight heparin/vitamin k antagonist (LMWH/VKA) on hospital resource use among patients with venous thromboembolism (VTE). A model was developed to assess the impact of apixaban vs LMWH/VKA for treatment of VTE and prevention of recurrences on hospital resource use and costs. Resource use items included total hospitalizations, length of stay (LOS), and emergency department (ED) visits, estimated for all incident VTE patients in the UK over a 5-year time horizon. Rates of hospitalizations, ED visits, and LOS associated with recurrent VTE, major, and clinically relevant non-major bleeding were obtained from the AMPLIFY trial; costs were obtained from UK published sources. Over a 5-year time horizon, the model predicted that, compared to 6 months of LMWH/VKA, 6 months of apixaban led to 3,954 fewer hospitalizations (consisting of 2,341 fewer new admissions and 1,613 fewer re-admissions) and 32,214 fewer bed days, among 332,607 incident VTE patients. ED visits were reduced by 1,582. The reduction in hospital resource use led to a cost saving of ∼£4.5 million in a market of patients treated with apixaban as compared to a market treated with LMWH/VKA. Sensitivity analysis indicated these findings were robust over a wide range of inputs. 6-month treatment with apixaban for treatment of VTE and prevention of recurrences on hospital resource use led to a reduction in hospitalizations and LOS in comparison to LMWH/VKA. These findings can help the efforts in reducing the growing burden of preventable re-admissions to hospitals.

Safety and efficacy of low molecular weight heparins in children: a systematic review of the literature and meta-analysis of single-arm studies.

PubMed

Bidlingmaier, Christoph; Kenet, Gili; Kurnik, Karin; Mathew, Prasad; Manner, Daniela; Mitchell, Lesley; Krümpel, Anne; Nowak-Göttl, Ulrike

2011-10-01

Within the last two decades low molecular weight heparins (LMWH) have gained increasing widespread use as anticoagulants in children. The use of LMWH has been implemented into clinical care even though there is a lack of firm evidence on the efficacy and safety of LMWH in this population due to the absence of sufficiently powered randomized controlled trials. In the absence of clinical trials, we performed a meta-analysis of available single-arm studies using LMWH in children. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1980 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients, ethnicity, venous thromboembolic events type, and frequency of recurrence and major bleedings were abstracted. Pooled incidence rates (IR) including 95% confidence intervals (95% CIs) on efficacy and safety data of LMWH administration on primary prophylaxis, as well as on secondary prophylaxis in children following symptomatic thromboembolism (TE) were shown. We included 2251 pediatric patients derived from 35 single-arm studies from 12 study countries who were eligible for analysis in the present systematic review. Pooled incidence rates (95% CI) to develop first TE on primary prophylaxis, further TE event on LMWH secondary prophylaxis, or a major bleeding event on LMWH were 0.047 (0.023 to 0.091), 0.052 (0.037 to 0.073) for efficacy, and 0.054 (0.039 to 0.074) for safety (treatment data only), respectively. Efficacy and safety data are comparable with adult data. The present systematic review suggests that use of LMWH in children as primary prophylaxis and in treatment of symptomatic thrombosis is effective and safe. However, properly designed randomized controlled trials are needed. © Thieme Medical Publishers.

[Superficial venous thrombosis. A state of art].

PubMed

Sándor, Tamás

2017-01-01

For a long time superficial thrombophlebitis has been thought to be a rather benign condition. Recently, when duplex ultrasound technique is used for the diagnosis more and more often, the disease is proved to be more dangerous than anticipated. Thrombosis propagates to the deep veins in 6-44% and pulmonary embolism was observed on the patients in 1,5-33%. We can calculate venous thromboembolic complications on every fourth patient. Diagnosis is clinical, but duplex ultrasound examination is mandatory, for estimation of the thrombus extent, for exclusion of the deep venous thrombosis and for follow up. Both legs should be checked with ultrasound, because simultaneous deep venous thrombosis can develop on the contralateral limb. Two different forms can be distinguished: superficial venous thrombosis with, or without varicose veins. In cases of spontaneous, non varicous form, especially when the process is migrating or recurrent, a careful clinical examination is necessery for exclusion of malignant diseases and thrombophilia. The treatment options are summarised on the basis of recent international consensus statements. The American and German guidelines are similar. Compression and mobilisation are cornerstones of the therapy. For a short segment thrombosis non steroidal antiinflammatory drugs are effective. For longer segments low molecular-weight heparins are preferred. Information on the effect of the novel oral anticoagulants for the therapy is lacking but they may appear to be effective in the future for this indication. When thrombus is close to the sapheno-femoral or sapheno-popliteal junction crossectomy (high ligation), or low molecular-weight heparin in therapeutic doses are indicated. The term superficial thrombophlebitis should be discouraged, because inflammation and infection is not the primary pathology. It should be called correctly superficial venous thrombosis in order to avoid the unnecessary administration of antibiotics and the misconception, that superficial venous thrombosis is benign disease. Orv. Hetil., 2017, 158(4), 129-138.

Expression and characterization of an enhanced recombinant heparinase I with chitin binding domain.

PubMed

Xu, Shuqin; Qiu, Meiling; Zhang, Xuanyue; Chen, Jinghua

2017-12-01

Heparinase I (Hep I) can efficiently depolymerize heparin and heparin sulfate to oligosaccharides or unsaturated disaccharides, which resulted in loss of physiological function such as blood coagulation. In order to realize the immobilization of Hep I on chitin carriers, we cloned Hep I with the chitin binding domain (ChBD) as a chitin-affinity tag, and the Small Ubiquitin-like MOdifier (SUMO) linker as a solvation enhancer in different fusion sequence. DNA and protein gels suggested that 4 kinds of recombinants were successfully constructed and expressed in Escherichia coli (E. coli). And the triple functional heparinases isolated from cell lysate could be efficiently purified by chitin beads. After optimizing fermentation conditions, it gave the specific enzyme activities of 1.88±0.11, 3.69±0.45, 3.44±0.38, and 2.73±0.29IU/mg total proteins for ChBD-Hep I, ChBD-SUMO-Hep I, SUMO-ChBD-Hep I, and ChBD-Hep I-SUMO, respectively, with unfractionated heparin as substrate. The optimal reaction temperature and pH were determined to be 30°C and 7.0 for all the fusion enzymes. ChBD-SUMO-Hep I exhibited the maximum half-life (48min) at 30°C and best thermo-stability under 15-50°C. All the fusion enzymes showed broad pH-stability in the range of 5.4-9.0. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibitory Effects of Medium Molecular Weight Heparinyl Amino Acid Derivatives on Ischemic Paw Edema in Mice.

PubMed

Takeda, Seiichi; Toda, Takao; Nakamura, Kazuki

2016-01-01

We investigated the radical-scavenging effects of heparin (HE), medium molecular weight heparinyl phenylalanine (MHF), and medium molecular weight heparinyl leucine (MHL) using ischemic paw edema in mice. We also examined the activated partial thromboplastin time (APTT) of mice that were administered these compounds as an index of their side-effects. HE had a preventative effect and significant reduced ischemic paw edema. However, its effect was not dose-dependent and the dose-response curve was bell-shaped. The effective dose of HE also exhibited a prolonged APTT. Pretreatment using MHF and MHL were effective against ischemic paw edema without a prolonged APTT. Remarkably, the action of MHF was not only preventively, but also therapeutically active. These results suggest that MHF and MHL are superior to HE as safe radical scavengers in vivo. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

A new therapeutic strategy for electrical cardioversion of atrial fibrillation.

PubMed

de Luca, I; Sorino, M; Del Salvatore, B; de Luca, L

2001-11-01

The conventional approach to cardioversion of atrial fibrillation includes a period of anticoagulation with oral anticoagulant therapy (OAT) extending from 3 weeks precardioversion to 4 weeks postcardioversion. The protocol of rapid anticoagulation (such as that of the ACUTE study) consists of a precardioversion transesophageal echocardiography (TEE) followed by OAT for 4 weeks. In the last few years low-molecular-weight heparins have established themselves as a safe and efficacious alternative to traditional antithrombotic therapies. The aim of this study was to demonstrate that the exclusion of thrombi by precardioversion TEE together with the exclusion of atrial stunning by a second TEE performed after 1 week, to date not suggested in the literature, could reduce to 7 days the period of pericardioversion anticoagulation. This therapy would be carried out using low-molecular-weight heparins with no need for biological monitoring and with the possibility of self-administration. We have studied 57 consecutive patients who had atrial fibrillation or flutter with a history of atrial fibrillation lasting > 48 hours. All patients received enoxaparin at a dosage of 100 IU antiXa/kg twice daily before undergoing multiplane TEE. Previous informed consent and ethical committee authorization had been obtained. Twenty-four hours following TEE, in the absence of thrombi and/or spontaneous moderate/severe echocontrast in the atrial chambers, the patients underwent electrical cardioversion and were discharged within 24 hours of sinus rhythm restoration. These patients were prescribed enoxaparin at the indicated dosage twice daily until TEE, performed in an outpatients setting 7 days following cardioversion. In the absence of thrombi and/or atrial and/or left atrial appendage stunning, OAT was terminated. Enoxaparin was associated with OAT for the following 3 weeks if any of the following signs of stunning were present: A wave inferior to the normal value for age at transmitral Doppler; a left atrial appendage emptying velocity < 40 cm/s; the appearance or increase in the severity of spontaneous echocontrast. For all patients, clinical and electrocardiographic follow-up was carried out at 1 month. In one patient TEE was not tolerated and one refused it. In 7 patients cardioversion was not performed: 4 because of the presence of thrombi, 1 because of moderate/severe spontaneous echocontrast and 2 owing to spontaneous cardioversion. Of the remaining 48 patients, cardioversion proved to be efficacious in 38, with sustained sinus rhythm at 1 week in 33 patients. One of these refused the second TEE and of the remaining 32 patients, 24 (75%) showed no signs of stunning at the second TEE and so anticoagulation was terminated. Thus, after 1 week, 75% (24/33) of patients in sinus rhythm could benefit from a shortened anticoagulation therapy which lasted for a mean of only 8.5 days. No patients showed signs of a thromboembolic accident at 1 and 2 months of follow-up. Most patients undergoing electrical cardioversion for atrial fibrillation could benefit from a shorter period of anticoagulation with low-molecular-weight heparins for 1 week if TEE precardioversion and 7 days postcardioversion excludes thrombi and atrial stunning. The management of patients with atrial fibrillation would be greatly simplified.

Fractionation of enzymatic hydrolysis lignin by sequential extraction for enhancing antioxidant performance.

PubMed

An, Liangliang; Wang, Guanhua; Jia, Hongyu; Liu, Cuiyun; Sui, Wenjie; Si, Chuanling

2017-06-01

The heterogeneity of lignin chemical structure and molecular weight results in the lignin inhomogeneous properties which also covers the antioxidant performance. In order to evaluate the effects of lignin heterogeneity on its antioxidant activity, four lignin fractions from enzymatic hydrolysis lignin were classified by sequential organic solvent extraction and further evaluated by DPPH (1,1-Diphenyl-2-Picrylhydrazyl) free radical scavenging capacity and reducing power analysis. The characterization including FTIR, 1 H NMR and GPC showed that the fractionation process could effectively separate lignin fractions with distinctly different molecular weight and weaken the heterogeneity of unfractionated lignin. The antioxidant performance comparison of lignin fractions indicated that the dichloromethane fraction (F1) with lowest molecular weight (4585g/mol) and highest total phenolics content (246.13mg GAE/g) exhibited the highest antioxidant activity whose value was close to commercial antioxidant BHT (butylated hydroxytoluene). Moreover, the relationship between the antioxidant activity and the structure of lignin was further discussed to elucidate the mechanism of antioxidant activity improvement of lignin fractionation. Consequently, this study suggested that the sequential extraction was an effective way to obtain relatively homogeneous enzymatic hydrolysis lignin fractions which showed the potential for the value-added antioxidant application. Copyright © 2017 Elsevier B.V. All rights reserved.

Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review.

PubMed

Poudel, Dilli Ram; Ghimire, Sushil; Dhital, Rashmi; Forman, Daniel A; Warkentin, Theodore E

2017-09-01

Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year-old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 × 10 9 /L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient's serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4-dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 × 10 9 /L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 × 10 9 /L by POD45 and 199 × 10 9 /L by POD79. The patient's serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1-1.2 μg/mL, i.e., in vitro fondaparinux "cross-reactivity"). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT.

Bovine and porcine heparins: different drugs with similar effects on human haemodialysis

PubMed Central

2013-01-01

Background Heparins from porcine and bovine intestinal mucosa differ in their structure and also in their effects on coagulation, thrombosis and bleeding. However, they are used as undistinguishable drugs. Methods We compared bovine and porcine intestinal heparin administered to patients undergoing a particular protocol of haemodialysis. We compared plasma concentrations of these two drugs and also evaluated how they affect patients and the dialyzer used. Results Compared with porcine heparin, bovine heparin achieved only 76% of the maximum plasma concentration as IU mL-1. This observation is consistent with the activities observed in the respective pharmaceutical preparations. When the plasma concentrations were expressed on weight basis, bovine heparin achieved a maximum concentration 1.5 fold higher than porcine heparin. The reduced anticoagulant activity and higher concentration, on weight basis, achieved in the plasma of patients under dialysis using bovine instead of porcine heparin did not affect significantly the patients or the dialyzer used. The heparin dose is still in a range, which confers security and safety to the patients. Discussion Despite no apparent difference between bovine and porcine intestinal heparins in the haemodialysis practice, these two types of heparins should be used as distinct drugs due to their differences in structure and biological effects. Conclusions The reduced anticoagulant activity achieved in the plasma of patients under dialysis using bovine instead of porcine heparin did not affect significantly the patients or the dialyzer. PMID:23763719

The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients.

