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Sample records for plasma thrombin generation

  1. Thrombin generation in rheumatoid arthritis: dependence on plasma factor composition.

    PubMed

    Undas, Anetta; Gissel, Matthew; Kwasny-Krochin, Beata; Gluszko, Piotr; Mann, Kenneth G; Brummel-Ziedins, Kathleen E

    2010-08-01

    Growing evidence indicates that rheumatoid arthritis (RA) is associated with an increased risk for thromboembolic cardiovascular events. We investigated thrombin generation profiles in RA patients and their dependence on plasma factor/inhibitor composition. Plasma factor (F) compositions (II, V, VII, VIII, IX, X), antithrombin and free tissue factor pathway inhibitor (TFPI) from 46 consecutive RA patients with no cardiovascular events (39 female, 7 male, aged 57 [range, 23-75] years; DAS28 [Disease Activity Score] 5.2 +/- 1.1) were compared with those obtained in age- and sex-matched apparently healthy controls. Using each individual's plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed both computationally and empirically. RA patients had higher fibrinogen (4.18 [IQR 1.09] vs. 2.56 [0.41] g/l, p<0.0001), FVIII (226 +/- 40 vs. 113 +/- 15%, p<0.001), PC (107 [16] vs. 100 [14]%, p<0.001), and free TFPI levels (22.3 [2.2] vs. 14.7 [2.1] ng/ml, p<0.001). DAS28, but not age, RA duration, or C-reactive protein, was associated with FV, FVIII, FIX, FX, antithrombin, and free TFPI (r from 0.27 to 0.48, p<0.05). Intergroup comparison of computational thrombin generation profiles showed that in RA patients, maximum thrombin levels (p=0.01) and the rate of thrombin formation (p<0.0001) were higher, whereas the initiation phase of thrombin generation (p<0.0001) and the time to maximum thrombin levels (p<0.0001) were longer. Empirical reconstructions of the populations reproduced the thrombin generation profiles generated by the computational model. Simulations of thrombin formation suggest that blood plasma composition, i.e. a marked increase in FVIII, somewhat counterbalanced by free TFPI, contributes to the prothrombotic phenotype in RA patients.

  2. Calibrated automated thrombin generation measurement in clotting plasma.

    PubMed

    Hemker, H Coenraad; Giesen, Peter; Al Dieri, Raed; Regnault, Véronique; de Smedt, Eric; Wagenvoord, Rob; Lecompte, Thomas; Béguin, Suzette

    2003-01-01

    Calibrated automated thrombography displays the concentration of thrombin in clotting plasma with or without platelets (platelet-rich plasma/platelet-poor plasma, PRP/PPP) in up to 48 samples by monitoring the splitting of a fluorogenic substrate and comparing it to a constant known thrombin activity in a parallel, non-clotting sample. Thus, the non-linearity of the reaction rate with thrombin concentration is compensated for, and adding an excess of substrate can be avoided. Standard conditions were established at which acceptable experimental variation accompanies sensitivity to pathological changes. The coefficients of variation of the surface under the curve (endogenous thrombin potential) are: within experiment approximately 3%; intra-individual: <5% in PPP, <8% in PRP; interindividual 15% in PPP and 19% in PRP. In PPP, calibrated automated thrombography shows all clotting factor deficiencies (except factor XIII) and the effect of all anticoagulants [AVK, heparin(-likes), direct inhibitors]. In PRP, it is diminished in von Willebrand's disease, but it also shows the effect of platelet inhibitors (e.g. aspirin and abciximab). Addition of activated protein C (APC) or thrombomodulin inhibits thrombin generation and reflects disorders of the APC system (congenital and acquired resistance, deficiencies and lupus antibodies) independent of concomitant inhibition of the procoagulant pathway as for example by anticoagulants. Copyright 2003 S. Karger AG, Basel

  3. Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I).

    PubMed

    de Bosch, N B; Mosesson, M W; Ruiz-Sáez, A; Echenagucia, M; Rodriguez-Lemoin, A

    2002-08-01

    The adsorption of thrombin to fibrin during clotting defines "Antithrombin I" activity. We confirmed that thrombin generation in afibrinogenemic or in Reptilase defibrinated normal plasma was higher than in normal plasma. Repletion of these fibrinogen-deficient plasmas with fibrinogen 1 (gamma A/gamma A), whose fibrin has two "low affinity" non-substrate thrombin binding sites, resulted in moderately reduced thrombin generation by 29-37%. Repletion with fibrinogen 2 (gamma'/gamma A), which in addition to low affinity thrombin-binding sites in fibrin, has a "high affinity" non-substrate thrombin binding site in the carboxy-terminal region of its gamma' chain, was even more effective and reduced thrombin generation by 57-67%. Adding peptides that compete for thrombin binding to fibrin [S-Hir53-64 (hirugen) or gamma'414-427] caused a transient delay in the onset of otherwise robust thrombin generation, indicating that fibrin formation is necessary for full expression of Antithrombin I activity. Considered together, 1) the increased thrombin generation in afibrinogenemic or fibrinogen-depleted normal plasma that is mitigated by fibrinogen replacement; 2) evidence that prothrombin activation is increased in afibrinogenemia and normalized by fibrinogen replacement; 3) the severe thrombophilia that is associated with defective thrombin-binding in dysfibrinogenemias Naples I and New York I, and 4) the association of afibrinogenemia or hypofibrinogenemia with venous or arterial thromboembolism, indicate that Antithrombin I (fibrin) modulates thromboembolic potential by inhibiting thrombin generation in blood.

  4. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition.

    PubMed

    Brummel-Ziedins, K; Undas, A; Orfeo, T; Gissel, M; Butenas, S; Zmudka, K; Mann, K G

    2008-01-01

    Acute coronary syndrome (ACS) is associated with thrombin formation, triggered by ruptured or eroded coronary atheroma. We investigated whether thrombin generation based on circulating coagulation protein levels, could distinguish between acute and stable coronary artery disease (CAD). Plasma coagulation factor (F) compositions from 28 patients with ACS were obtained after onset of chest pain. Similar data were obtained from 25 age- and sex-matched patients with stable CAD. All individuals took aspirin. Patients on anticoagulant therapy were excluded. The groups were similar in demographic characteristics, comorbidities and concomitant treatment. Using each individual's coagulation protein composition, tissue factor (TF) initiated thrombin generation was assessed both computationally and empirically. TF pathway inhibitor (TFPI), antithrombin (AT), factor II (FII) and FVIII differed significantly (P < 0.01) between the groups, with levels of FII, FVIII and TFPI higher and AT lower in ACS patients. When thrombin generation profiles from individuals in each group were compared, simulated maximum thrombin levels (P < 0.01) and rates (P < 0.01) were 50% higher with ACS while the initiation phases of thrombin generation were shorter. Empirical reconstructions of the populations reproduced the thrombin generation profiles generated by the computational model. The differences between the thrombin generation profiles for each population were primarily dependent upon the collective contribution of AT, FII and FVIII. Simulations of thrombin formation based on plasma composition can discriminate between acute and stable CAD.

  5. The effect of plasma antithrombin concentration on thrombin generation and fibrin gel structure.

    PubMed

    Elgue, G; Sanchez, J; Fatah, K; Olsson, P; Blombäck, B

    1994-07-15

    Congenital deficiency of antithrombin (AT) is associated with thrombotic events and AT consumption occurs in some severe disorders and after treatment with heparin. The aim of this study was to investigate whether variations in the level of plasma AT modify thrombin generation and the fibrin formation process after the intrinsic coagulation mechanism is triggered. Normal plasma was depleted of AT by immunoadsorption on CNBr-Sepharose coupled with the anti-AT-IgG fraction of antiserum. The AT-depleted plasma was reconstituted with AT (between 0.3 and 1.5 AT units per ml). Thrombin generation was measured as the development of thrombin-antithrombin complexes (TAT). The lag phase preceding fibrin formation depended on the concentration of AT. The short lag phase was seen in completely AT-depleted plasma and the long in plasma with 1.5 AT units per ml. TAT generation, determined in parallel consecutive samples, showed that the rate at which thrombin was generated was inverse to the AT concentration in plasma. The network structure of hydrated fibrin gels in the clotted plasma was studied by measuring the wavelength dependence of gel turbidity. The mass/length ratio value, -i.e. the thickness of fiber strands and porosity of the gel increased with increasing AT concentrations. It is concluded that plasma AT regulates the rate of prothrombin-thrombin conversion, the clotting time and the consequently network structure of the fibrin gel.

  6. Thrombin generation in chronic obstructive pulmonary disease: dependence on plasma factor composition.

    PubMed

    Undas, Anetta; Jankowski, Milosz; Kaczmarek, Przemysław; Sladek, Krzysztof; Brummel-Ziedins, Kathleen

    2011-10-01

    Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for thromboembolic events. We investigated thrombin generation profiles in COPD patients and their dependence on plasma factor/inhibitor composition. Factors (f) (fII, fV, fVII, fVIII, fIX, fX), antithrombin, protein C (PC) and free tissue factor pathway inhibitor (fTFPI) from 60 COPD patients (aged 64.2 ± 10.1 years; a mean forced expiratory volume in 1 second [FEV(1)], 55.6 ± 15.8% of predicted values) were compared with those for 43 controls matched for age, sex, weight and smoking. Patients receiving anticoagulation were excluded. Using each individual's plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed computationally. COPD patients had higher fII (115 ± 16 vs 102 ± 10%, p < 0.0001), fV (114 ± 19 vs 102 ± 12%, p = 0.0002), fVII (111 ± 15 vs 102 ± 17%, p = 0.002), fVIII (170 ± 34 vs 115 ± 27%, p < 0.0001), and fIX (119 ± 21 vs 107 ± 17%, p = 0.003), and lower fTFPI (17.7 ± 3.2 vs 18.9 ± 3.2 ng/ml, p = 0.047) compared with controls, while fX, antithrombin, and PC were similar in both groups. Computational thrombin generation profiles showed that compared with controls, COPD patients had higher maximum thrombin levels (+28.3%, p < 0.0001), rates of thrombin generation (+46.1%, p < 0.0001) and total thrombin formation (+14.4%, p < 0.001), together with shorter initiation phase of thrombin generation (p < 0.0001) and the time to maximum thrombin levels (p < 0.0001). Thrombin generation profiles in COPD patients can be normalized via correction of fII, fVIII , fIX and TFPI. The severity of COPD and inflammatory markers were not associated with thrombin generation profiles. Prothrombotic phenotype in COPD patients is largely driven by increased prothrombin, fVIII, fIX, and lower fTFPI. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. In vitro effects of dalteparin on thrombin generation in canine plasma.

    PubMed

    Gara-Boivin, Carolyn; Del Castillo, Jérôme R E; Dunn, Marilyn E; Bédard, Christian

    2017-09-01

    The calibrated automated thrombogram (CAT) is a functional thrombin generation (TG) assay that may provide a new approach for monitoring anticoagulant therapy in dogs. The effects of dalteparin on TG variables in dogs are unknown. Objectives were to establish normal TG variable ranges in dogs and measure the in vitro TG variables in canine pooled platelet-poor plasma (PPP) spiked with different dalteparin concentrations. In the first experiment, plasma samples from 25 adult healthy Beagle dogs and 11 client-owned healthy dogs of multiple breeds was measured individually for obtaining normal TG values. In the second experiment, separate pools of the remaining PPP from 24 of the 25 previous adult Beagles and from 45 different client-owned dogs were spiked with dalteparin at 9 concentrations with increasing anti-factor Xa (anti-FXa) activity. Activated partial thromboplastin time, tissue factor-induced TG, and anti-FXa activity were measured for each concentration. Concentration-response relationships were determined with ADAPT v.5, using various nonlinear regression models for stimulatory or inhibitory effects. Thrombin generation ranges of client-owned dogs and Beagles were equivalent only for time-to-peak (P < .05). In vitro dalteparin resulted in a concentration-dependent decrease in endogenous thrombin potential (ETP) in pooled PPP. The estimated dalteparin concentration that produced half the maximal inhibition of baseline ETP (IC50 ) was 0.289 U/mL. Thrombin generation and anti-FXa activity were more sensitive than APTT to detect the effects of dalteparin. The CAT assay can measure the effects of dalteparin in canine plasma, resulting in significant dose-dependent decreases in ETP, prompting further in vivo investigation. © 2017 American Society for Veterinary Clinical Pathology.

  8. Clotting factor VIII (FVIII) and thrombin generation in camel plasma: A comparative study with humans

    PubMed Central

    Abdel Gader, Abdel Galil M.; Al Momen, Abdul Karim M.; Alhaider, Abdulqader; Brooks, Marjory B.; Catalfamo, James L.; Al Haidary, Ahmed A.; Hussain, Mansour F.

    2013-01-01

    The objective of this study was to characterize the highly elevated levels of clotting factor VIII (FVIII) in camel plasma. Whole blood was collected from healthy camels and factor VIII clotting activity (FVIII:C) assays were conducted using both the clotting and the chromogenic techniques. The anticoagulant citrate phosphate dextrose adenine (CPDA) produced the highest harvest of FVIII:C, the level of plasma factor VIII, compared to heparin:saline and heparin:CPDA anticoagulants. Camel FVIII can be concentrated 2 to 3 times in cryoprecipitate. There was a significant loss of camel FVIII when comparing levels of FVIII in camel plasma after 1 h of incubation at 37°C (533%), 40°C (364%), and 50°C (223%). Thrombin generation of camel plasma is comparable to that of human plasma. It was concluded that camel plasma contains very elevated levels of FVIII:C, approaching 8 times the levels in human plasma, and that these elevated levels could not be attributed to excessive thrombin generation. Unlike human FVIII:C, camel FVIII:C is remarkably heat stable. Taken together, these unique features of camel FVIII could be part of the physiological adaptation of hemostasis of the Arabian camel in order to survive in the hot desert environment. PMID:24082408

  9. Plasma factor and inhibitor composition contributes to thrombin generation dynamics in patients with acute or previous cerebrovascular events

    PubMed Central

    Gissel, Matthew; Undas, Anetta; Slowik, Agnieszka; Mann, Kenneth G.; Brummel-Ziedins, Kathleen E.