PubMed

Al-Yaseen, E; Wells, P S; Anderson, J; Martin, J; Kovacs, M J

2005-01-01

Data evaluating the safety of using weight-based low-molecular-weight heparin in the treatment of obese patients with acute venous thromboembolism are limited. The product monograph of dalteparin suggests the maximum dose should be limited to 18,000 U subcutaneously once daily. There are no specific data regarding the risk of recurrence or bleeding in patients given dalteparin in a weight-based dose of 200 IU kg(-1). We report a retrospective chart review of 193 obese patients who weighed more than 90 kg and who received dalteparin at or near to 200 IU kg(-1) actual body weight for 5-7 days for acute venous thromboembolism with 90 day follow-up information. Of the patients, 77% had idiopathic venous thromboembolism, 16% had an underlying malignancy, and 7% had a transient risk factor. Warfarin was initiated within 2 days with a target International Normalized Ratio range of 2.0-3.0. All patients were followed for 12 weeks post diagnosis. Only two patients had a major hemorrhage, 4 and 8 weeks from diagnosis. This study supports the safety of dosing dalteparin based on actual body weight in obese patients.

Molecular dynamics simulations on networks of heparin and collagen.

PubMed

Kulke, Martin; Geist, Norman; Friedrichs, Wenke; Langel, Walter

2017-06-01

Synthetic scaffolds containing collagen (Type I) are of increasing interest for bone tissue engineering, especially for highly porous biomaterials in combination with glycosaminoglycans. In experiments the integration of heparin during the fibrillogenesis resulted in different types of collagen fibrils, but models for this aggregation on a molecular scale were only tentative. We conducted molecular dynamic simulations investigating the binding of heparin to collagen and the influence of the telopeptides during collagen aggregation. This aims at explaining experimental findings on a molecular level. Novel structures for N- and C-telopeptides were developed with the TIGER2 replica exchange algorithm and dihedral principle component analysis. We present an extended statistical analysis of the mainly electrostatic interaction between heparin and collagen and identify several binding sites. Finally, we propose a molecular mechanism for the influence of glycosaminoglycans on the morphology of collagen fibrils. Proteins 2017; 85:1119-1130. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology.

PubMed

Ranta, Susanna; Tuckuviene, Ruta; Mäkipernaa, Anne; Albertsen, Birgitte K; Frisk, Tony; Tedgård, Ulf; Jónsson, Ólafur G; Pruunsild, Kaie; Gretenkort Andersson, Nadine; Winther Gunnes, Maria; Saulyte Trakymiene, Sonata; Frandsen, Thomas; Heyman, Mats; Ruud, Ellen; Helgestad, Jon

2015-02-01

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication. © 2014 John Wiley & Sons Ltd.

Thrombosis prevention in lower extremity arthroplasty: mobile compression device or pharmacological therapy.

PubMed

Colwell, Clifford W

2014-11-01

Venous thromboembolic (VTE) events, either deep vein thromboses (DVT) or pulmonary emboli (PE), are important complications in patients undergoing knee or hip arthroplasty. Symptomatic VTE rates observed in total joint arthroplasty patients using the mobile compression device with home use capability were non-inferior to rates reported for pharmacological prophylaxis, including warfarin, enoxaparin, rivaroxaban, and dabigatran. Major bleeding in total hip arthroplasty was less using the mobile compression device than using low molecular weight heparin. A cost analysis demonstrated a cost savings based on decreased major bleeding. Use of a mobile compression device with or without aspirin for patients undergoing total joint arthroplasty provides a non-inferior risk for developing VTE compared with current pharmacological protocols.

Spontaneous hemothorax following thrombolytic and anticoagulant therapy for massive pulmonary embolism.

PubMed

Wang, Chung-Cheng; Ng, Chip-Jin; Seak, Chen-Ken; Seak, Chen-June

2013-06-01

Massive spontaneous hemothorax following combined thrombolytic and anticoagulant therapy for pulmonary embolism(PE) is a rare event that is little documented in the literature. Here, we describe a rare case of spontaneous hemothorax in a 23-year-old woman with underlying systemic lupus erythematosus following combined administration of tissue plasminogen activator and low-molecular-weight heparin for massive PE. This report of our successful treatment of this case by video-assisted thoracoscopic thoracotomy demonstrates that although the occurrence is rare, massive hemothorax following anticoagulant and/or thrombolytic therapy for PE should be suspected if patients experience chest pain, dyspnea, or signs of anemia, and follow-up physical examination and hemogram should be performed to facilitate diagnosis of this life-threatening complication.

Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D).

PubMed

Young, Annie M; Marshall, Andrea; Thirlwall, Jenny; Chapman, Oliver; Lokare, Anand; Hill, Catherine; Hale, Danielle; Dunn, Janet A; Lyman, Gary H; Hutchinson, Charles; MacCallum, Peter; Kakkar, Ajay; Hobbs, F D Richard; Petrou, Stavros; Dale, Jeremy; Poole, Christopher J; Maraveyas, Anthony; Levine, Mark

2018-05-10

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.

Postpartum thromboprophylaxis in a multireligious cohort: a retrospective review of indications and uptake.

PubMed

Voon, Hian Yan; Chai, Ming Cheng; Hii, Ling Yien; Amin, Rafaie; Suharjono, Haris Njoo

2018-02-12

Strategies to prevent mortality from obstetric venous thromboembolism begin with identification, risk stratification and subsequently, implementation of prophylactic measures. We sought to identify the burden of pharmacologic thromboprophylaxis in postpartum women, including the main clinical indications and its uptake in a multireligious population, with Islam as the official religion. A total of 2514 deliveries between 1st January to 31st December 2016, across three centres in Malaysia were reviewed retrospectively from hospital-based registries. 770 (30.62%) patients fulfilled the criteria for thromboprophylaxis based on the revised 2015 criteria proposed by the Royal College of Obstetricians and Gynaecologists. A combination of age, parity, BMI, caesarean section and preterm births were the main indications. One out of the five patients who delivered vaginally required thromboprophylaxis. In our setting with a sizable Muslim population, low molecular weight heparin was the thromboprophylaxis of choice in more than two-third of the patients. The information obtained from this study allows better local resource planning. Impact statement What is already known on this subject: Risk factors for venous thromboembolism in pregnancy and puerperium are largely drawn from registries due to the rarity of the index event. Up to 7% of women require antenatal thromboprophylaxis based on the criteria proposed by the Royal College of Obstetrician and Gynaecologists in 2009. What do the results of this study add: Using the RCOG guideline revised in 2015, a significant proportion of women delivering vaginally would require postnatal thromboprophylaxis based on age, parity and BMI. When either age or parity, both with relatively low odds ratio for thrombosis were omitted, a substantial proportion of women would not achieve the threshold for prophylaxis. Despite a sizable Muslim population in the country, the uptake of low molecular weight heparin was relatively high. What are the implications of these findings for clinical practice and/or future research: Cost-benefit studies should consider the adjusted odds ratio of individual indications on a VTE event. While uptake and acceptability is high, prospective studies on medication adherence is equally pertinent.

Approach to chest pain and acute myocardial infarction.

PubMed

Pandie, S; Hellenberg, D; Hellig, F; Ntsekhe, M

2016-03-01

Patient history, physical examination, 12-lead electrocardiogram (ECG) and cardiac biomarkers are key components of an effective chest pain assessment. The first priority is excluding serious chest pain syndromes, namely acute coronary syndromes (ACSs), aortic dissection, pulmonary embolism, cardiac tamponade and tension pneumothorax. On history, the mnemonic SOCRATES (Site Onset Character Radiation Association Time Exacerbating/relieving factor and Severity) helps differentiate cardiac from non-cardiac pain. On examination, evaluation of vital signs, evidence of murmurs, rubs, heart failure, tension pneumothoraces and chest infections are important. A 12-lead ECG should be interpreted within 10 minutes of first medical contact, specifically to identify ST elevation myocardial infarction (STEMI). High-sensitivity troponins improve the rapid rule-out of myocardial infarction (MI) and confirmation of non-ST elevation MI (NSTEMI). ACS (STEMI and NSTEMI/unstable anginapectoris (UAP)) result from acute destabilisation of coronary atheroma with resultant complete (STEMI) or subtotal (NSTEMI/UAP) thrombotic coronary occlusion. The management of STEMI patients includes providing urgent reperfusion: primary percutaneous coronary intervention(PPCI) if available, deliverable within 60 - 120 minutes, and fibrinolysis if PPCI is not available. Essential adjunctive therapies include antiplatelet therapy (aspirin, P2Y12 inhibitors), anticoagulation (heparin or low-molecular-weight heparin) and cardiac monitoring.

Home versus in-patient treatment for deep vein thrombosis.

PubMed

Othieno, Richard; Okpo, Emmanuel; Forster, Rachel

2018-01-09

Deep vein thrombosis (DVT) occurs when a blood clot blocks blood flow through a vein, which can occur after surgery, after trauma, or when a person has been immobile for a long time. Clots can dislodge and block blood flow to the lungs (pulmonary embolism (PE)), causing death. DVT and PE are known by the term venous thromboembolism (VTE). Heparin (in the form of unfractionated heparin (UFH)) is a blood-thinning drug used during the first three to five days of DVT treatment. Low molecular weight heparins (LMWHs) allow people with DVT to receive their initial treatment at home instead of in hospital. This is an update of a review first published in 2001 and updated in 2007. To compare the incidence and complications of venous thromboembolism (VTE) in patients treated at home versus patients treated with standard in-patient hospital regimens. Secondary objectives included assessment of patient satisfaction and cost-effectiveness of treatment. For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (last searched 16 March 2017), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), and trials registries. We also checked the reference lists of relevant publications. Randomised controlled trials (RCTs) examining home versus hospital treatment for DVT, in which DVT was clinically confirmed and was treated with LMWHs or UFH. One review author selected material for inclusion, and another reviewed the selection of trials. Two review authors independently extracted data and assessed included studies for risk of bias. Primary outcomes included combined VTE events (PE and recurrent DVT), gangrene, heparin complications, and death. Secondary outcomes were patient satisfaction and cost implications. We performed meta-analysis using fixed-effect models with risk ratios (RRs) and 95% confidence intervals (CIs) for dichotomous data. We included in this review seven RCTs involving 1839 randomised participants with comparable treatment arms. All seven had fundamental problems including high exclusion rates, partial hospital treatment of many in the home treatment arms, and comparison of UFH in hospital versus LMWH at home. These trials showed that patients treated at home with LMWH were less likely to have recurrence of VTE events than those given hospital treatment with UFH or LMWH (fixed-effect risk ratio (RR) 0.58, 95% confidence interval (CI) 0.39 to 0.86; 6 studies; 1708 participants; P = 0.007; low-quality evidence). No clear difference was seen between groups for major bleeding (RR 0.67, 95% CI 0.33 to 1.36; 6 studies; 1708 participants; P = 0.27; low-quality evidence), minor bleeding (RR 1.29, 95% CI 0.94 to 1.78; 6 studies; 1708 participants; P = 0.11; low-quality evidence), or mortality (RR 0.69, 95% CI 0.44 to 1.09; 6 studies; 1708 participants; P = 0.11; low-quality evidence). The included studies reported no cases of venous gangrene. We could not combine patient satisfaction and quality of life outcomes in meta-analysis owing to heterogeneity of reporting, but two of three studies found evidence that home treatment led to greater improvement in quality of life compared with in-patient treatment at some point during follow-up, and the third study reported that a large number of participants chose to switch from in-patient care to home-based care for social and personal reasons, suggesting it is the patient's preferred option (very low-quality evidence). None of the studies included in this review carried out a full cost-effectiveness analysis. However, a small randomised economic evaluation of the two alternative treatment settings involving 131 participants found that direct costs were higher for those in the in-patient group. These findings were supported by three other studies that reported on their costs (very low-quality evidence).Quality of evidence for data from meta-analyses was low to very low. This was due to risk of bias, as many of the included studies used unclear randomisation techniques, and blinding was a concern for many. Also, indirectness was a concern, as most studies included a large number of participants randomised to the home (LMWH) treatment group who were treated in hospital for some or all of the treatment period. A further issue for some outcomes was heterogeneity that was evident in measurement and reporting of outcomes. Low-quality evidence suggests that patients treated at home with LMWH are less likely to have recurrence of VTE than those treated in hospital. However, data show no clear differences in major or minor bleeding, nor in mortality (low-quality evidence), indicating that home treatment is no worse than in-patient treatment for these outcomes. Because most healthcare systems are moving towards more LMWH usage in the home setting it is unlikely that additional large trials will be undertaken to compare these treatments. Therefore, home treatment is likely to become the norm, and further research will be directed towards resolving practical issues by devising local guidelines that include clinical prediction rules, developing biomarkers and imaging that can be used to tailor therapy to disease severity, and providing training for community healthcare workers who administer treatment and monitor treatment progress.

Association between Activated Partial Thromboplastin Time and the Amount of Infused Heparin at Bone Marrow Transplantation.

PubMed

Kusuda, Machiko; Kimura, Shun-Ichi; Misaki, Yukiko; Yoshimura, Kazuki; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Ugai, Tomotaka; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Nakasone, Hideki; Kako, Shinichi; Tanihara, Aki; Kanda, Yoshinobu

2018-03-27

The actual heparin concentration of harvested allogeneic bone marrow varies among harvest centers. We monitor the activated partial thromboplastin time (APTT) of the patient during bone marrow infusion and administer prophylactic protamine according to the APTT. We retrospectively reviewed the charts of consecutive patients who underwent bone marrow transplantation without bone marrow processing at our center between April 2007 and March 2016 (n = 94). APTT was monitored during marrow transfusion in 52 patients. We analyzed the relationship between the APTT ratio and several parameters related to heparin administration. As a result, the weight-based heparin administration rate (U/kg/hour) seemed to be more closely related to the APTT ratio (r = .38, P = .005) than to the total amount of heparin. There was no significant correlation between the APTT ratio and renal or liver function. Bleeding complications during and early after infusion were seen in 3 of 52 patients, and included intracranial, nasal, and punctured-skin bleeding. The APTT ratio during transfusion was over 5.88 in the former 2 patients and 2.14 in the latter. All of these patients recovered without sequelae. In conclusion, slow bone marrow infusion is recommended to decrease the weight-based heparin administration rate when the heparin concentration per patient body weight is high. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

[Prevention, diagnosis and treatment of perioperative complications of bariatric and metabolic surgery].