    2010-01-01

    Introduction More than 80% of cerebrovascular events are ischemic and largely thromboembolic by nature. We evaluated whether plasma factor composition and thrombin generation dynamics might be a contributor to the thrombotic phenotype of ischemic cerebrovascular events. Materials and Methods We studied (1) 100 patients with acute ischemic stroke (n=50) or transient ischemic attack (TIA) (n=50) within the first 24 hours from symptom onset, and (2) 100 individuals 1 to 4 years following ischemic stroke (n=50) or TIA (n=50). The tissue factor pathway to thrombin generation was simulated with a mathematical model using plasma levels of clotting factors (F)II, V, VII, VIII, IX, X, antithrombin and free tissue factor pathway inhibitor (TFPI). Results The plasma levels of free TFPI, FII, FVIII, and FX were higher, while antithrombin was lower, in the acute patients compared to the previous event group (all p≤0.02). Thrombin generation during acute events was enhanced, with an 11% faster maximum rate, a 15% higher maximum level and a 26% larger total production (all p<0.01). The increased thrombin generation in acute patients was determined by higher FII and lower antithrombin, while increased free TFPI mediated this effect. When the groups are classified by etiology, all stroke sub-types except cardioembolic have increased TFPI and decreased AT and total thrombin produced. Conclusion Augmented thrombin generation in acute stroke/TIA is to some extent determined by altered plasma levels of coagulation factors. PMID:20709367

  10. Antiplatelet Agents Can Promote Two-Peaked Thrombin Generation in Platelet Rich Plasma: Mechanism and Possible Applications

    PubMed Central

    Tarandovskiy, Ivan D.; Artemenko, Elena O.; Panteleev, Mikhail A.; Sinauridze, Elena I.; Ataullakhanov, Fazoil I.

    2013-01-01

    Background Thrombin generation assay is a convenient and widely used method for analysis of the blood coagulation system status. Thrombin generation curve (TGC) is usually bell-shaped with a single peak, but there are exceptions. In particular, TGC in platelet-rich plasma (PRP) can sometimes have two peaks. Objective We sought to understand the mechanism underlying the occurrence of two peaks in the PRP thrombin generation curve. Methods Tissue factor-induced thrombin generation in PRP and platelet-poor plasma (PPP) was monitored using continuous measurement of the hydrolysis rate of the thrombin-specific fluorogenic substrate Z-Gly-Gly-Arg-AMC. Expression of phosphatidylserine (PS) and CD62P on the surface of activated platelets was measured by flow cytometry using corresponding fluorescently labeled markers. Results The addition of the P2Y12 receptor antagonist MeS-AMP (160 µM), 83 nM prostaglandin E1 (PGE1), or 1.6% DMSO to PRP caused the appearance of two peaks in the TGC. The PS exposure after thrombin activation on washed platelets in a suspension supplemented with DMSO, PGE1 or MeS-AMP was delayed, which could indicate mechanism of the second peak formation. Supplementation of PRP with 1.6% DMSO plus 830 nM PGE1 mediated the disappearance of the second peak and decreased the amplitude of the first peak. Increasing the platelet concentration in the PRP promoted the consolidation of the two peaks into one. Conclusions Procoagulant tenase and prothrombinase complexes in PRP assemble on phospholipid surfaces containing PS of two types - plasma lipoproteins and the surface of activated platelets. Thrombin generation in the PRP can be two-peaked. The second peak appears in the presence of platelet antagonists as a result of delayed PS expression on platelets, which leads to delayed assembly of the membrane-dependent procoagulant complexes and a second wave of thrombin generation. PMID:23405196

  11. Interconnectedness of global hemostasis assay parameters in simultaneously evaluated thrombin generation, fibrin generation and clot lysis in normal plasma

    PubMed Central

    Xin, Kevin Z.; Chang, William; Ovanesov, Mikhail V.

    2015-01-01

    Background Fluorogenic thrombin generation (TG) assays and turbidity-based fibrin generation (FG)- and fibrinolysis (FL)-resistance assays have been sought to assess bleeding and clotting disorders. Theoretically, TG, FG and FL tests should provide overlapping information because thrombin is responsible for FG and induces protection from FL. The relationships between TG, FG and FL parameters remain poorly investigated, partly because existing experimental systems do not permit simultaneous detection of both TG and FG in the same sample of plasma, and are instead tested in separate experiments. Objectives and methods We evaluated the potential benefits of a combined TG/FG/FL assay by testing responses of normal plasma to a wide range of tissue factor (TF) and tissue plasminogen activator (tPA) concentrations. Correlations between multiple parameters extracted from the TG and FG/FL curves were also compared. Results Rate of FG correlated well with TG peak height at all TF concentrations, but correlations between TG and FL parameters depended on the TF concentration. Without thrombomodulin, all FG/FL parameters at high TF could be predicted from TG parameters and no FL protection was observed. With thrombomodulin and high TF, TF-dependent FL protection did not correlate with TF-dependent TG. The fluorogenic thrombin substrate did not interfere with optical density readings, and meaningful tPA concentrations did not interfere with TG readings. Conclusions In normal plasma, TG, FG and FL parameters may provide interchangeable information. Evaluation of FL-resistance may provide additional data under special assay conditions, but the value of this information should be studied under disease conditions. PMID:26632515

  12. Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance.

    PubMed

    Crowley, Maeve P; Kevane, Barry; O'Shea, Susan I; Quinn, Shane; Egan, Karl; Gilligan, Oonagh M; Ní Áinle, Fionnuala

    2016-09-01

    The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.

  13. Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogram characteristics.

    PubMed

    Vanschoonbeek, K; Feijge, M A H; Van Kampen, R J W; Kenis, H; Hemker, H C; Giesen, P L A; Heemskerk, J W M

    2004-03-01

    The hemostatic activity of plasma is determined by platelet activation and coagulation, which processes are mutually stimulatory. We studied this interaction by measuring the cleavage of fluorescent thrombin substrate in platelet-rich plasma (PRP), using the calibrated thrombogram method. In freshly isolated human plasma, thrombin formation triggered by tissue factor was fully dependent on the presence of platelets. It was abolished by annexin A5, indicating dependence on phosphatidylserine (PS) exposure at activated platelets. Comparison of plasmas from various subjects showed considerable interindividual variation in total amount of thrombin generation, regardless of whether platelets or PS-containing phospholipids were present. Integrin alphaIIbbeta3 antagonists and ADP receptor blockage, but not aspirin, decreased the rate of thrombin generation (thrombin peak level) and extended the time of onset. Platelet inhibition with cAMP-elevating agents decreased the thrombin-forming rate, but surprisingly shortened the onset time. Stimulation of platelets with agonists of Gi/q-coupled receptors and, to a larger extent, with collagen or Ca2+-ionophore increased the rate of thrombin generation and shortened its onset. In PRP from donors with low and high generation, platelet inhibitors and activators were similarly effective. Taken together, these results indicate that, in tissue factor-triggered PRP, PS exposure on activated platelets regulates both onset and rate of thrombin generation. However, coagulant activity rather than platelet activation determines the total amount of thrombin formed, i.e. the endogenous thrombin potential. Thus, kinetics of thrombin generation in PRP are controlled by platelet inhibitors and agonists, but the process is restricted in amount by the subject-dependent variation in coagulation.

  14. Thrombin Generation in Acute Ischaemic Stroke

    PubMed Central

    Roberts, Lara N.; Patel, Raj; Pathansali, Rohan; Kalra, Lalit; Arya, Roopen

    2016-01-01

    Introduction. Stroke remains a global leading cause of death and disability. Traditional description of plasma biology in the aftermath of acute ischaemic stroke favours development of hypercoagulability, resulting from complex interplay between plasma and endothelial factors. However, no single assay measures the overall global coagulation process. We postulate that thrombin generation would assist in identifying coagulation abnormalities after acute stroke. Aim. To investigate the coagulation abnormalities after acute ischaemic stroke using thrombin generation. Methods. We evaluated thrombin generation, measured with calibrated automated thrombography in stroke of different aetiological types (n = 170) within 48 hours of symptoms onset (baseline) and in the second week (time 2) and in normal healthy volunteers (n = 71). Results. Two-point thrombin generation assays showed prolonged lag time and time to peak at baseline (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.005) and (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.002), respectively, and at time 2 (3.5 (2.9, 4.2) versus 4.0 (3.1, 4.9); p = 0.004) and (5.9 (5.3, 6.6) versus 6.8 (5.8, 7.7) p = 0.05), respectively, in cardioembolic stroke (n = 39), when compared to noncardioembolic stroke (n = 117). The result was reproduced in multiple comparisons between acute ischaemic stroke subgroups and normal healthy volunteers. Endogenous thrombin potential and peak thrombin did not indicate hypercoagulability after acute ischaemic stroke, and thrombolytic therapy did not affect thrombin generation assays. Conclusion. Our findings suggest that thrombin generation in platelet poor plasma is not useful in defining hypercoagulability in acute ischaemic stroke. This is similar to observed trend in coronary artery disease and contrary to other hypercoagulable states. PMID:28116215

  15. Failure of corn trypsin inhibitor to affect the thrombin generation assay in plasma from severe hemophiliacs.

    PubMed

    Mohammed, B M; Martin, E J; Salinas, V; Carmona, R; Young, G; Brophy, D F

    2014-09-01

    The thrombin generation assay (TGA) is an important global coagulation assay; however, it suffers from the lack of preanalytical standardization. The addition of corn trypsin inhibitor (CTI) to blood collection tubes before TGA has been previously advocated to block the contact activation pathway. Emerging data, however, suggest that CTI may only be necessary when minimal tissue factor (TF) concentrations < 1 pmol are used. To determine whether blood collection tubes containing CTI influenced TGA parameters. This cross-sectional, observational study performed the TGA using TF 1 pmol L(-1) in 15 healthy volunteers, 14 severely factor VIII (FVIII)-deficient patients, and 15 severely FVIII-deficient patients with documented FVIII inhibitors. TGA was conducted using blood tubes that contained CTI 33 μg mL(-1) and no CTI. CTI markedly reduced peak thrombin (P = 0.002) and endogenous thrombin potential (P < 0.001) in the healthy volunteers but had no significant effect on TGA parameters in severely FVIII-deficient patients or those with inhibitors. This lack of effect raises additional questions regarding the need for CTI as a preanalytical addition to blood collection tubes during TGA in severe hemophiliacs, particularly when activating samples with TF 1 pmol L(-1) . © 2014 International Society on Thrombosis and Haemostasis.

  16. Thrombin generation in clinical conditions.

    PubMed

    Ten Cate, Hugo

    2012-03-01

    Commercial assays for determining thrombin generation in plasma are being tested in clinical conditions associated with thrombosis or bleeding. While pre-analytical conditions remain a source of inter laboratory variation, demanding for further standardization, clinical research proceeds. In patients at risk of venous thrombosis thrombin generation (TG) analysis may be utilized to detect underlying thrombophilia and this has been achieved both with addition of thrombomodulin or activated protein C, to test the contribution of the protein C system. In patients with documented venous thromboembolism, increased TG values are seen in those patients at greatest risk for recurrence, although the data are not consistent yet. In patients with arterial vascular disease, effects on TG patterns are seen that both reflect atherosclerosis (and its risk factors) and link to risk of recurrent atherothrombosis (coronary or stroke), but the data are limited. In patients with a bleeding diathesis, like hemophilia, the main importance of TG assays lies in the application for monitoring replacement therapy, either with factor concentrate or rFVIIa. An interesting application is in conjunction with thromboelastography, for monitoring peri-operative transfusion policy. Finally, TG analysis may contribute to monitoring anticoagulant drug treatment, but these and other applications would greatly benefit from whole blood, point of care applications of TG testing.

  17. Thrombin Generation in Zebrafish Blood

    PubMed Central

    Hemker, Coenraad; Lindhout, Theo; Kelchtermans, Hilde; de Laat, Bas

    2016-01-01

    To better understand hypercoagulability as an underlying cause for thrombosis, the leading cause of death in the Western world, new assays to study ex vivo coagulation are essential. The zebrafish is generally accepted as a good model for human hemostasis and thrombosis, as the hemostatic system proved to be similar to that in man. Their small size however, has been a hurdle for more widespread use in hemostasis related research. In this study we developed a method that enables the measurement of thrombin generation in a single drop of non-anticoagulated zebrafish blood. Pre-treatment of the fish with inhibitors of FXa and thrombin, resulted in a dose dependent diminishing of thrombin generation, demonstrating the validity of the assay. In order to establish the relationship between whole blood thrombin generation and fibrin formation, we visualized the resulting fibrin network by scanning electron microscopy. Taken together, in this study we developed a fast and reliable method to measure thrombin generation in whole blood collected from a single zebrafish. Given the similarities between coagulation pathways of zebrafish and mammals, zebrafish may be an ideal animal model to determine the effect of novel therapeutics on thrombin generation. Additionally, because of the ease with which gene functions can be silenced, zebrafish may serve as a model organism for mechanistical research in thrombosis and hemostasis. PMID:26872266

  18. Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test – Demonstrated in vitro and ex vivo

    PubMed Central

    Madsen, Daniel Elenius; Nichols, Timothy C.; Merricks, Elizabeth P.; Waters, Emily K.; Wiinberg, Bo

    2017-01-01

    Introduction Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of compound efficacy using a plasma based global coagulation method. One such widely used method is the thrombin generation test (TGT). Unfortunately, commercially available TGTs are incapable of distinguishing between normal and haemophilia canine plasma, and therefore in vitro prediction using TGT has so far not been possible in canine plasma material. Aim Establish a modified TGT capable of: 1) distinguishing between normal and haemophilia canine plasma, 2) monitoring correlation between canine plasma levels of coagulation factor VIII (FVIII) and IX (FIX) and thrombin generation, 3) assessing for agreement between compound activity and thrombin generation in ex vivo samples. Methods A modified TGT assay was established where coagulation was triggered using a commercially available activated partial thromboplastin time reagent. Results With the modified TGT a significant difference was observed in thrombin generation between normal and haemophilia canine plasma. A dose dependent thrombin generation was observed when assessing haemophilia A and B plasma spiked with dilution series of FVIII and FIX, respectively. Correlation between FVIII activity and thrombin generation was observed when analyzing samples from haemophilia A dogs dosed with canine FVIII. Limit of detection was 0.1% (v/v) FVIII or FIX. Conclusion A novel modified TGT suitable for monitoring and prediction of replacement therapy efficacy in plasma from haemophilia A and B dogs was established. PMID:28384182

  19. Differential Contributions of Intrinsic and Extrinsic Pathways to Thrombin Generation in Adult, Maternal and Cord Plasma Samples

    PubMed Central

    Rice, Nicklaus T.; Szlam, Fania; Varner, Jeffrey D.; Bernstein, Peter S.; Szlam, Arthur D.; Tanaka, Kenichi A.