PubMed

Wu, Haifu; Zhong, Ming; Zhou, Di; Shi, Chenye; Jiao, Heng; Wu, Wei; Chang, Xinxia; Cang, Jing; Bian, Hua

2017-04-25

Surgical operation in treating obesity and type 2 diabetes is popularizing rapidly in China. Correct prevention and recognition of perioperation-related operative complications is the premise of ensuring surgical safety. Familiar complications of the operation include deep venous thrombosis, pulmonary artery embolism, anastomotic bleeding, anastomotic fistula and marginal ulcer. The prevention of deep venous thrombosis is better than treatment. The concrete measures contain physical prophylaxis (graduated compression stocking and intermittent pneumatic compression leg sleeves) and drug prophylaxis (unfractionated heparin and low molecular heparin), and the treatment is mainly thrombolysis or operative thrombectomy. The treatment of pulmonary artery embolism includes remittance of pulmonary arterial hypertension, anticoagulation, thrombolysis, operative thrombectomy, interventional therapy and extracorporeal membrane oxygenation (ECMO). Hemorrhage is a rarely occurred but relatively serious complication after bariatric surgery. The primary cause of anastomotic bleeding after laparoscopic gastric bypass is incomplete hemostasis or weak laparoscopic repair. The common bleeding site in laparoscopic sleeve gastrectomy is gastric stump and close to partes pylorica, and the bleeding may be induced by malformation and weak repair technique. Patients with hemodynamic instability caused by active bleeding or excessive bleeding should timely received surgical treatment. Anastomotic fistula in gastric bypass can be divided into gastrointestinal anastomotic fistula and jejunum-jejunum anastomotic fistula. The treatment of postoperative anastomotic fistula should vary with each individual, and conservative treatment or operative treatment should be adopted. Anastomotic stenosis is mainly related to the operative techniques. Stenosis after sleeve gastrectomy often occurs in gastric angle, and the treatment methods include balloon dilatation and stent implantation, and surgical treatment should be performed when necessary. Marginal ulcer after gastric bypass is a kind of peptic ulcer occurring close to small intestine mucosa in the junction point of stomach and jejunum. Ulcer will also occur in the vestige stomach after laparoscopic sleeve gastrectomy, and the occurrence site locates mostly in the gastric antrum incisal margin. Preoperative anti-HP (helicobacter pylorus) therapy and postoperative continuous administration of proton pump inhibitor (PPI) for six months is the main means to prevent and treat marginal ulcer. For patients on whom conservative treatment is invalid, endoscopic repair or surgical repair should be considered. Different surgical procedures will generate different related operative complications. Fully understanding and effectively dealing with the complications of various surgical procedures through multidisciplinary cooperation is a guarantee for successful operation.

Substantiating In Vivo Magnetic Brain Tumor Targeting of Cationic Iron Oxide Nanocarriers via Adsorptive Surface Masking

PubMed Central

Chertok, Beata; David, Allan E.; Moffat, Bradford A.; Yang, Victor C.

2009-01-01

Cationic magnetic nanoparticles are attractive as potential vehicles for tumor drug delivery due to their favorable interactions with both the tumor milieu and the therapeutic cargo. However, systemic delivery of these nanoparticles to the tumor site is compromised by their rapid plasma clearance. We developed a simple method for in vivo protection of cationic nanocarriers, using non-covalent surface masking with a conjugate of low molecular weight heparin and polyethylene glycol. Surface masking resulted in an 11-fold increase in plasma AUC and a 2-fold increase in the magnetic capture of systemically injected nanoparticles in orthotopic rodent brain tumors. Overall, the described methodology could expand the prospective applications for cationic magnetic nanoparticles in magnetically-mediated gene/drug delivery. PMID:19782394

Early diagnosis of iliofemoral DVT in pregnancy in the emergency department.

PubMed

van Zyl Smit, Nellis; Govind, Abha; Sharma, Devesh

2012-06-12

The case of a 26-year-old woman who was 23 weeks pregnant is described; the patient presented, on a weekend, to the emergency department (ED) with left groin pain. There were few clinical signs of deep venous thrombosis (DVT) but ED ultrasound (US) showed a left external iliac vein thrombus. This is a new technique in the ED. Not only does this case show the importance of using this technique in the ED, but it also shows the importance of correct training in how to examine for thrombus in the external iliac vein in the pregnant patient. The patient was admitted to the hospital and started on low-molecular-weight heparin. A formal radiology department US performed the next week confirmed the diagnosis of DVT.

Multifunctional and biologically active matrices from multicomponent polymeric solutions

NASA Technical Reports Server (NTRS)

Kiick, Kristi L. (Inventor); Yamaguchi, Nori (Inventor)

2010-01-01

The present invention relates to a biologically active functionalized electrospun matrix to permit immobilization and long-term delivery of biologically active agents. In particular the invention relates to a functionalized polymer matrix comprising a matrix polymer, a compatibilizing polymer and a biomolecule or other small functioning molecule. In certain aspects the electrospun polymer fibers comprise at least one biologically active molecule functionalized with low molecular weight heparin. Examples of active molecules that may be used with the multicomponent polymer of the invention include, for example, a drug, a biopolymer, for example a growth factor, a protein, a peptide, a nucleotide, a polysaccharide, a biological macromolecule or the like. The invention is further directed to the formation of functionalized crosslinked matrices, such as hydrogels, that include at least one functionalized compatibilizing polymer capable of assembly.

[Acute illness following chicken pox: spleen infarction as a complication of varicella zoster infection].

PubMed

Teeninga, Nynke; Willemze, Annemieke J; Emonts, Marieke; Appel, Inge M

2011-01-01

Varicella zoster virus (VZV) infection can cause temporary acquired protein S or C deficiency via cross reacting antibodies and consequently inducing a hypercoagulable state. A 6-year-old girl with a history of congenital cardiac disease was seen at an Emergency Department with acute chest pain, dyspnoea and fever, seven days after developing chicken pox. Diagnostic tests revealed massive infarction of the spleen, and a protein S and C deficiency. In addition, blood cultures revealed a Lancefield group A β-haemolytic streptococcus (GABHS). The patient recovered fully after treatment with low molecular weight heparin and antibiotics. In this patient, septic emboli caused splenic infarction. Thromboembolic complications should be suspected in children with VZV who present with acute symptoms, in particular if bacterial superinfection is found.

An interesting cause of pulmonary emboli: Acute carbon monoxide poisoning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sevinc, A.; Savli, H.; Atmaca, H.

Carbon monoxide poisoning, a public health problem of considerable significance, is a relatively frequent event today, resulting in thousands of hospitalizations annually. A 70-year-old lady was seen in the emergency department with a provisional diagnosis of carbon monoxide poisoning. The previous night, she slept in a tightly closed room heated with coal ember. She was found unconscious in the morning with poor ventilation. She had a rare presentation of popliteal vein thrombosis, pulmonary emboli, and possible tissue necrosis with carbon monoxide poisoning. Oxygen treatment with low-molecular-weight heparin (nadroparine) and warfarin therapy resulted in an improvement in both popliteal and pulmonarymore » circulations. In conclusion, the presence of pulmonary emboli should be sought in patients with carbon monoxide poisoning.« less

[Stroke and Cancer: Are Cryptogenic Strokes a Paraneoplastic Syndrome?].

PubMed

Eschle, Daniel

2015-07-22

Cancer is an independent risk factor for ischemic stroke, and stroke can precede tumour diagnosis by many months. A paraneoplastic hypercoagulability has been implicated. Overall, cancer is a rare cause, but should be suspected in cases of cryptogenic stroke. In patients with cryptogenic stroke, two criteria – ischemic lesions in multiple vascular territories and D-dimer values >2,15 µg/ml – predict cancer with 100% specificity according to one relevant study. An adenocarcinoma at an advanced stage is identified in many cases, the risk of stroke-recurrence is high. There is a lack of evidence-based recommendations regarding secondary prevention in these cases. In analogy to the guidelines for venous thromboembolism in cancer patients, low molecular weight heparins might be more efficient compared to other anti-clotting agents.

Extensive cerebral Sinovenous Thrombosis in a 5 Year Old Girl, Following Mild Dehydration. (Case Report and Review of Literature).

PubMed

Ashrafzadeh, Farah; Akhondian, Javad; Beiraghi Toosi, Mehran; Hashemi, Nargess

2013-12-01

Cerebral sinovenous thrombosis (CSVT) in children has rarely been reported in the literature, especially without underlying disorder. It has increasingly been diagnosed due to clinical awareness and sensitive neuroimaging techniques. The aim of this article was to report a case of cerebral sinovenous thrombosis without underlying disorder. We reported a 5 year old girl, presented with severe headache and seizure. She had a history of fever and diarrhea before the onset of headache. Neuroimaging showed evidence of CSVT on MRI and magnetic resonance venography. Investigations showed no inherited thrombophilia. The patient was treated with low molecular weight heparin (LMWH) which continued by warfarin. This case illustrated severe complications of dehydration in pediatrics without any evidence of underlying disorders.

Determination of enoxaparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent.

PubMed

Schaden, Eva; Schober, Andreas; Hacker, Stefan; Spiss, Christian; Chiari, Astrid; Kozek-Langenecker, Sibylle

2010-04-01

Drug monitoring of low molecular weight heparin is generally not recommended, but could be reasonable in critically ill patients, whose risk for bleeding or thrombosis shows a high interpatient variability. Anti-Xa assays are not available around the clock even in central hospitals, whereas rotational thrombelastometry (ROTEM) becomes increasingly used at the bedside. Prothrombinase-induced clotting time (PiCT) reagent allows determination of factor Xa-inhibition in plasma. The aim of our study was to evaluate enoxaparin determination in whole blood with the ROTEM using specific test modifications, including PiCT. After ethics committee's approval, citrated whole blood obtained from overall 16 healthy volunteers was incubated with enoxaparin at 16 different anti-Xa concentrations. Main endpoint was the clotting time (CT) in ROTEM representing initial activation of clot formation. CT was determined in the new PiCT-ROTEM test, in a low-tissue factor-activated modification (LowTF-ROTEM) as well as in the commercially available heparin-sensitive ROTEM assays (HEPTEM and INTEM). In the absence of enoxaparin, CT values were 168.6 +/- 6.1 s (PiCT-ROTEM), 247.3 +/- 18.6 s (LowTF-ROTEM), and -6.2 +/- 7.9 s (INTEM-HEPTEM). A linear dependency (P < 0.01) between anti-Xa concentration and CT was found for PiCT-ROTEM, LowTF-ROTEM, and for INTEM-HEPTEM with correlation coefficients of 0.93 for PiCT-ROTEM, 0.94 for LowTF-ROTEM, and 0.81 for INTEM-HEPTEM. This in-vitro experiment demonstrates a strong correlation between enoxaparin anti-Xa concentrations and specific ROTEM tests. These promising assays should be further evaluated for monitoring anticoagulation in high-risk patients in clinical studies.

Surface modification of silk fibroin fabric using layer-by-layer polyelectrolyte deposition and heparin immobilization for small-diameter vascular prostheses.

PubMed

Elahi, M Fazley; Guan, Guoping; Wang, Lu; Zhao, Xinzhe; Wang, Fujun; King, Martin W

2015-03-03

There is an urgent need to develop a biologically active implantable small-diameter vascular prosthesis with long-term patency. Silk-fibroin-based small-diameter vascular prosthesis is a promising candidate having higher patency rate; however, the surface modification is indeed required to improve its further hemocompatibility. In this study, silk fibroin fabric was modified by a two-stage process. First, the surface of silk fibroin fabric was coated using a layer-by-layer polyelectrolyte deposition technique by stepwise dipping the silk fibroin fabric into a solution of cationic poly(allylamine hydrochloride) (PAH) and anionic poly(acrylic acid) (PAA) solution. The dipping procedure was repeated to obtain the PAH/PAA multilayers deposited on the silk fibroin fabrics. Second, the polyelectrolyte-deposited silk fibroin fabrics were treated in EDC/NHS-activated low-molecular-weight heparin (LMWH) solution at 4 °C for 24 h, resulting in immobilization of LMWH on the silk fibroin fabrics surface. Scanning electron microscopy, atomic force microscopy, and energy-dispersive X-ray data revealed the accomplishment of LMWH immobilization on the polyelectrolyte-deposited silk fibroin fabric surface. The higher the number of PAH/PAA coating layers on the silk fibroin fabric, the more surface hydrophilicity could be obtained, resulting in a higher fetal bovine serum protein and platelets adhesion resistance properties when tested in vitro. In addition, compared with untreated sample, the surface-modified silk fibroin fabrics showed negligible loss of bursting strength and thus reveal the acceptability of polyelectrolytes deposition and heparin immobilization approach for silk-fibroin-based small-diameter vascular prostheses modification.

Analyses of Interactions Between Heparin and the Apical Surface Proteins of Plasmodium falciparum

NASA Astrophysics Data System (ADS)

Kobayashi, Kyousuke; Takano, Ryo; Takemae, Hitoshi; Sugi, Tatsuki; Ishiwa, Akiko; Gong, Haiyan; Recuenco, Frances C.; Iwanaga, Tatsuya; Horimoto, Taisuke; Akashi, Hiroomi; Kato, Kentaro

2013-11-01

Heparin, a sulfated glycoconjugate, reportedly inhibits the blood-stage growth of the malaria parasite Plasmodium falciparum. Elucidation of the inhibitory mechanism is valuable for developing novel invasion-blocking treatments based on heparin. Merozoite surface protein 1 has been reported as a candidate target of heparin; however, to better understand the molecular mechanisms involved, we characterized the molecules that bind to heparin during merozoite invasion. Here, we show that heparin binds only at the apical tip of the merozoite surface and that multiple heparin-binding proteins localize preferentially in the apical organelles. To identify heparin-binding proteins, parasite proteins were fractionated by means of heparin affinity chromatography and subjected to immunoblot analysis with ligand-specific antibodies. All tested members of the Duffy and reticulocyte binding-like families bound to heparin with diverse affinities. These findings suggest that heparin masks the apical surface of merozoites and blocks interaction with the erythrocyte membrane after initial attachment.

Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

PubMed

Singer, Daniel E; Albers, Gregory W; Dalen, James E; Fang, Margaret C; Go, Alan S; Halperin, Jonathan L; Lip, Gregory Y H; Manning, Warren J

2008-06-01

This chapter about antithrombotic therapy in atrial fibrillation (AF) is part of the American College of Chest Physicians Evidence-Based Guidelines Clinical Practice Guidelines (8th Edition). Grade 1 recommendations indicate that most patients would make the same choice and Grade 2 suggests that individual patient's values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following (all vitamin K antagonist [VKA] recommendations have a target international normalized ratio [INR] of 2.5; range 2.0-3.0, unless otherwise noted). In patients with AF, including those with paroxysmal AF, who have had a prior ischemic stroke, transient ischemic attack (TIA), or systemic embolism, we recommend long-term anticoagulation with an oral VKA, such as warfarin, because of the high risk of future ischemic stroke faced by this set of patients (Grade 1A). In patients with AF, including those with paroxysmal AF, who have two or more of the risk factors for future ischemic stroke listed immediately below, we recommend long-term anticoagulation with an oral VKA (Grade 1A). Two or more of the following risk factors apply: age >75 years, history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function and/or heart failure. In patients with AF, including those with paroxysmal AF, with only one of the risk factors listed immediately above, we recommend long-term antithrombotic therapy (Grade 1A), either as anticoagulation with an oral VKA, such as warfarin (Grade 1A), or as aspirin, at a dose of 75-325 mg/d (Grade 1B). In these patients at intermediate risk of ischemic stroke we suggest a VKA rather than aspirin (Grade 2A). In patients with AF, including those with paroxysmal AF, age < or =75 years and with none of the other risk factors listed above, we recommend long-term aspirin therapy at a dose of 75-325 mg/d (Grade 1B), because of their low risk of ischemic stroke. For patients with atrial flutter, we recommend that antithrombotic therapy decisions follow the same risk-based recommendations as for AF (Grade 1C). For patients with AF and mitral stenosis, we recommend long-term anticoagulation with an oral VKA (Grade 1B). For patients with AF and prosthetic heart valves we recommend long-term anticoagulation with an oral VKA at an intensity appropriate for the specific type of prosthesis (Grade 1B). See CHEST 2008; 133(suppl):593S-629S. For patients with AF of > or =48 h or of unknown duration for whom pharmacologic or electrical cardioversion is planned, we recommend anticoagulation with an oral VKA, such as warfarin, for 3 weeks before elective cardioversion and for at least 4 weeks after sinus rhythm has been maintained (Grade 1C). For patients with AF of > or = 48 h or of unknown duration undergoing pharmacological or electrical cardioversion, we also recommend either immediate anticoagulation with unfractionated IV heparin, or low-molecular-weight heparin (LMWH), or at least 5 days of warfarin by the time of cardioversion (achieving an INR of 2.0-3.0) as well as a screening multiplane transesophageal echocardiography (TEE). If no thrombus is seen, cardioversion is successful, and sinus rhythm is maintained, we recommend anticoagulation for at least 4 weeks. If a thrombus is seen on TEE, then cardioversion should be postponed and anticoagulation should be continued indefinitely. We recommend obtaining a repeat TEE before attempting later cardioversion (Grade 1B addressing the equivalence of TEE-guided vs non-TEE-guided cardioversion). For patients with AF of known duration <48 h, we suggest cardioversion without prolonged anticoagulation (Grade 2C). However, in patients without contraindications to anticoagulation, we suggest beginning IV heparin or LMWH at presentation (Grade 2C).

Thrombotic complications of central venous catheters in cancer patients.

PubMed

Kuter, David J

2004-01-01

Central venous catheters (CVCs), such as the tunneled catheters and the totally implanted ports, play a major role in general medicine and oncology. Aside from the complications (pneumothorax, hemorrhage) associated with their initial insertion, all of these CVCs are associated with the long-term risks of infection and thrombosis. Despite routine flushing with heparin or saline, 41% of CVCs result in thrombosis of the blood vessel, and this markedly increases the risk of infection. Only one-third of these clots are symptomatic. Within days of insertion, almost all CVCs are coated with a fibrin sheath, and within 30 days, most CVC-related thrombi arise. Aside from reducing the function of the catheter, these CVC-related thrombi can cause postphlebitic syndrome in 15%-30% of cases and pulmonary embolism in 11% (only half of which are symptomatic). Risk factors for CVC thrombosis include the type of malignancy, type of chemotherapy, type of CVC, and locations of insertion site and catheter tip, but not inherited thrombophilic risk factors. Efforts to reduce CVC thrombosis with systemic prophylactic anticoagulation with low-molecular-weight heparin have failed. Low-dose warfarin prophylaxis remains controversial; all studies are flawed, with older studies, but not newer ones, showing benefit. Currently, less than 10% of patients with CVCs receive any systemic prophylaxis. Although its general use cannot be recommended, low-dose warfarin may be a low-risk treatment in patients with good nutrition and adequate hepatic function. Clearly, additional studies are required to substantiate the prophylactic use of low-dose warfarin. Newer anticoagulant treatments, such as pentasaccharide and direct thrombin inhibitors, need to be explored to address this major medical problem.

Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model.

PubMed

Fichter, Andreas M; Ritschl, Lucas M; Robitzky, Luisa K; Wagenpfeil, Stefan; Mitchell, David A; Wolff, Klaus-Dietrich; Mücke, Thomas

2016-10-21

The effects of antithrombotic drugs on random and free flap survival have been investigated in the past, but the experimental and clinical results are not in agreement. A perforator-based critical ischaemia model was used to evaluate the effects of different perioperatively administered pharmaceutical agents on tissue ischaemia and to assess the potential additional haemorheological or vasodilative effects of antithrombotics on flap microcirculation. Combined laser Doppler flowmetry and remission spectroscopy revealed an increase in certain microcirculation parameters in most groups in comparison with saline controls, and these changes correlated with flap survival. Clopidogrel and hirudin significantly improved the amount of viable flap tissue in comparison with controls, while unfractioned heparin had a negative effect on flap survival. Low molecular weight heparin, aspirin, pentoxifylline, and hydroxyethyl starch had no impact on the amount of viable flap tissue. A higher complication rate was observed in all experimental groups, but only clopidogrel had a negative impact on the flap viability. Our results add to the body of evidence supporting the conclusion that perioperative antithrombotic treatment improves flap survival. Clopidogrel and hirudin are effective pharmacological agents that significantly increased the viability of perforator-based skin flaps in rats, but at a higher risk of postoperative bleeding.

Clinical Outcome of a Portosplenomesenteric Venous Thrombosis in Necrotizing Acute Pancreatitis with Protein C and S Deficiency Treated by Anticoagulation Therapy Alone.

PubMed

Ankouane, Firmin; Kowo, Mathurin; Ngo Nonga, Bernadette; Magny, Eric; Hell Medjo, Edith; Ndjitoyap Ndam, Elie Claude

2015-01-01

Cases of splanchnic venous thrombosis have not been described in Cameroon. Their prevalence in acute pancreatitis is variable. With the emergence of acute intra-abdominal infections including typhoid fever and peritoneal tuberculosis in situations of acquired immunodeficiency syndrome, these cases will become frequent. We report the case of a portosplenomesenteric venous thrombosis related to necrotizing acute pancreatitis associated with proteins C and S deficiency, in a 46-year-old Cameroonian man, without particular past medical history. He was admitted for abdominal pain which had been evolving for 3 weeks and accompanied by vomiting. In the absence of hemorrhagic risk factor, the patient received low molecular weight heparin followed by oral warfarin. The abdominal ultrasound check on the 12th day showed a partial recanalization of venous thrombosis. The abdominal contrast-enhanced CT scanner at day 30 on oral anticoagulation therapy showed collateral vessels and small bowel edema. At the same time the upper gastrointestinal endoscopy showed grade II esophageal varices. We have maintained oral anticoagulation therapy. This case highlights that an early effective anticoagulation heparin therapy is needed for a clear benefit in case of suspected PSMVT. It is certain that the sooner the treatment is given, the better outcome will be.

Structure and haemostatic effects of generic versions of enoxaparin available for clinical use in Brazil: similarity to the original drug.

PubMed

Glauser, Bianca F; Vairo, Bruno C; Oliveira, Stephan-Nicollas M C G; Cinelli, Leonardo P; Pereira, Mariana S; Mourão, Paulo A S

2012-02-01

Patent protection for enoxaparin has expired. Generic preparations are developed and approved for clinical use in different countries. However, there is still skepticism about the possibility of making an exact copy of the original drug due to the complex processes involved in generating low-molecular-weight heparins. We have undertaken a careful analysis of generic versions of enoxaparin available for clinical use in Brazil. Thirty-three batches of active ingredient and 70 of the final pharmaceutical product were obtained from six different suppliers. They were analysed for their chemical composition, molecular size distribution, in vitro anticoagulant activity and pharmacological effects on animal models of experimental thrombosis and bleeding. Clearly, the generic versions of enoxaparin available for clinical use in Brazil are similar to the original drug. Only three out of 33 batches of active ingredient from one supplier showed differences in molecular size distribution, resulting from a low percentage of tetrasaccharide or the presence of a minor component eluted as monosaccharide. Three out of 70 batches of the final pharmaceutical products contained lower amounts of the active ingredient than that declared by the suppliers. Our results suggest that the generic versions of enoxaparin are a viable therapeutic option, but their use requires strict regulations to ensure accurate standards.

A Turn-on Fluorescence Sensor for Heparin Detection Based on a Release of Taiwan Cobra Cardiotoxin from a DNA Aptamer or Adenosine-Based Molecular Beacon.

PubMed

Shi, Yi-Jun; Wang, Liang-Jun; Lee, Yuan-Chin; Huang, Chia-Hui; Hu, Wan-Ping; Chang, Long-Sen

2018-02-19

This study presents two sensitive fluorescent assays for sensing heparin on the basis of the electrostatic interaction between heparin and Naja naja atra cardiotoxin 3 (CTX3). Owing to CTX3-induced folded structure of an adenosine-based molecular beacon (MB) or a DNA aptamer against CTX3, a reduction in the fluorescent signal of the aptamer or MB 5'-end labeled with carboxyfluorescein (FAM) and 3'-end labeled with 4-([4-(dimethylamino)phenyl]azo)-benzoic acid (DABCYL) was observed upon the addition of CTX3. The presence of heparin and formation of the CTX3-heparin complex caused CTX3 detachment from the MB or aptamer, and restoration of FAM fluorescence of the 5'-FAM-and-3'-DABCYL-labeled MB and aptamer was subsequently noted. Moreover, the detection of heparin with these CTX3-aptamer and CTX3-MB sensors showed high sensitivity and selectivity toward heparin over chondroitin sulfate and hyaluronic acid regardless of the presence of plasma. The limit of detection for heparin in plasma was determined to be 16 ng/mL and 15 ng/mL, respectively, at a signal-to-noise ratio of 3. This study validates the practical utility of the CTX3-aptamer and CTX3-MB systems for determining the concentration of heparin in a biological matrix.

In vivo antithrombotic properties of a heparin from the oocyte test cells of the sea squirt Styela plicata(Chordata-Tunicata).

PubMed

Cardilo-Reis, L; Cavalcante, M C M; Silveira, C B M; Pavão, M S G

2006-11-01

In the ascidian Styela plicata, the oocytes are surrounded by two types of accessory cells named follicle cells and test cells. A heparin-like substance with an anticoagulant activity equivalent to 10% of mammalian heparin and about 5% as potent as the mammalian counterpart for the inhibition of thrombin by antithrombin was isolated from the oocyte test cells. In the present study, we compared the antithrombotic and hemorrhagic effects of sea squirt oocyte test cell heparin with those of porcine heparin in rat models of venous thrombosis and blood loss. Intravenous administration of the oocyte test cell heparin to Wistar rats (both sexes, weighing approximately 300 g, N = 4 in each group) at a dose of 5.0 mg/kg body weight, which produced a 1.8-fold increase in plasma activated partial thromboplastin time, inhibited thrombosis by 45 +/- 13.5% (mean +/- SD) without any bleeding effect. The same dose of porcine heparin inhibited thrombosis by 100 +/- 1.4%, but produced a blood loss three times greater than that of the saline-treated control. However, 10-fold reduction of the dose of porcine heparin to 0.5 mg/kg body weight, which produced a 5-fold increase in plasma-activated partial thromboplastin time, inhibited thrombosis by 70 +/- 13% without any bleeding effect. The antithrombotic properties of a new heparin isolated from test cells of the sea squirt S. plicata, reported here for the first time, indicate that, although sea squirt oocyte test cell heparin was a poor anticoagulant compared to porcine heparin, it had a significant antithrombotic effect without causing bleeding.

[Prevention of venous thromboembolism following cardiac, vascular or thoracic surgery].

PubMed

Piriou, V; Rossignol, B; Laroche, J-P; Ffrench, P; Lacroix, P; Squara, P; Sirieix, D; D'Attellis, N; Samain, E

2005-08-01

In the absence of thromboprophylaxis, coronary artery bypass graft surgery (CABG), intrathoracic surgery (thoracotomy or video-assisted thoracoscopy), abdominal aortic surgery and infrainguinal vascular surgery are high-risk surgeries for the development of venous thromboembolic events (VTE). The incidence of VTE following surgery of the intrathoracic aorta, carotid endarterectomy or mediastinoscopy is unknown. Data from the litterature are lacking to draw evidence-based recommandations for venous thromboprophylaxis after these three types of surgeries, and the following guidelines are but experts'opinions (Grade D recommendations). Thromboprophylaxis is recommended after CABG (Grade D), with either subcutaneous (SC) low molecular weight heparin (LMWH) or SC or intravenous (i.v.) unfractioned heparin (UH) (PTT target = 1.1-1.5 time control value) (both grade D). This may be combined with the use of intermittent pneumatic compression device (Grade B). After valve surgery. The anticoagulation recommended to prevent valve thrombosis is sufficient in order to prevent VTE. We recommend thromboprophylaxis with either LMWH or low dose UH to prevent VTE after aortic or lower limbs infrainguinal vascular surgery (both grade B and D). Vitamine K antagonists (VKA) are not recommended in this indication (Grade D). We recommend thromprophylaxis following intrathoracic surgery via thoracotomy or videoassisted thoracoscopy (grade C). Either subcutaneous LMWH or subcutaneous or i.v. low dose UH may be used (Grade C). Efficacy of intermittent pneumatic compression device has been demonstrated in a study (grade C). VKA are not recommended (grade D). No further recommendation regarding the duration of thromboprophylaxis after these three types of surgeries can be made.

Investigation of the heparin-thrombin interaction by dynamic force spectroscopy.

PubMed

Wang, Congzhou; Jin, Yingzi; Desai, Umesh R; Yadavalli, Vamsi K

2015-06-01

The interaction between heparin and thrombin is a vital step in the blood (anti)coagulation process. Unraveling the molecular basis of the interactions is therefore extremely important in understanding the mechanisms of this complex biological process. In this study, we use a combination of an efficient thiolation chemistry of heparin, a self-assembled monolayer-based single molecule platform, and a dynamic force spectroscopy to provide new insights into the heparin-thrombin interaction from an energy viewpoint at the molecular scale. Well-separated single molecules of heparin covalently attached to mixed self-assembled monolayers are demonstrated, whereby interaction forces with thrombin can be measured via atomic force microscopy-based spectroscopy. Further these interactions are studied at different loading rates and salt concentrations to directly obtain kinetic parameters. An increase in the loading rate shows a higher interaction force between the heparin and thrombin, which can be directly linked to the kinetic dissociation rate constant (koff). The stability of the heparin/thrombin complex decreased with increasing NaCl concentration such that the off-rate was found to be driven primarily by non-ionic forces. These results contribute to understanding the role of specific and nonspecific forces that drive heparin-thrombin interactions under applied force or flow conditions. Copyright © 2015 Elsevier B.V. All rights reserved.

Developing a Highly Active Blood Anticoagulant—a Heparin Complex with Glutamic Acid—by Simulating Chemical Equilibria Based on pH-Metric Data

NASA Astrophysics Data System (ADS)

Nikolaeva, L. S.; Semenov, A. N.

2018-02-01

The anticoagulant activity of high-molecular-weight heparin is increased by developing a new highly active heparin complex with glutamate using the thermodynamic model of chemical equilibria based on pH-metric data. The anticoagulant activity of the developed complexes is estimated in the pH range of blood plasma according to the drop in the calculated equilibrium Ca2+ concentration associated with the formation of mixed ligand complexes of Ca2+ ions, heparin (Na4hep), and glutamate (H2Glu). A thermodynamic model is calculated by mathematically modelling chemical equilibria in the CaCl2-Na4hep-H2Glu-H2O-NaCl system in the pH range of 2.30 ≤ pH ≤ 10.50 in diluted saline that acts as a background electrolyte (0.154 M NaCl) at 37°C and initial concentrations of the main components of ν × 10-3 M, where n ≤ 4. The thermodynamic model is used to determine the main complex of the monomeric unit of heparin with glutamate (HhepGlu5-) and the most stable mixed ligand complex of Ca2+ with heparin and glutamate (Ca2hepGlu2-) in the pH range of blood plasma (6.80 ≤ pH ≤ 7.40). It is concluded that the Ca2hepGlu2- complex reduces the Ca2+ concentration 107 times more than the Ca2+ complex with pure heparin. The anticoagulant effect of the developed HhepGlu5- complex is confirmed in vitro and in vivo via coagulation tests on the blood plasma of laboratory rats. Additional antithrombotic properties of the developed complex are identified. The new highly active anticoagulant, HhepGlu5- complex with additional antithrombotic properties, is patented.

Periprocedural Prophylactic Antithrombotic Strategies in Interventional Radiology: Current Practice in the Netherlands and Comparison with the United Kingdom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wiersema, Arno M., E-mail: arno@wiersema.nu; Vos, Jan-Albert, E-mail: j.a.vos@antonius.net; Bruijninckx, Cornelis M. A., E-mail: cmabruijninckx@planet.nl

Purpose: The use of prophylactic antithrombotic drugs to prevent arterial thrombosis during the periprocedural period during (percutaneous) peripheral arterial interventions (PAIs) is still a matter of dispute, and clear evidence-based guidelines are lacking. To create those guidelines, a study group was formed in the Netherlands in cooperation with the Dutch Society of Vascular Surgery and the Society of Interventional Radiology. The study group is called 'Consensus on Arterial PeriProcedural Anticoagulation (CAPPA).' Materials and Methods: The CAPPA study group devised and distributed a comprehensive questionnaire amongst Dutch interventional radiologists (IRs). Results: One hundred forty-two IRs responded (68 %) to the questionnaire.more » Almost no IR stopped acetyl salicylic acid before interventions, and 40 % stopped clopidogrel before PAI but not before carotid artery stenting (CAS). A flushing solution on the sideport of the sheath was used routinely by 30 % of IRs in PAI and by 50 % of IRs during CAS. A minority of IRs used a heparinised flushing solution (28 %). Unfractionated heparin was used by 95 % of IRs as bolus; 5000 IU was the most used dosage. Timing of administration varied widely. A majority of IRs (75 %) repeated heparin administration after 1 h. Conclusion: A substantial variety exists amongst IRs in the Netherlands regarding the use of prophylactic periprocedural antithrombotic drugs to prevent arterial thrombosis during PAI. When compared with varying results regarding the use of heparin in the United Kingdom, the variety in the Netherlands showed a different pattern. The proven variety in these countries, and also between these countries, emphasises the need for authoritative studies to develop evidence-based practical guidelines.« less

Enoxaparin. A pharmacoeconomic appraisal of its use in thromboembolic prophylaxis after total hip arthroplasty.

PubMed

Dunn, C J; Goa, K L

1996-08-01

Total hip arthroplasty (THA) is a major orthopaedic procedure with a high risk of postoperative thromboembolism. Increasing demand for this type of surgery, together with its high cost, has led to examination of means by which the cost of THA may be minimised. Current clinical opinion favours the use of suitable pharmacological thromboprophylaxis in patients undergoing THA; such prophylaxis may be provided with subcutaneous standard unfractionated heparin (UFH), oral warfarin or subcutaneous low molecular weight heparin (LMWH). Traditionally, LMWHs have been perceived as being more expensive to use than UFH or warfarin because of their relatively high acquisition cost. However, recent pharmacoeconomic data have shown that cost savings are possible when LMWHs are used. This is attributed mainly to reduced frequency of administration, reductions in costs associated with diagnosis and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the lack of need for laboratory monitoring of blood coagulation parameters. LMWHs have proportionally less anti-factor IIa (antithrombin) activity relative to anti-factor Xa activity than UFH. Enoxaparin, a LMWH with a mean molecular weight of 4 to 5kD, is reported to have approximately 5 times less activity against thrombin than UFH, for equivalent anti-factor Xa activity. Randomised clinical trials in patients undergoing THA have shown enoxaparin to be at least as effective as UFH in the prevention of DVT and PE, with consistent trends towards a lower incidence of DVT with enoxaparin than with UFH. Similar rates of haemorrhagic complications were reported for enoxaparin and UFH in most trials, although a significantly higher total transfusion requirement was reported for UFH than for enoxaparin in a double-blind study. A significantly higher incidence of bleeding was observed with UFH than with enoxaparin in another study, with similar transfusion requirements for both treatment groups. Cost comparisons in which costs were assigned retrospectively to clinical data have shown cost advantages for LMWHs in general over UFH when costs of administration, hospital bed occupancy and laboratory/radiology procedures are calculated. Cost savings with LMWHs were attributed mainly to reductions in the cost of managing thromboembolic complications in patients receiving these drugs. One meta-analysis showed a saving of $US50 000 (1993 figures) for LMWH over UFH (both subcutaneously twice daily) for every 1000 patients. Subcutaneous enoxaparin at a dosage of 30mg twice daily was shown to be more cost effective than oral warfarin in the prophylaxis of DVT and PE in 2 North American studies in which costs were related to outcomes. One study comprised the application of a decision analysis to a hypothetical group of 10 000 patients; an incremental cost effectiveness of $US12 288 (1993 figures) per death averted was reported for enoxaparin. Enoxaparin was also associated with an overall incremental cost effectiveness of $Can29 140 (1992 figures) per year of life saved (YLS) in the other study, in which costs were applied to clinical data obtained retrospectively from 10 randomised trials. Although no cost-effectiveness analyses have been carried out to compare enoxaparin with UFH, a UK cost comparison reported an overall cost saving of pounds 20 per patient (figures from 1989 to 1990) with enoxaparin 40mg once daily subcutaneously over subcutaneous UFH 5000IU 3 times daily. It has also been suggested that the use of once- or twice-daily enoxaparin in preference to UFH may reduce the overall length of hospital stay; a significant difference emerged in 1 analysis (9.9 or 9.5 vs 11.3 days). Pharmacoeconomic data therefore support the use of enoxaparin as an effective thromboprophylactic treatment with potential cost advantages over warfarin and UFH. Cost-effecti

Pheochromocytoma with inferior vena cava thrombosis: An unusual association.

PubMed

Kota, Sunil K; Kota, Siva K; Jammula, Sruti; Meher, Lalit K; Modi, Kirtikumar D

2012-04-01

Pheochromocytomas have been described in association with vascular abnormalities like renal artery stenosis. A 48-year-old man was admitted to our hospital with the complaints of headache, sweating, anxiety, dizziness, nausea, vomiting and hypertension. For last several days, he was having a dull aching abdominal pain. Abdominal computed tomography (CT) revealed the presence of a left adrenal pheochromocytoma. An inferior vena cava (IVC) venogram via the right jugular vein demonstrated occlusion of the IVC inferior to the right atrium. Surgical removal of pheochromocytoma was done, followed by anticoagulant treatment for IVC thrombosis, initially with subcutaneous low molecular weight heparin, and then with oral warfarin, resulting in restoration of patency. To the best of our knowledge, the occurrence of pheochromocytoma in IVC thrombosis has not been reported so far from India. Possible mechanisms of such an involvement are discussed.

[Mondor's disease of penis: A case report].

PubMed

Marsaudon, E; Legal, C; Gayoux, D; Weber, O

2016-09-01

Mondor's disease is a rare superficial thrombophlebitis, historically involving the thoracic venous system of women. However, it can occur in both gender and all over the skin. We report a 40-year-old man with type one diabetes who presented with a thrombosis of the superficial dorsal vein of the penis that he treated as a fungal infection. Treatment with non-steroidal anti-inflammatory drugs and low molecular weight heparin contributed to a favorable outcome in 2 weeks. Pathogenesis and treatment of Mondor's disease remain incompletely dominated. Some predisposing factors have been highlighted in the literature. It might be interesting to add diabetes, due to its frequent pelvic problems leading to a potential venous inflammatory trigger. Copyright © 2015 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Refractory Mycoplasma pneumoniae pneumonia with concomitant acute cerebral infarction in a child: A case report and literature review.

PubMed

Jin, Xingnan; Zou, Yingxue; Zhai, Jia; Liu, Jie; Huang, Bing

2018-03-01

Mycoplasma pneumoniae pneumonia, a common cause of community-acquired pneumonia in children, is rarely complicated with acute cerebral infarction. We present a 7-year-old boy with severe M pneumoniae pneumonia who developed impaired consciousness, aphasia, and reduced limb muscle power 7 days postadmission. Mycoplasma pneumoniae pneumonia with concomitant acute cerebral infarction. The patient recovered with aggressive antibiotic therapy, antiinflammation therapy with methylprednisolone, and gamma immunoglobulin and anticoagulation therapy with aspirin and low molecular weight heparin along with rehabilitation training. At 8 days postadmission, his consciousness was improved and at the 6-month follow-up visit, his muscle power of bilateral upper and lower limbs was normal except still poor right handgrip power. Stroke or cerebral infarction should be considered and promptly managed in rare cases of M pneumoniae pneumonia with neurologic manifestations.

The management of venous thromboembolism in cancer patients.

PubMed

Dolan, Shelley; Fitch, Margaret

Venous thromboembolism (VTE), encompassing deep venous thrombosis and pulmonary embolism (PE), is a common complication of cancer and an important cause of preventable mortality in people with cancer. Because VTE can be clinically silent, fatal PE generally occurs without warning, and preventive measures are, therefore, necessary in high-risk patients. Clinical guidelines recommend the use of low-molecular-weight heparins in the treatment and prevention of VTE in patients with cancer, in addition to non-pharmacological interventions aimed at reducing thrombotic risk. Nurses have an important role in helping to identify patients at risk of developing VTE, and in the implementation of preventive or therapeutic regimens, and monitoring the development of complications. Furthermore, nurses are in an ideal position to educate patients on the importance of preventive measures and to help ensure compliance with thromboprophylactic interventions.

Partial segmental thrombosis of the corpus cavernosum (PSTCC) diagnosed by contrast-enhanced ultrasound: a case report.