    2016-01-01

    Background Thrombin generation (TG) is a pivotal process in achieving hemostasis. Coagulation profiles during pregnancy and early neonatal period are different from that of normal (non-pregnant) adults. In this ex vivo study, the differences in TG in maternal and cord plasma relative to normal adult plasma were studied. Methods Twenty consented pregnant women and ten consented healthy adults were included in the study. Maternal and cord blood samples were collected at the time of delivery. Platelet-poor plasma was isolated for the measurement of TG. In some samples, anti-FIXa aptamer, RB006, or a TFPI inhibitor, BAX499 were added to elucidate the contribution of intrinsic and extrinsic pathway to TG. Additionally, procoagulant and inhibitor levels were measured in maternal and cord plasma, and these values were used to mathematically simulate TG. Results Peak TG was increased in maternal plasma (393.6±57.9 nM) compared to adult and cord samples (323.2±38.9 nM and 209.9±29.5 nM, respectively). Inhibitory effects of RB006 on TG were less robust in maternal or cord plasma (52% vs. 12% respectively) than in adult plasma (81%). Likewise the effectiveness of BAX499 as represented by the increase in peak TG was much greater in adult (21%) than in maternal (10%) or cord plasma (12%). Further, BAX499 was more effective in reversing RB006 in adult plasma than in maternal or cord plasma. Ex vivo data were reproducible with the results of the mathematical simulation of TG. Conclusion Normal parturient plasma shows a large intrinsic pathway reserve for TG compared to adult and cord plasma, while TG in cord plasma is sustained by extrinsic pathway, and low levels of TFPI and AT. PMID:27196067

  20. Comparative biochemical studies of fresh frozen plasma and pooled solvent/detergent-treated plasma (octaplasLG(®) ) with focus on protein S and its impact in different thrombin generation assay set-ups.

    PubMed

    Heger, A; Janisch, S; Pock, K; Römisch, J

    2016-10-01

    The solvent/detergent treatment enables effective and robust inactivation of all lipid-enveloped viruses, but also inactivates partly sensitive plasma proteins such as protein S. The aim of this study was to investigate the thrombin generation capacity of octaplasLG(®) , in particular focusing on the function of protein S in thrombin generation assay and the impact of assay settings. Sixteen octaplasLG(®) batches and 32 units of single donor fresh frozen plasma (FFP) were investigated. For protein S, both functional activity and free antigen levels were measured. Thrombin generation assay was performed using two fluorogenic tests with different triggers. Finally, rotational thromboelastometry was performed. Mean protein S levels were lower in octaplasLG(®) , but a wider range of values was found for FFP. Clotting parameters and thrombin generation capacities overlapped between the two plasma groups as demonstrated using both thrombin generation assays and different triggers. Spiking studies with protein S-depleted plasma, human purified protein S or antibodies against protein S confirmed a correlation between protein S and thrombin generation capacity under specific assay conditions, especially in an assay with low tissue factor concentration. Correlation between protein S and thrombin generation capacity was demonstrated in the TGA. Due to higher variability in protein S content in the FFP group, overlapping haemostatic potentials of the two plasma groups were found. © 2016 International Society of Blood Transfusion.

  1. [Thrombin generation assays and their clinical application].

    PubMed

    Kern, Anita; Várnai, Katalin; Vásárhelyi, Barna

    2014-06-01

    Thrombin is a key enzyme of the coagulation system, having both pro- and anticoagulant functions. Thus, the generation of thrombin is one of the most important steps in coagulation. Global haemostasis assay, the so-called thrombin generation test is appropriate for its assessment. Since thrombin generation is sensible for both pro- and anticoagulant processes it can be applied for the general characterisation of the risk of thrombosis and bleeding, too. Clinical studies confirmed augmented thrombin generation in patients with high risk of venous or arterial thrombosis. Anticoagulant therapy (also novel oral anticoagulant treatment) can be monitored by thrombin generation. In case of haemophilia thrombin generation assays reflect bleeding severity. It is applicable for monitoring of both conventional haemophilia treatment and inhibitor-bypassing therapy, which is needed when inhibitors develop in patients. Standardization of thrombin generation methods and determination of cut off values are required before its application in clinical practice.

  2. Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B.

    PubMed

    Hansson, K M; Gustafsson, D; Skärby, T; Frison, L; Berntorp, E

    2015-07-01

    The present study was carried out to investigate the impact of FII levels, and their increase, on the hemostatic potential in plasma from hemophilia A and B patients with and without inhibitors. Recombinant human factor (F) II (rhFII) was added ex vivo to plasma from 68 patients with hemophilia A and B, with or without inhibitors. The hemostatic potential as measured by thrombin generation (calibrated automated thrombogram [CAT]) was focused on the endogenous thrombin potential (ETP) as it has been shown to correlate with the clinical phenotype of bleeding in hemophilia patients and has also been used to guide bypassing therapy in hemophilia patients with inhibitors before elective surgery. The factor eight inhibitor bypassing agent (FEIBA(®) ) was used as a reference to the clinical situation. The study shows that rhFII concentration-dependently increased ETP by a similar magnitude in hemophilia A and B, both with and without inhibitors. Compared with FEIBA, rhFII showed a shallower concentration-response curve. In both types of hemophilia 100 mg L(-1) of rhFII roughly doubled the ETP. A corresponding response was obtained by 0.5 U mL(-1) of FEIBA. These data support the theory that FII is one of the major components responsible for the efficacy of FEIBA. The data also indicate that rhFII may be useful, alone or in combination with other coagulation factors, in some of the conditions for which FEIBA is used today, although more data are needed to substantiate this. © 2015 International Society on Thrombosis and Haemostasis.

  3. Comparison of the effect of fondaparinux and enoxaparin on thrombin generation during in-vitro clotting of whole blood and platelet-rich plasma.

    PubMed

    Gerotziafas, Grigoris T; Depasse, François; Chakroun, Tahar; Van Dreden, Patrick; Samama, Meyer M; Elalamy, Ismail

    2004-03-01

    Fondaparinux, a selective antithrombin-dependent inhibitor of activated factor X (FXa), is effective in the prevention and treatment of deep vein thrombosis and seems to be superior to enoxaparin. However, the exact mechanism of fondaparinux antithrombotic action is still unclear. We compared the effect of clinically relevant concentrations of fondaparinux and enoxaparin on the initiation and propagation phase of prothrombin activation and on the endogenous thrombin potential (ETP). Coagulation was triggered either in whole blood or in platelet-rich plasma (PRP) by recalcification in the presence of diluted thromboplastin. Prothrombin activation in whole blood was assessed with an original method by measuring the kinetics of prothrombin F1+2 formation using an enzyme-linked immunosorbent assay. We also assessed the maximum concentration of thrombin (Cmax) and the ETP in PRP using the Thrombogram-Thrombinoscope assay. Concentrations of fondaparinux achieved in prophylaxis (0.11-0.28 anti-FXa IU/ml) prolonged the initiation phase and reduced the velocity of the propagation phase of F1+2 formation. Concentrations of enoxaparin achieved in prophylaxis (0.1-0.25 anti-FXa IU/ml) did not significantly modify these parameters. Concentrations of fondaparinux equal to or higher than 0.57 anti-FXa IU/ml significantly reduced the Cmax of F1+2 or thrombin as well as the ETP. At fondaparinux concentrations equal to or higher than 0.91 anti-FXa IU/ml, a maximum 60% inhibition of thrombin generation was observed. In the presence of enoxaparin concentrations equal to or higher than 0.8 anti-FXa IU/ml, the inhibition of thrombin generation was higher than 80%. Fondaparinux prolonged the initiation phase, decreased the velocity of the propagation phase of thrombin generation and partially reduced the total amount of generated thrombin. The inhibitory effect of fondaparinux on the initiation and propagation phase of thrombin generation seems to be responsible for its antithrombotic

  4. Thrombin Generation in the Glasgow Myocardial Infarction Study

    PubMed Central

    Smid, Machiel; Dielis, Arne W. J. H.; Spronk, Henri M. H.; Rumley, Ann; van Oerle, Rene; Woodward, Mark; ten Cate, Hugo; Lowe, Gordon