PubMed

Sauer, Stephanie; Goltz, Jan P; Gassenmaier, Tobias; Kunz, Andreas S; Bley, Thorsten A; Klein, Detlef; Petritsch, Bernhard

2014-12-17

Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease predominantly occurring in young men. Cardinal symptoms are pain and perineal swelling. Although several risk factors are described in the literature, the exact etiology of penile thrombosis remains unclear in most cases. MRI or ultrasound (US) is usually used for diagnosing this condition. We report a case of penile thrombosis after left-sided varicocele ligature in a young patient. The diagnosis was established using contrast-enhanced ultrasound (CEUS) and was confirmed by contrast-enhanced magnetic resonance imaging (ceMRI). Successful conservative treatment consisted of systemic anticoagulation using low molecular weight heparin and acetylsalicylic acid. PSTCC is a rare condition in young men and appears with massive pain and perineal swelling. In case of suspected PSTCC utilization of CEUS may be of diagnostic benefit.

Management of rivaroxaban in relation to bodyweight and body mass index

PubMed Central

Uprichard, James

2016-01-01

Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery. In addition, there is evidence that obesity represents a significant driving factor for the current and projected prevalence of atrial fibrillation. Rivaroxaban and other direct oral anticoagulants offer fixed-dose regimens for these indications. They do not require therapeutic drug monitoring or dose adjustment according to the weight of the patient. However, primary care physicians seem to be hesitant to accept the concept of a fixed-dose regimen for patients at extremes of weight, perhaps because of familiarity with weight-based dosing of other drugs including low molecular weight heparins. The main concerns related to unadjusted dosing are increased exposure in underweight patients leading to a risk of excessive bleeding and conversely to underanticoagulation of overweight patients. Rivaroxaban has shown similar efficacy and a similar or better safety profile compared with standard treatment for several venous and arterial indications, including venous thromboembolism, nonvalvular atrial fibrillation, and acute coronary syndrome. Prespecified subgroup analyses of patients stratified by weight or body mass index demonstrated outcomes that were consistent with the overall analysis and within each weight and body mass index group. The results suggest that standard-dose rivaroxaban can be safely prescribed in adult patients of all weights. PMID:27090286

Pharmacokinetics of heparin and related polysaccharides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boneu, B.; Dol, F.; Caranobe, C.

1989-01-01

The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activitymore » present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where /sup 125/I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses.« less

[The percutaneous effect of a heparin-allantoin-dexpanthenol combination in a specific ointment base. Anti-allergic, anti-inflammatory effect in the PCA test in the rat].

PubMed

Rudolph, C; Tauschel, H D

1984-01-01

Local application of a heparin-allantoin-dexpanthenol (Hepathrombin-Adenylchemie) ointment to rats 15 min prior to induction of a passive cutaneous anaphylaxis (PCA) reaction inhibits the anaphylactic reaction as compared to the ointment base. Also, the Evans Blue content as a measure for vascular permeability and the oedema weights are reduced under the heparin containing ointment. The antiallergic/antiinflammatory effect is probably due to heparin.

Crosslinked self-assemblies of lipoid acid-substituted low molecular weight (1800 Da) polyethylenimine as reductive-sensitive non-viral gene vectors

NASA Astrophysics Data System (ADS)

Chen, Xiaojiao; Yuan, Zhefan; Yi, Xiaoqing; Zhuo, Renxi; Li, Feng

2012-10-01

In this study, amphiphilic polyethylenimine-graft-thioctic acid (PEI-TA) and polyethylenimine-graft-lauric acid (PEI-LA) were synthesized. Both PEI-TA and PEI-LA could self-assemble into micelles. Due to the existence of disulfide-linked rings at the end of hydrophobic moieties, PEI-TA could form stable micelles with disulfide crosslinked cores (PEI-TA-SS). In comparison with the PEI-LA micelle, PEI-TA-SS possessed higher DNA binding ability according to the gel retardation assay and heparin replacement assay. In vitro transfection experiments indicated that PEI-TA-SS showed comparably high transfection efficiency as compared to 25 kDa PEI. More interestingly, the luciferase expression of PEI-TA-SS was superior to that of PEI-LA at low N/P ratio, which might be ascribed to the stronger binding capacity of PEI-TA-SS facilitating the entering of PEI-TA-SS/pDNA complexes into cells.

[Case of CNS-limited ANCA-associated vasculitis presenting as recurrent ischemic stroke].

PubMed

Wakisaka, Kayo; Hagiwara, Noriko; Kanazawa, Yuka; Arakawa, Shuji; Ago, Tetsuro; Kitazono, Takanari

2014-01-01

A 73-year-old man was admitted to our hospital because of a decrease in spontaneity. His medical history included two stroke episodes, probably related to hypertension. Brain MRI on admission demonstrated acute infarction in the right caudate nucleus and left putamen. Intravenous infusion of a low molecular-weight heparin added to oral antiplatelets was started. Following admission, he developed a low grade fever and severe inflammatory reaction. The focus of infection was not evident, and none of the antibiotics tried were effective. Ten days after admission, he developed right hemiparesis, and an additional brain MRI showed new multiple infarctions. We also determined the presence of a high MPO-ANCA titer (57 EU), and we diagnosed the patient's condition to be ANCA-associated vasculitis (AAV). Steroid therapy improved his inflammatory reaction and stroke recurrence was not observed. We suggest that vasculitis should be considered as a potential risk factor for repeated small infarctions with fever of unknown origin, especially those of perforating artery territories.

Mechanisms of Staphylococcus epidermidis adhesion to model biomaterial surfaces: Establising a link between thrombosis and infection

NASA Astrophysics Data System (ADS)

Higashi, Julie Miyo

Infections involving Staphylococcus epidermidis remain a life threatening complication associated with the use of polymer based cardiovascular devices. One of the critical steps in infection pathogenesis is the adhesion of the bacteria to the device surface. Currently, mechanisms of S. epidermidis adhesion are incompletely understood, but are thought to involve interactions between bacteria, device surface, and host blood elements in the form of adsorbed plasma proteins and surface adherent platelets. Our central hypothesis is that elements participating in thrombosis also promote S. epidermidis adhesion by specifically binding to the bacterial surface. The adhesion kinetics of S. epidermidis RP62A to host modified model biomaterial surface octadecyltrichlorosilane (OTS) under hydrodynamic shear conditions were characterized. Steady state adhesion to adsorbed proteins and surface adherent platelets was achieved at 90-120 minutes and 60-90 minutes, respectively. A dose response curve of S. epidermidis adhesion in the concentration range of 10sp7{-}10sp9 bac/mL resembled a multilayer adsorption isotherm. Increasing shear stress was found to LTA, and other LTA blocking agents significantly decreased S. epidermidis adhesion to the fibrin-platelet clots, suggesting that this interaction between S. epidermidis and fibrin-platelet clots is specific. Studies evaluated the adhesion of S. epidermidis to polymer immobilized heparin report conflicting results. Paulsson et al., showed that coagulase negative staphylococci adhered in comparable numbers to both immobilized heparin and nonheparinized surfaces, while exhibiting significantly greater adhesion to both surfaces than S. aureus. Preadsorption of the surfaces with specific heparin binding plasma proteins vitronectin, fibronectin, laminin, and collagen significantly increased adhesion. It was postulated that immobilized heparin contained binding sites for the plasma proteins, exposing bacteria binding domains of the protein. Aggregation of heparin coated (adsorbed) polystyrene beads by the same S. epidermidis strains did not correlate with the adherence assays on the immobilized heparin surfaces and staphylococcal binding was dependent on media ionic strength and pH, suggesting that the conformation of the heparin polysaccharide chains was crucial to the interaction (132). Another study by Arciola et al., showed that heparin modified PMMA intraocular lenses sustained significantly less adherent bacteria than unmodified PMMA lenses, and that the chromatogram of structural fatty acids of only the S. epidermidis adherent to heparin modified PMMA changed (133). Because neither of these investigators thoroughly characterized their heparin modified surfaces, the difference in their results could easily be explained by the notorious heterogeneity of the heparin molecular weight, bioactivity, or surface coverage on these polymers.

Heparins from porcine and bovine intestinal mucosa: Are they similar drugs?

PubMed

Aquino, Rafael S; Pereira, Mariana S; Vairo, Bruno C; Cinelli, Leonardo P; Santos, Gustavo R C; Fonseca, Roberto J C; Mourão, Paulo A S

2010-05-01

Increasing reports of bleeding and peri- or post-operative blood dyscrasias in Brazil were possibly associated with the use of heparin from bovine instead of porcine intestine. These two pharmaceutical grade heparins were analysed for potential differences. NMR analyses confirmed that porcine heparin is composed of mainly trisulfated disaccharides -->4-alpha-IdoA2S-1-->4-alpha-GlcNS6S-1-->. Heparin from bovine intestine is also composed of highly 2-sulfated alpha-iduronic acid residues, but the sulfation of the alpha-glucosamine units vary significantly: approximately 50% are 6- and N -disulfated, as in porcine heparin, while approximately 36% are 6-desulfated and approximately 14% N -acetylated. These heparins differ significantly in their effects on coagulation, thrombosis and bleeding. Bovine heparin acts mostly through factor Xa. Compared to porcine heparin on a weight basis, bovine heparin exhibited approximately half of the anticoagulant and antithrombotic effects, but similar effect on bleeding. These two heparins also differ in their protamine neutralisation curves. The doses of heparin from bovine intestine required for effective antithrombotic protection and the production of adverse bleeding effects are closer than those for porcine heparin. This observation may explain the increasing bleeding observed among Brazilian patients. Our results suggest that these two types of heparin are not equivalent drugs.

Addressing endotoxin issues in bioengineered heparin.

PubMed

Suwan, Jiraporn; Torelli, Amanda; Onishi, Akihiro; Dordick, Jonathan S; Linhardt, Robert J

2012-01-01

Heparin is a widely used clinical anticoagulant that is prepared from pig intestine. A contamination of heparin in 2008 has led to a reexamination of animal-derived pharmaceuticals. A bioengineered heparin prepared by bacterial fermentation and chemical and enzymatic processing is currently under development. This study examines the challenges of reducing or removing endotoxins associated with this process that are necessary to proceed with preclinical in vivo evaluation of bioengineered heparin. The current process is assessed for endotoxin levels, and strategies are examined for endotoxin removal from polysaccharides and enzymes involved in this process. © 2012 International Union of Biochemistry and Molecular Biology, Inc.

PF4/heparin antibody testing and treatment of heparin-induced thrombocytopenia in the intensive care unit.

PubMed

Wanat, Matthew; Fitousis, Kalliopi; Hall, Jeff; Rice, Lawrence

2013-06-01

The diagnosis of heparin-induced thrombocytopenia (HIT) may be challenging in critically ill patients, as heparin exposures are ubiquitous, and thrombocytopenia is common. Unwarranted ordering and incorrect interpretation of heparin antibody tests can expose a patient to adverse drug events and imposes a significant economic burden on our health care system. A prospective, observational study was performed over 4 months on all adult patients located in 5 intensive care units, with a heparin antibody test ordered. A platelet factor 4/heparin enzyme-linked immunosorbent assay (ELISA) test was ordered in 131 patients. In total, 110 patients had a low 4Ts score (0-3), and of these 103 had a negative ELISA result. In patients with a low 4Ts score, 0 (0%) of 110 had an optical density value >1.0. One hundred twenty-nine patients (98%) had another possible cause of thrombocytopenia identified. In critically ill patients, low 4Ts scores indicate a low probability of HIT, and heparin antibody testing in these patients is not useful.

A comparative analysis of warfarin and low-dose heparin as thromboembolism prophylaxis in total hip replacement patinets.

PubMed Central

Ritter, M A; HamiltonCW

1975-01-01

Warfarin, low-dose heparin, or a combination of low-dose heparin and hydrocortisone was administered to 300 patients undergoing total hip replacement. The lowest incidence of thromboembolic (5 per cent) was attained with Warfarin. Further investigation into the method of administration of low-dose heparin is necessary before it can be used effectively as thromboembolism prophylaxis in total hip replacement patients. The addition of hydrocortisone was not found useful. PMID:1138642

Foam fractionation as a tool to study the air-water interface structure-function relationship of wheat gluten hydrolysates.

PubMed

Wouters, Arno G B; Rombouts, Ine; Schoebrechts, Nele; Fierens, Ellen; Brijs, Kristof; Blecker, Christophe; Delcour, Jan A

2017-03-01

Enzymatic hydrolysis of wheat gluten protein improves its solubility and produces hydrolysates with foaming properties which may find applications in food products. First, we here investigated whether foam-liquid fractionation can concentrate wheat gluten peptides with foaming properties. Foam and liquid fractions had high and very low foam stability (FS), respectively. In addition, foam fractions were able to decrease surface tension more pronouncedly than un-fractionated samples and liquid fractions, suggesting they are able to arrange themselves more efficiently at an interface. As a second objective, foam fractionation served as a tool to study the structural properties of the peptides, causing these differences in air-water interfacial behavior. Zeta potential and surface hydrophobicity measurements did not fully explain these differences but suggested that hydrophobic interactions at the air-water interface are more important than electrostatic interactions. RP-HPLC showed a large overlap between foam and liquid fractions. However, a small fraction of very hydrophobic peptides with relatively high average molecular mass was clearly enriched in the foam fraction. These peptides were also more concentrated in un-fractionated DH 2 hydrolysates, which had high FS, than in DH 6 hydrolysates, which had low FS. These peptides most likely play a key role in stabilizing the air-water interface. Copyright © 2016 Elsevier B.V. All rights reserved.

Simultaneous determination of Ca, Cu, Ni, Zn and Cd binding strengths with fulvic acid fractions by Schubert's method

USGS Publications Warehouse

Brown, G.K.; MacCarthy, P.; Leenheer, J.A.