    2013-01-01

    Background Thrombin is a key protease in coagulation also implicated in complex pathology including atherosclerosis. To address the role of thrombin in relation to myocardial infarction (MI) we explored thrombin generation analysis in plasma from patients and controls that had participated in the Glasgow MI Study (GLAMIS). Methods Thrombin generation at 1 and 2 pM TF and with and without thrombomodulin (TM) was performed on plasmas from 356 subjects (171 cases, 185 age and sex matched controls) from GLAMIS collected between 3 and 9 months after the MI event. Results Although thrombin generation was slightly delayed in cases (lag time increased from 3.3 to 3.6 min) at the highest trigger, the overall potential to generate thrombin was increased by 7% for the ETP and by 15% for the peak height (both at the 1 pM TF trigger) in cases. Addition of TM did not reveal differences. Furthermore, an increased thrombin generation was associated with MI [normalized ETP: adjusted OR for the highest percentile = 2.4 (95% CI 1.3–4.5) and normalized peak height: adjusted OR = 2.6 (1.3–5.0)] at the lowest trigger; normalized ETP and peak height being 2.1 (1.1–3.8) and 2.0 (1.0–4.1) at the higher 2 pM trigger. Conclusion In GLAMIS, patients with a previous MI had an increased thrombin generation compared to controls. The absence of a clear difference in TM reduction suggests an unaltered anticoagulant activity in these patients. Further research is needed in order to unravel the underlying mechanisms of enhanced thrombin generation after MI. PMID:23826181

  5. Thrombin generation in patients after acute deep-vein thrombosis.

    PubMed

    ten Cate-Hoek, Arina J; Dielis, Arne W J H; Spronk, Henri M H; van Oerle, René; Hamulyák, Karly; Prins, Martin H; ten Cate, Hugo

    2008-08-01

    Thrombin generation measurement may be of value for assessing the risk of venous thromboembolism, but its long term profile has not been assessed in patients. We evaluated thrombin generation by Calibrated Automated Thrombogram (CAT) in plasma during follow up of 104 consecutive patients after an acute episode of deep venous thrombosis. Blood was drawn three times over the course of 24 months. Thrombin generation was measured in absence and presence of thrombomodulin and compared to a reference range derived from thrombin generation curves in 137 healthy volunteers. Thrombin generation of patients showed significantly higher endogenous thrombin potential (ETP) and peak height compared to the reference population. Differences were more pronounced in assays triggered with 1 pM TF. Inhibition by thrombomodulin was attenuated in patients off anticoagulants as compared to the reference population (21% vs. 42.2%, p < 0.0001); inhibition in patients on anticoagulant treatment was less pronounced (9.7%, p < 0.0001). Protein C activity, protein S antigen as well as free protein S showed highly negative correlation with ETP in all patients. A significant negative relation was found between FVIII levels and thrombomodulin induced reduction of ETP and peak height. In conclusion, thrombin generation by CAT reflects changes in coagulation status in patients following a thromboembolic event and is most sensitive at CAT analysis triggered with 1 pM TF. A role for factor VIII as an important attributable cause of hypercoagulability is reflected by the reduced inhibitory effect of thrombomodulin at high factor VIII levels.

  6. Mechanistic Modeling of the Effects of Acidosis on Thrombin Generation.

    PubMed

    Mitrophanov, Alexander Y; Rosendaal, Frits R; Reifman, Jaques

    2015-08-01

    Acidosis, a frequent complication of trauma and complex surgery, results from tissue hypoperfusion and IV resuscitation with acidic fluids. While acidosis is known to inhibit the function of distinct enzymatic reactions, its cumulative effect on the blood coagulation system is not fully understood. Here, we use computational modeling to test the hypothesis that acidosis delays and reduces the amount of thrombin generation in human blood plasma. Moreover, we investigate the sensitivity of different thrombin generation parameters to acidosis, both at the individual and population level. We used a kinetic model to simulate and analyze the generation of thrombin and thrombin-antithrombin complexes (TAT), which were the end points of this study. Large groups of temporal thrombin and TAT trajectories were simulated and used to calculate quantitative parameters, such as clotting time (CT), thrombin peak time, maximum slope of the thrombin curve, thrombin peak height, area under the thrombin trajectory (AUC), and prothrombin time. The resulting samples of parameter values at different pH levels were compared to assess the acidosis-induced effects. To investigate intersubject variability, we parameterized the computational model using the data on clotting factor composition for 472 subjects from the Leiden Thrombophilia Study. To compare acidosis-induced relative parameter changes in individual ("virtual") subjects, we estimated the probabilities of relative change patterns by counting the pattern occurrences in our virtual subjects. Distribution overlaps for thrombin generation parameters at distinct pH levels were quantified using the Bhattacharyya coefficient. Acidosis in the range of pH 6.9 to 7.3 progressively increased CT, thrombin peak time, AUC, and prothrombin time, while decreasing maximum slope of the thrombin curve and thrombin peak height (P < 10). Acidosis delayed the onset and decreased the amount of TAT generation (P < 10). As a measure of intrasubject

  7. Thrombin generation testing for monitoring hemophilia treatment: a clinical perspective.

    PubMed

    Salvagno, Gian Luca; Berntorp, Erik

    2010-10-01

    Thrombin generation is a key process that determines the extent of a hemostatic plug or a thrombotic process. The ensuing thrombin burst is crucial for the formation of a stable fibrin clot. During its active life, thrombin exerts a multitude of highly regulated actions on the blood and the vessel wall, among which is the clotting of fibrinogen. The inappropriate generation of thrombin may lead to pathological processes, foremost of which are hemorrhagic or thrombotic diseases. The coagulation system is usually investigated by means of two in vitro classical clotting tests, the activated partial thromboplastin time and prothrombin time. These assays assess only the time taken to form a clot and do not entirely reflect global hemostatic balance. They permit identification of connectivity between the component activities identified as required for plasma coagulation and define the concept of intrinsic and extrinsic coagulation pathways, which converge at the step of formation of the prothrombinase complex. However, the mechanisms established by in vitro tests are not always mirrored in the human pathologies associated with bleeding or thrombosis. The recent development of newer tests based on the continuous registration of thrombin generation (TG) under in vitro conditions that mimic more closely what occurs in vivo prompted us to reinvestigate the balance between procoagulants and anticoagulants in patients. Thrombin generation assays (TGA) not only provide an overall assessment of hemostasis, but they also target potential extrahemostatic effects of the generated thrombin, a potent agonist of a multitude of cellular activation pathways. Moreover, estimation of an individual's thrombin generation potential may correlate more closely with a hyper- or hypocoagulable phenotype, compared with traditional coagulation tests. In this review, we discuss to what extent TG can be expected to reflect the clotting function of blood, the development and use of different TGA

  8. Mechanistic Modeling of the Effects of Acidosis on Thrombin Generation

    PubMed Central

    Mitrophanov, Alexander Y.; Rosendaal, Frits R.