1999-01-01

The equilibrium binding of Ca2+, Ni2+, Cd2+, Cu2+ and Zn2+ with unfractionated Suwannee river fulvic acid (SRFA) and an enhanced metal binding subfraction of SRFA was measured using Schubert's ion-exchange method at pH 6.0 and at an ionic strength (??) of 0.1 (NaNO3). The fractionation and subfractionation were directed towards obtaining an isolate with an elevated metal binding capacity or binding strength as estimated by Cu2+ potentiometry (ISE). Fractions were obtained by stepwise eluting an XAD-8 column loaded with SRFA with water eluents of pH 1.0 to pH 12.0. Subfractions were obtained by loading the fraction eluted from XAD-8 at pH 5.0 onto a silica gel column and eluting with solvents of increasing polarity. Schuberts ion exchange method was rigorously tested by measuring simultaneously the conditional stability constants (K) of citric acid complexed with the five metals at pH 3.5 and 6.0. The logK of SRFA with Ca2+, Ni2+, Cd2+, Cu2+ and Zn2+ determined simultaneously at pH 6.0 follow the sequence of Cu2+>Cd2+>Ni2+>Zn2+>Ca2+ while all logK values increased for the enhanced metal binding subfraction and followed a different sequence of Cu2+>Cd2+>Ca2+>Ni2+>Zn2+. Both fulvic acid samples and citric acid exhibited a 1:1 metal to ligand stochiometry under the relatively low metal loading conditions used here. Quantitative 13C nuclear magnetic resonance spectroscopy showed increases in aromaticity and ketone content and decreases in aliphatic carbon for the elevated metal binding fraction while the carboxyl carbon, and elemental nitrogen, phosphorus, and sulfur content did not change. The more polar, elevated metal binding fraction did show a significant increase in molecular weight over the unfractionated SRFA. Copyright (C) 1999 Elsevier Science B.V.

The impact of preparation parameters on typical attributes of chitosan-heparin nanohydrogels: particle size, loading efficiency, and drug release.

PubMed

Shahbazi, Mohammad-Ali; Hamidi, Mehrdad

2013-11-01

Today, developing an optimized nanoparticle (NP) preparation procedure is of paramount importance in all nanoparticulate drug delivery researches, leading to expanding more operative and clinically validated nanomedicines. In this study, a one-at-a-time experimental approach was used for evaluating the effect of various preparation factors on size, loading, and drug release of hydrogel NPs prepared with ionotropic gelation between heparin and chitosan. The size, loading efficiency (LE) and drug release profile of the NPs were evaluated when the chitosan molecular weight, chitosan concentration, heparin addition time to chitosan solution, heparin concentration, pH value of chitosan solution, temperature, and mixing rate were changed separately while other factors were in optimum condition. The results displayed that size and LE are highly influenced by chitosan concentration, getting an optimum of 63 ± 0.57 and 75.19 ± 2.65, respectively, when chitosan concentration was 0.75 mg/ml. Besides, heparin addition time of 3 min leaded to 74.1 ± 0.79 % LE with no sensible effect on size and release profile. In addition, pH 5.5 showed a minimum size of 63 ± 1.87, maximum LE of 73.81 ± 3.13 and the slowest drug release with 63.71 ± 3.84 % during one week. Although LE was not affected by temperature, size and release reduced to 63 ± 0 and 74.21 ± 1.99% when temperature increased from 25°C to 55°C. Also, continuous increase of mixer rate from 500 to 3500 rpm resulted in constant enhancement of LE from 58.3 ± 3.6 to 74.4 ± 2.59 as well as remarkable decrease in size from 148 ± 4.88 to 63 ± 2.64.

The role of the pharmacy technician in the skill-mixed district nursing team.

PubMed

McGraw, Caroline; Coleman, Bridget; Ashman, Lea; Hayes, Sarah

2012-09-01

Registered nurses in the district nursing service delegate a broad range of medication administration activities to healthcare assistants. Although healthcare assistants have provided extra capacity, not all activities are suitable for delegation to unregulated practitioners. At the same time, their competency assessment is often patient-specific and demands significant registered nursing input. The purpose of this 6-month pilot programme was to test the premise that the employment of a pharmacy technician in the district nursing service would enhance productivity levels and deliver cost savings. Activities delegated included the administration of oral tablets and subcutaneous insulin and low molecular weight heparin injections. The evaluation found that the introduction of the pharmacy technician was associated with neither enhanced productivity nor more than modest cost savings. However, role redesign is a long-term activity and their role could be built on with further competency analysis.

Engineering the mechanical and biological properties of nanofibrous vascular grafts for in situ vascular tissue engineering.

PubMed

Henry, Jeffrey J D; Yu, Jian; Wang, Aijun; Lee, Randall; Fang, Jun; Li, Song

2017-08-17

Synthetic small diameter vascular grafts have a high failure rate, and endothelialization is critical for preventing thrombosis and graft occlusion. A promising approach is in situ tissue engineering, whereby an acellular scaffold is implanted and provides stimulatory cues to guide the in situ remodeling into a functional blood vessel. An ideal scaffold should have sufficient binding sites for biomolecule immobilization and a mechanical property similar to native tissue. Here we developed a novel method to blend low molecular weight (LMW) elastic polymer during electrospinning process to increase conjugation sites and to improve the mechanical property of vascular grafts. LMW elastic polymer improved the elasticity of the scaffolds, and significantly increased the amount of heparin conjugated to the micro/nanofibrous scaffolds, which in turn increased the loading capacity of vascular endothelial growth factor (VEGF) and prolonged the release of VEGF. Vascular grafts were implanted into the carotid artery of rats to evaluate the in vivo performance. VEGF treatment significantly enhanced endothelium formation and the overall patency of vascular grafts. Heparin coating also increased cell infiltration into the electrospun grafts, thus increasing the production of collagen and elastin within the graft wall. This work demonstrates that LMW elastic polymer blending is an approach to engineer the mechanical and biological property of micro/nanofibrous vascular grafts for in situ vascular tissue engineering.

Expert panel evaluation of health information technology effects on adverse events.

PubMed

Abramson, Erika L; Kern, Lisa M; Brenner, Samantha; Hufstader, Meghan; Patel, Vaishali; Kaushal, Rainu

2014-08-01

Adverse events (AEs) among hospitalized patients occur frequently and result in significant sequelae. Federal policy is incentivizing health information technology (HIT) use, although research demonstrating safety benefits from HIT is mixed. Our objective was to evaluate the potential effects of HIT on reducing 21 different inpatient AEs. Identifying AEs most likely to be reduced by HIT can inform the design of future studies evaluating its effectiveness. We conducted a modified Delphi panel of national experts in HIT and safety. We conducted a focused literature review to inform the experts. Using a novel framework, experts rated each AE as 'definitely reduced by health IT,' 'possibly reduced by health IT' and 'not likely to be reduced by health IT'. From our panel discussion, experts identified six AEs as 'definitely reduced by health IT': (1) adverse drug events (ADEs) associated with digoxin; (2) ADE associated with IV heparin; (3) ADE associated with hypoglycaemic agents; (4) ADE associated with low molecular weight heparin and factor Xa inhibitor; (5) contrast nephropathy associated with catheter angiography; and (6) ADE hospital-acquired antibiotic-associated Clostridium difficile. Understanding the effects of HIT on patient outcomes will be essential to ensuring that the significant federal investment results in anticipated improvements. This study serves as an important early step in helping with the design of future work evaluating level of HIT infrastructure and rates of inpatient AEs. © 2014 John Wiley & Sons, Ltd.

Coagulation Testing in the Core Laboratory.

PubMed

Winter, William E; Flax, Sherri D; Harris, Neil S

2017-11-08

Primary hemostasis begins with endothelial injury. VWF, produced by endothelial cells, binds to platelets and links them to subendothelial collagen. Platelet-derived ADP and thromboxane activate non-adhered platelets via their GPIIb/IIIa receptors, allowing these platelets to participate in platelet aggregation. Secondary hemostasis is initiated with the binding of factor VII to extravascular tissue factor (TF). Factors II, VII, IX and X are vitamin K-dependent factors. The role of vitamin K is to assist in the addition of gamma carboxylate groups to glutamic acids in the "GLA" domains of these factors.In vitro the intrinsic pathway is initiated when fresh whole blood is placed in a glass tube. The negative charge of the glass initiates the "contact pathway" where FXII is activated and then FXIa cleaves FIX to FIXa. The extrinsic pathway is triggered when tissue factor, phospholipid and calcium are added to plasma anticoagulated with citrate. In vitro, FVII is activated to FVIIa, and TF-FVIIa preferentially converts FX to FXa activating the common pathway.The prothrombin time is commonly used to monitor warfarin anticoagulant therapy. To correct for differences in reagent and instrument, the international normalized ratio was developed to improve standardization of PT reporting globally. The activated partial thromboplastin time (aPTT) is used to evaluate the intrinsic and common pathways of coagulation. The aPTT is useful clinically as a screening test for inherited and acquired factor deficiencies as well as to monitor unfractionated heparin therapy although the anti-Xa assay is now the preferred measure of the effects of unfractionated heparin. The Clauss assay is the most commonly performed fibrinogen assay and uses diluted plasma where clotting is initiated with a high concentration of reagent thrombin.The mixing study assists in the assessment of an abnormally prolonged PT or aPTT. An equal volume of citrated patient plasma is mixed with normal pooled plasma and the PT or aPTT are repeated on the 1:1 mix. Factor activity assays are most commonly performed as a one-stage assay. The patient's citrated plasma is diluted and mixed 1-to-1 with a single factor-deficient substrate plasma. A PT or aPTT is performed on the above mix, depending on the factor being tested.Factor inhibitors are antibodies that are most commonly diagnosed in male patients with severe hemophilia A (FVIII deficiency) where they are induced by factor replacement therapy.Factor inhibitors can also appear in the form of spontaneous autoantibodies in both male and female individuals who were previously well. This is an autoimmune condition called "acquired hemophilia."Most coagulation laboratories can measure the plasma concentration of VWF protein (VWF antigen) by an immunoturbidimetric technique. Testing the functional activity of VWF, utilizes the drug ristocetin.The state of multimerization of VWF is important and is assessed by electrophoresis on agarose gels. Type 2a and 2b VWD are associated with the lack of intermediate- and high molecular weight multimers.The antiphospholipid syndrome (APLS) is an acquired autoimmune phenomenon associated with an increased incidence of both venous and arterial thromboses, as well as fetal loss. Typically, there is a paradoxical prolongation of the aPTT in the absence of any clinical features of bleeding. This is the so-called "lupus anticoagulant (LA) effect." The laboratory definition of the APLS requires the presence of either a "lupus anticoagulant" or a persistent titer of antiphospholipid antibodies.There are now 2 broad classes of direct-acting oral anticoagulants (DOACs): [1] The oral direct thrombin inhibitors (DTIs) such as dabigatran; and [2] The oral direct factor Xa inhibitors such as rivaroxaban and apixaban. The PT and aPTT are variably affected by the DOACs and are generally unhelpful in monitoring their concentrations. Most importantly, a normal PT or aPTT does NOT exclude the presence of any of the DOACs. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Treatment of pregnancy-associated venous thromboembolism - position paper from the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH).

PubMed

Linnemann, Birgit; Scholz, Ute; Rott, Hannelore; Halimeh, Susan; Zotz, Rainer; Gerhardt, Andrea; Toth, Bettina; Bauersachs, Rupert

2016-01-01

Venous thromboembolism (VTE) is a major cause of maternal morbidity during pregnancy and the postpartum period. However, because there is a lack of adequate study data, management strategies for pregnancy-associated VTE must be deduced from observational stu-dies and extrapolated from recommendations for non-pregnant patients. In this review, the members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH) have summarised the evidence that is currently available in the literature to provide a practical approach for treating pregnancy-associated VTE. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low molecular weight heparin (LMWH) is the anticoagulant treatment of choice in cases of acute VTE during pregnancy. No differences between once and twice daily LMWH dosing regimens have been reported, but twice daily dosing seems to be advisable, at least peripartally. It remains unclear whether determining dose adjustments according to factor Xa activities during pregnancy provides any benefit. Management of delivery deserves attention and mainly depends on the time interval between the diagnosis of VTE and the expected delivery date. In particular, if VTE manifests at term, delivery should be attended by an experienced multidisciplinary team. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months. Although recommendations are provided for the treatment of pregnancy-associated VTE, there is an urgent need for well-designed prospective studies that compare different management strategies and define the optimal duration and intensity of anticoagulant treatment.

Effect of buffer at nanoscale molecular recognition interfaces - electrostatic binding of biological polyanions.

PubMed

Rodrigo, Ana C; Laurini, Erik; Vieira, Vânia M P; Pricl, Sabrina; Smith, David K

2017-10-19

We investigate the impact of an over-looked component on molecular recognition in water-buffer. The binding of a cationic dye to biological polyanion heparin is shown by isothermal calorimetry to depend on buffer (Tris-HCl > HEPES > PBS). The heparin binding of self-assembled multivalent (SAMul) cationic micelles is even more buffer dependent. Multivalent electrostatic molecular recognition is buffer dependent as a result of competitive interactions between the cationic binding interface and anions present in the buffer.

Emissive H-Aggregates of an Ultrafast Molecular Rotor: A Promising Platform for Sensing Heparin.

PubMed

Mudliar, Niyati H; Singh, Prabhat K

2016-11-23

Constructing "turn on" fluorescent probes for heparin, a most widely used anticoagulant in clinics, from commercially available materials is of great importance, but remains challenging. Here, we report the formation of a rarely observed emissive H-aggregate of an ultrafast molecular rotor dye, Thioflavin-T, in the presence of heparin, which provides an excellent platform for simple, economic and rapid fluorescence turn-on sensing of heparin. Generally, H-aggregates are considered as serious problem in the field of biomolecular sensing, owing to their poorly emissive nature resulting from excitonic interaction. To the best of our knowledge, this is the first report, where contrastingly, the turn-on emission from the H-aggregates has been utilized in the biomolecule sensing scheme, and enables a very efficient and selective detection of a vital biomolecule and a drug with its extensive medical applications, i.e., heparin. Our sensor system offers several advantages including, emission in the biologically advantageous red-region, dual sensing, i.e., both by fluorimetry and colorimetry, and most importantly constructed from in-expensive commercially available dye molecule, which is expected to impart a large impact on the sensing field of heparin. Our system displays good performance in complex biological media of serum samples. The novel Thioflavin-T aggregate emission could be also used to probe the interaction of heparin with its only clinically approved antidote, Protamine.

Synthesis and structural study of two new heparin-like hexasaccharides.

PubMed

Lucas, Ricardo; Angulo, Jesús; Nieto, Pedro M; Martín-Lomas, Manuel

2003-07-07

Two new heparin-like hexasaccharides, 5 and 6, have been synthesised using a convergent block strategy and their solution conformations have been determined by NMR spectroscopy and molecular modelling. Both hexasaccharides contain the basic structural motif of the regular region of heparin but with negative charge distributions which have been designed to get insight into the mechanism of fibroblast growth factors (FGFs) activation.

Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF Study.

PubMed

Paciaroni, Maurizio; Agnelli, Giancarlo; Falocci, Nicola; Caso, Valeria; Becattini, Cecilia; Marcheselli, Simona; Rueckert, Christina; Pezzini, Alessandro; Poli, Loris; Padovani, Alessandro; Csiba, Laszló; Szabó, Lilla; Sohn, Sung-Il; Tassinari, Tiziana; Abdul-Rahim, Azmil H; Michel, Patrik; Cordier, Maria; Vanacker, Peter; Remillard, Suzette; Alberti, Andrea; Venti, Michele; Scoditti, Umberto; Denti, Licia; Orlandi, Giovanni; Chiti, Alberto; Gialdini, Gino; Bovi, Paolo; Carletti, Monica; Rigatelli, Alberto; Putaala, Jukka; Tatlisumak, Turgut; Masotti, Luca; Lorenzini, Gianni; Tassi, Rossana; Guideri, Francesca; Martini, Giuseppe; Tsivgoulis, Georgios; Vadikolias, Kostantinos; Liantinioti, Chrissoula; Corea, Francesco; Del Sette, Massimo; Ageno, Walter; De Lodovici, Maria Luisa; Bono, Giorgio; Baldi, Antonio; D'Anna, Sebastiano; Sacco, Simona; Carolei, Antonio; Tiseo, Cindy; Acciarresi, Monica; D'Amore, Cataldo; Imberti, Davide; Zabzuni, Dorjan; Doronin, Boris; Volodina, Vera; Consoli, Domenico; Galati, Franco; Pieroni, Alessio; Toni, Danilo; Monaco, Serena; Baronello, Mario Maimone; Barlinn, Kristian; Pallesen, Lars-Peder; Kepplinger, Jessica; Bodechtel, Ulf; Gerber, Johannes; Deleu, Dirk; Melikyan, Gayane; Ibrahim, Faisal; Akhtar, Naveed; Mosconi, Maria Giulia; Bubba, Valentina; Silvestri, Ilenia; Lees, Kennedy R

2015-08-01

The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke. The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke. Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30-0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively (P=0.003). Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants. © 2015 American Heart Association, Inc.

Cost-effectiveness of apixaban versus low molecular weight heparin/vitamin k antagonist for the treatment of venous thromboembolism and the prevention of recurrences.

PubMed

Lanitis, Tereza; Leipold, Robert; Hamilton, Melissa; Rublee, Dale; Quon, Peter; Browne, Chantelle; Cohen, Alexander T

2017-01-23

Prior analyses beyond clinical trials are yet to evaluate the projected lifetime benefit of apixaban treatment compared to low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) for treatment of venous thromboembolism (VTE) and prevention of recurrences. The objective of this study is to assess the cost-effectiveness of initial plus extended treatment with apixaban versus LMWH/VKA for either initial treatment only or initial plus extended treatment. A Markov cohort model was developed to evaluate the lifetime clinical and economic impact of treatment of VTE and prevention of recurrences with apixaban (starting at 10 mg BID for 1 week, then 5 mg BID for 6 months, then 2.5 mg BID for an additional 12 months) versus LMWH/VKA for 6 months and either no further treatment or extended treatment with VKA for an additional 12 months. Clinical event rates to inform the model were taken from the AMPLIFY and AMPLIFY-EXT trials and a network meta-analysis. Background mortality rates, costs, and utilities were obtained from published sources. The analysis was conducted from the perspective of the United Kingdom National Health Service. The evaluated outcomes included the number of events avoided in a 1000-patient cohort, total costs, life-years, quality-adjusted life-years (QALYs), and cost per QALY gained. Initial plus extended treatment with apixaban was superior to both treatment durations of LMWH/VKA in reducing the number of bleeding events, and was superior to initial LMWH/VKA for 6 months followed by no therapy, in reducing VTE recurrences. Apixaban treatment was cost-effective compared to 6-month treatment with LMWH/VKA at an incremental cost-effectiveness ratio (ICER) of £6692 per QALY. When initial LMWH/VKA was followed by further VKA therapy for an additional 12 months (i.e., total treatment duration of 18 months), apixaban was cost-effective at an ICER of £8528 per QALY gained. Sensitivity analysis suggested these findings were robust over a wide range of inputs and scenarios for the model. In the UK, initial plus extended treatment with apixaban for treatment of VTE and prevention of recurrences appears to be economical and a clinically effective alternative to LMWH/VKA, whether used for initial or initial plus extended treatment.

Effect of low molecular weight heparin (enoxaparin) on congenital cataract surgery.

PubMed

Caça, Ihsan; Sahin, Alparslan; Cingü, Abdullah Kürsat; Ari, Seyhmus; Alakuş, Fuat; Cinar, Yasin

2012-01-01

To assess the efficacy of intracameral enoxaparin (a low-molecular-weight heparin) infusion, in variable doses on postoperative inflammatory response in congenital cataract surgery. It is a prospective, randomized controlled trial. Eighty eyes of 53 children with congenital cataract were enrolled in this study. Every eye had primary posterior capsulorrhexis and intraocular lens (IOL) implantation after lens aspiration. The eyes were divided into 4 equal groups. In group 1 balanced salt solution (BSS) without enoxaparin was used as an irrigation solution. Whereas in group 2, 3 and 4, 40mg, 20mg and 10mg enoxaparin in 500mL BSS was used respectively. The inflammatory response in the anterior chamber was compared among the groups with slit-lamp biomicroscopy. The mean follow-up period was (17.75±3.95) months in group 1, (18.00±5.15) months in group 2, (19.20±5.47) months in group 3 and (18.65±5.16) months in group 4. Mean number of inflammatory cells in the anterior chamber in group 1 was significantly higher than that of group 2, 3, 4 (P<0.001). There was fibrin formation in the anterior chambers of 3 eyes in group 1 and one eye in group 4. There was synechiae formation in 3 eyes of group 1 and one eye of group 4. There was no significant difference among the groups by means of fibrin or synechiae formation (P>0.05). There were IOL precipitates in 4 eyes of group 1 and 2 eyes of group 4. IOL precipitate formation was significantly higher in group 1 than that of group 2 and 3 in which there was no IOL precipitate (P=0.048). There was IOL subluxation in only one eye of group 1, 3 and 4 while no subluxation was observed in group 2 (P>0.05). There was no statistically significant difference detected about IOL subluxation occurance in all 4 groups (P>0.05). Complications of cataract surgery in congenital cataract patients associated with postoperative inflammatory response found to be decreased with the use of enoxaparin in intraocular infusion solutions. Furthermore according to our results the anti-inflammatory effect of enoxaparin was dose dependant.

Effect of low molecular weight heparin (enoxaparin) on congenital cataract surgery

PubMed Central

Çaça, Ihsan; Şahin, Alparslan; Cingü, Abdullah Kürsat; Ari, Şeyhmus; Alakuş, Fuat; Çinar, Yasin

2012-01-01

AIM To assess the efficacy of intracameral enoxaparin (a low-molecular-weight heparin) infusion, in variable doses on postoperative inflammatory response in congenital cataract surgery. METHODS It is a prospective, randomized controlled trial. Eighty eyes of 53 children with congenital cataract were enrolled in this study. Every eye had primary posterior capsulorrhexis and intraocular lens (IOL) implantation after lens aspiration. The eyes were divided into 4 equal groups. In group 1 balanced salt solution (BSS) without enoxaparin was used as an irrigation solution. Whereas in group 2, 3 and 4, 40mg, 20mg and 10mg enoxaparin in 500mL BSS was used respectively. The inflammatory response in the anterior chamber was compared among the groups with slit-lamp biomicroscopy. RESULTS The mean follow-up period was (17.75±3.95) months in group 1, (18.00±5.15) months in group 2, (19.20±5.47) months in group 3 and (18.65±5.16) months in group 4. Mean number of inflammatory cells in the anterior chamber in group 1 was significantly higher than that of group 2, 3, 4 (P<0.001). There was fibrin formation in the anterior chambers of 3 eyes in group 1 and one eye in group 4. There was synechiae formation in 3 eyes of group 1 and one eye of group 4. There was no significant difference among the groups by means of fibrin or synechiae formation (P>0.05). There were IOL precipitates in 4 eyes of group 1 and 2 eyes of group 4. IOL precipitate formation was significantly higher in group 1 than that of group 2 and 3 in which there was no IOL precipitate (P=0.048). There was IOL subluxation in only one eye of group 1, 3 and 4 while no subluxation was observed in group 2 (P>0.05). There was no statistically significant difference detected about IOL subluxation occurance in all 4 groups (P>0.05). CONCLUSION Complications of cataract surgery in congenital cataract patients associated with postoperative inflammatory response found to be decreased with the use of enoxaparin in intraocular infusion solutions. Furthermore according to our results the anti-inflammatory effect of enoxaparin was dose dependant. PMID:23166871

Emergent Triglyceride-lowering Therapy With Early High-volume Hemofiltration Against Low-Molecular-Weight Heparin Combined With Insulin in Hypertriglyceridemic Pancreatitis: A Prospective Randomized Controlled Trial.

PubMed

He, Wen-Hua; Yu, Min; Zhu, Yin; Xia, Liang; Liu, Pi; Zeng, Hao; Zhu, Yong; Lv, Nong-Hua

2016-10-01

To compare the value of emergent triglyceride (TG)-lowering therapies between early high-volume hemofiltration (HVHF) and low-molecular-weight heparin (LMWH) combined with insulin (LMWH+insulin) as well as their effects on the outcomes of hypertriglyceridemic pancreatitis (HTGP) patients. In this randomized controlled trial, 66 HTGP patients presenting within 3 days after the onset of symptoms from August 2011 to October 2013 were assigned randomly to receive either HVHF or LMWH+insulin as an emergent TG-lowering therapy. Thirty-three patients were included in each group, and the therapy was started as soon as possible after admission. TG levels, clinical outcomes, and inflammatory biomarkers were compared between the 2 groups. Thirty-two individuals in the HVHF group and 34 in the LMWH+insulin group were included in the final analysis. Characteristics of the patients in both groups were roughly comparable. HVHF could remove TG from the plasma and achieve its target (<500 mg/dL) in approximately 9 hours, whereas the target was not achieved within 48 hours in patients receiving the LMWH+insulin treatment (P<0.05). However, no differences were found in terms of the majority of the clinical outcomes, including local pancreatic complications (P>0.05), the requirement of surgical intervention (P=0.49), mortality (P=0.49), and the duration of hospitalization (P=0.144). Furthermore, an unexpectedly higher incidence of persistent organ failure was observed in the HVHF group compared with the LMWH+insulin group (risk ratio with HVHF, 2.42; 95% confidence interval, 1.15-5.11; P=0.01). Hospital charges for patients in the HVHF group were approximately 2-fold higher than those for patients in the LMWH+insulin group (5.20±4.90 vs. 2.92±3.21, P=0.03). We selected a systemic inflammatory response syndrome score of at least 2 at baseline as a predictor of SAP patients, and the subgroup analyses showed that HVHF cannot improve the prognosis of the predicted SAP patients compared with the LMWH+insulin group. HVHF can lower TG levels more efficiently than LMWH+insulin therapy, but it is not superior in terms of clinical outcomes and costs. Further multicenter studies with large samples are required to clarify the feasibility of administering the HVHF treatment to HTGP patients (ChiCTR-TRC-13003274).

Polyguluronate sulfate, polymannuronate sulfate, and their oligosaccharides have antithrombin III- and heparin cofactor II-independent anticoagulant activity

NASA Astrophysics Data System (ADS)

Zeng, Xuan; Lan, Ying; Zeng, Pengjiao; Guo, Zhihua; Hao, Cui; Zhang, Lijuan

2017-04-01

Cardiovascular disease is the leading causes of death. However, the complications can be treated with heparin and heparinoids, such as heparin pentasaccharide Fondaparinux, dermatan sulfate, and PSS made from alginate extracted from brown seaweeds by chemical sulfation. Alginate is composed of a linear backbone of polymannuronate (PM), polyguluronate (PG), and alternate residues of mannuronic acid and guluronic acid. It is unknown if heparin and sulfated PG (PGS)/PM (PMS) have the same or different anticoagulant molecular targets. In the current study, the anticoagulant activities of PGS, PMS, and their oligosaccharides were directly compared to that of heparin, Fondaparinux, and dermatan sulfate by the activated partial thrombinplastin time (aPTT) assay using normal, antithrombin III (ATIII)-deficient, heparin co-factor II (HCII)-deficient, and ATIII- and HCII-double deficient human plasmas. Our results showed that PGS, PMS, and their oligosaccharides had better anticoagulant activity than that of Fondaparinux in all four human plasmas tested. As expected, heparin was the best anticoagulant in normal plasma. Moreover, PGS, PGS6, PGS12, PGS25, PMS6, PMS12, and PMS25 were better anticoagulants than dermatan sulfate in HCII-deficient plasma. Most strikingly, PGS, PGS12, PGS25, PMS6, PMS12, and PMS25 were better anticoagulants than that of heparin in ATIII- and HCII-double deficient human plasma. The results revealed for the first time that sulfated alginate had ATIII- and HCII-independent anticoagulant activities. Therefore, developing PGS and PMS-based anticoagulants might require to discover their major molecular targets and to develop target-specific anticoagulant assays.