    2015-01-01

    BACKGROUND: Acidosis, a frequent complication of trauma and complex surgery, results from tissue hypoperfusion and IV resuscitation with acidic fluids. While acidosis is known to inhibit the function of distinct enzymatic reactions, its cumulative effect on the blood coagulation system is not fully understood. Here, we use computational modeling to test the hypothesis that acidosis delays and reduces the amount of thrombin generation in human blood plasma. Moreover, we investigate the sensitivity of different thrombin generation parameters to acidosis, both at the individual and population level. METHODS: We used a kinetic model to simulate and analyze the generation of thrombin and thrombin–antithrombin complexes (TAT), which were the end points of this study. Large groups of temporal thrombin and TAT trajectories were simulated and used to calculate quantitative parameters, such as clotting time (CT), thrombin peak time, maximum slope of the thrombin curve, thrombin peak height, area under the thrombin trajectory (AUC), and prothrombin time. The resulting samples of parameter values at different pH levels were compared to assess the acidosis-induced effects. To investigate intersubject variability, we parameterized the computational model using the data on clotting factor composition for 472 subjects from the Leiden Thrombophilia Study. To compare acidosis-induced relative parameter changes in individual (“virtual”) subjects, we estimated the probabilities of relative change patterns by counting the pattern occurrences in our virtual subjects. Distribution overlaps for thrombin generation parameters at distinct pH levels were quantified using the Bhattacharyya coefficient. RESULTS: Acidosis in the range of pH 6.9 to 7.3 progressively increased CT, thrombin peak time, AUC, and prothrombin time, while decreasing maximum slope of the thrombin curve and thrombin peak height (P < 10–5). Acidosis delayed the onset and decreased the amount of TAT generation (P

  9. Thrombin generation, ProC(®)Global, prothrombin time and activated partial thromboplastin time in thawed plasma stored for seven days and after methylene blue/light pathogen inactivation.

    PubMed

    Thiele, Thomas; Hron, Gregor; Kellner, Sarah; Wasner, Christina; Westphal, Antje; Warkentin, Theodore E; Greinacher, Andreas; Selleng, Kathleen

    2016-01-01

    Methylene blue pathogen inactivation and storage of thawed plasma both lead to changes in the activity of several clotting factors. We investigated how this translates into a global loss of thrombin generation potential and alterations in the protein C pathway. Fifty apheresis plasma samples were thawed and each divided into three subunits. One subunit was stored for 7 days at 4 °C, one was stored for 7 days at 22 °C and one was stored at 4 °C after methylene blue/light treatment. Thrombin generation parameters, ProC(®)Global-NR, prothrombin time and activated partial thromboplastin time were assessed on days 0 and 7. The velocity of thrombin generation increased significantly after methylene blue treatment (increased thrombin generation rate; time to peak decreased) and decreased after storage (decreased thrombin generation rate and peak thrombin; increased lag time and time to peak). The endogenous thrombin generation potential remained stable after methylene blue treatment and storage at 4 °C. Methylene blue treatment and 7 days of storage at 4 °C activated the protein C pathway, whereas storage at room temperature and storage after methylene blue treatment decreased the functional capacity of the protein C pathway. Prothrombin time and activated partial thromboplastin time showed only modest alterations. The global clotting capacity of thawed plasma is maintained at 4 °C for 7 days and directly after methylene blue treatment of thawed plasma. Thrombin generation and ProC(®)Global are useful tools for investigating the impact of pathogen inactivation and storage on the clotting capacity of therapeutic plasma preparations.

  10. Red blood cells and thrombin generation in sickle cell disease.

    PubMed

    Whelihan, Matthew F; Lim, Ming Y; Key, Nigel S

    2014-05-01

    The prothrombotic nature of sickle cell disease (SCD) is evidenced by the chronically elevated levels of almost all coagulation activation biomarkers, and an increased incidence of certain thrombotic events, including venous thromboembolism. Numerous studies have attempted to define the extent and elucidate the mechanism of the observed increase in thrombin generation in SCD patients in vivo. In general, these studies were performed using thrombin generation assays in platelet poor or platelet rich plasma and showed little difference in endogenous thrombin potential between the SCD cohort and healthy matched controls. In SCD, erythrocytes and monocytes have been demonstrated to exhibit procoagulant characteristics. Thus, the absence of these cellular components in standard thrombin generation assays may fail to reflect global hypercoagulability in the whole blood of patients with SCD. We were therefore surprised to see no difference in net thrombin generation in tissue factor-initiated initiated clotting of whole blood from patients with SCD. However, we are continuing to reconcile these seemingly disparate observations by slight modifications of the whole blood model that include alternative coagulation triggers and a re-examination of the net thrombin generation when the protein/protein S system is simultaneously interrogated.

  11. Hypercoagulability in splenectomized thalassemic patients detected by whole-blood thromboelastometry, but not by thrombin generation in platelet-poor plasma

    PubMed Central

    Tripodi, Armando; Cappellini, Maria Domenica; Chantarangkul, Veena; Padovan, Lidia; Fasulo, Maria Rosaria; Marcon, Alessia; Mannucci, Pier Mannuccio

    2009-01-01

    Background The mechanisms responsible for the increased thrombotic risk associated with thalassemia are still unclear. They might be related to the effects of red blood cell or endothelial cell derangements, increased numbers of platelets as well as abnormal plasma coagulation. Design and Methods To evaluate the relative role played by cells and plasma we investigated 169 patients with thalassemia by means of thromboelastometry and thrombin generation tests. Thromboelastometry measures indices of the viscoelastic properties of whole blood after activation of coagulation and is characterized by the clotting time, which may be considered as a conventional coagulation time, clot formation time, defined as the time needed for the clot to reach a fixed firmness, and the maximum clot firmness, defined as the maximal amplitude of the tracing. Results All the thromboelastometry parameters determined in whole blood (including shortened clotting time and clot formation time, and increased maximum clot firmness), were consistent with hypercoagulability, especially in splenectomized patients. Conversely, thrombin generation as determined in platelet-poor plasma was not. Conclusions These findings point to blood cells and/or platelets rather than to plasma abnormalities as the most important determinants of the thrombotic risk observed in thalassemic patients who had been splenectomized. These results might have important diagnostic and therapeutic implications. PMID:19648162

  12. Thrombin Generating Capacity and Phenotypic Association in ABO Blood Groups.

    PubMed

    Kremers, Romy M W; Mohamed, Abdulrahman B O; Pelkmans, Leonie; Hindawi, Salwa; Hemker, H Coenraad; de Laat, H Bas; Huskens, Dana; Al Dieri, Raed

    2015-01-01

    Individuals with blood group O have a higher bleeding risk than non-O blood groups. This could be explained by the lower levels of FVIII and von Willebrand Factor (VWF) levels in O individuals. We investigated the relationship between blood groups, thrombin generation (TG), prothrombin activation and thrombin inactivation. Plasma levels of VWF, FVIII, antithrombin, fibrinogen, prothrombin and α2Macroglobulin (α2M) levels were determined. TG was measured in platelet rich (PRP) and platelet poor plasma (PPP) of 217 healthy donors and prothrombin conversion and thrombin inactivation were calculated. VWF and FVIII levels were lower (75% and 78%) and α2M levels were higher (125%) in the O group. TG is 10% lower in the O group in PPP and PRP. Less prothrombin was converted in the O group (86%) and the thrombin decay capacity was lower as well. In the O group, α2M plays a significantly larger role in the inhibition of thrombin (126%). In conclusion, TG is lower in the O group due to lower prothrombin conversion, and a larger contribution of α2M to thrombin inactivation. The former is unrelated to platelet function because it is similar in PRP and PPP, but can be explained by the lower levels of FVIII.

  13. Investigation of the selectivity of thrombin-binding aptamers for thrombin titration in murine plasma.

    PubMed

    Trapaidze, Ana; Hérault, Jean-Pascal; Herbert, Jean-Marc; Bancaud, Aurélien; Gué, Anne-Marie

    2016-04-15

    Detection of thrombin in plasma raises timely challenges to enable therapeutic management of thrombosis in patients under vital threat. Thrombin binding aptamers represent promising candidates as sensing elements for the development of real-time thrombin biosensors; however implementation of such biosensor requires the clear understanding of thrombin-aptamer interaction properties in real-like environment. In this study, we used Surface Plasmon Resonance technique to answer the questions of specificity and sensitivity of thrombin detection by the thrombin-binding aptamers HD1, NU172 and HD22. We systematically characterized their properties in the presence of thrombin, as well as interfering molecular species such as the thrombin precursor prothrombin, thrombin in complex with some of its natural inhibitors, nonspecific serum proteins, and diluted plasma. Kinetic experiments show the multiple binding modes of HD1 and NU172, which both interact with multiple sites of thrombin with low nanomolar affinities and show little specificity of interaction for prothrombin vs. thrombin. HD22, on the other hand, binds specifically to thrombin exosite II and has no affinity to prothrombin at all. While thrombin in complex with some of its inhibitors could not be recognized by any aptamer, the binding of HD1 and NU172 properties is compromised by thrombin inhibitors alone, as well as with serum albumin. Finally, the complex nature of plasma was overwhelming for HD1, but we define conditions for the thrombin detection at 10nM range in 100-fold diluted plasma by HD22. Consequently HD22 showed key advantage over HD1 and NU172, and appears as the only alternative to design an aptasensor. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Inhibition of thrombin generation by aspirin is blunted in hypercholesterolemia.

    PubMed

    Szczeklik, A; Musial, J; Undas, A; Swadzba, J; Gora, P F; Piwowarska, W; Duplaga, M

    1996-08-01

    Recent evidence indicates that aspirin inhibits thrombin generation in clotting blood. We noticed that this effect was less pronounced in patients with hypercholesterolemia. The aim of the study was to prove this observation. The effects of aspirin on thrombin generation were evaluated in (1) 46 healthy volunteers, 2 hours after ingestion of a single, 500-mg dose and (2) 28 survivors of myocardial infarction who took 300 mg aspirin/d for 2 weeks. In both populations, two well-matched subgroups were distinguished, using a serum cholesterol level of 6.2 mmol/L (240 mg/dL) and an LDL cholesterol level of 4.0 mmol/L (155 mg/dL) as borderline. Thrombin generation was monitored ex vivo in blood emerging from a skin microvasculature injury and additionally, in a single-dose study in vitro in recalcified plasma. Aspirin depressed thrombin generation in the group of subjects with serum cholesterol < 6.2 mmol/L and LDL cholesterol < 4.0 mmol/L but not in the group with high blood cholesterol levels. Inhibitory effects of aspirin were more pronounced after the 2-week treatment than after a single dose. There was a significant correlation between total serum cholesterol or LDL cholesterol and total amount of thrombin generated after aspirin treatment. In subjects with high blood cholesterol levels, thrombin generation was not affected by aspirin. Blunting of aspirin action in hypercholesterolemia might be explained by (1) alterations in platelet lipid-protein matrix that render their membrane proteins less accessible for acetylation by aspirin and (2) changes in composition and structure of plasma lipoproteins that diminish the chance of aspirin to interact with prothrombin.

  15. Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia.

    PubMed

    Selmeczi, Anna; Roach, Rachel E J; Móré, Csaba; Batta, Zoltán; Hársfalvi, Jolán; van der Bom, Johanna G; Boda, Zoltán; Oláh, Zsolt

    2015-02-01

    Pregnancy is associated with increased risk of venous thromboembolism, especially in the presence of thrombophilia. However, there is no consensus on the optimal approach for thromboprophylaxis in this population. Recent evidence suggests that thrombin generation correlates with the overall procoagulant state of the plasma. Our aim was to evaluate thrombin generation in a prospective cohort of thrombophilic pregnant women, and investigate the effectiveness of low-molecular-weight heparin (LMWH) prophylaxis in pregnancy. Women with severe (n=8), mild (n=47) and no (n=15) thrombophilia were followed throughout their pregnancies. Thrombin generation was evaluated in each trimester as well as five days and eight weeks postpartum (as a reference category). In women undergoing LMWH prophylaxis, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration (peak effect). Thrombin generation was determined using Technothrombin TGA assay system. For the analysis, median peak thrombin and endogenous thrombin potential were used. Peak thrombin and endogenous thrombin potential were increased during pregnancy compared to the non-pregnant state with the highest results in the severe thrombophilia group. In women receiving LMWH prophylaxis a decrease was observed in thrombin generation at peak effect but over the progression of pregnancy the extent of this decrease reduced in a stepwise fashion. Our results show that thrombin generation demonstrates the hypercoagulable state in thrombophilic pregnancies. In addition, we found the effect of LMWH prophylaxis to progressively decrease with advancing stages of pregnancy.

  16. Abciximab does not inhibit the increase of thrombin generation produced in platelet-rich plasma in vitro by sodium arachidonate or tissue factor.

    PubMed

    Altman, Raul; Scazziota, Alejandra; Santoro, Silvina; Gonzalez, Claudio

    2005-07-01

    Aspirin and platelet membrane glycoprotein (GP) IIb/IIIa blockers are currently used for acute coronary events, and in percutaneous coronary intervention for preventing further coronary outcomes, because they inhibit platelet function. Aspirin also inhibits thrombin generation (TG) in platelet-rich plasma (PRP) activated by sodium arachidonate (AA). The effect of the platelet membrane GP IIb-IIIa (integrin alpha(IIb)beta(3)) blocker abciximab on thrombin generation was studied in vitro using PRP. Thirty healthy volunteers taking no medication, and 28 volunteers who had taken aspirin (160 mg/day for 3-4 days), were included in the protocol. Control or in vivo aspirinated PRP, stimulated or not by AA or tissue factor (TF), was investigated for the inhibitory effect of abciximab pre-incubated for 3 minutes. AA and TF added in vitro activated non-aspirinated PRP: lag-time (LT) and time to peak (TTP) were significantly shortened. Peak TG (PTG) and endogenous thrombin potential (ETG) were increased by AA but not TF; thus, AA seems to be more efficient than TF for TG in this system. Abciximab added in vitro to non-activated, non-aspirinated PRP had no effect on LT, TTP, or ETP, but caused a decrease in PTG that was not statistically significant. Abciximab (3 or 4 microg/mL) added in vitro to AA or TF-activated, non-aspirinated PRP produced no effect on TG, although in aspirinated platelets both LT and time to peak were prolonged. AA as well as TF added in vitro to PRP or in vivo aspirinated PRP increased TG, although AA seems to be more efficient in our assay system. Abciximab, which affects non-aspirinated, nonactivated PRP weakly, has no effect on AA or TF in activated control PRP or in vivo aspirinated PRP.

  17. Large external quality assessment survey on thrombin generation with CAT: further evidence for the usefulness of normalisation with an external reference plasma.

    PubMed

    Perrin, Julien; Depasse, François; Lecompte, Thomas

    2015-07-01

    Calibrated Automated Thrombography (CAT) has been widely used to assess in vitro thrombin generation as an informative intermediary phenotype of coagulation. Interlaboratory exercises have documented a worrisome poor reproducibility. There are some data on the normalisation with an appropriate external reference plasma (RP). This multicentre study of the French-speaking CAT Club aimed at providing further evidence for the usefulness of such a normalisation. Lyophilised aliquots of a RP along with 3 plasmas (P1=normal; P2=hypo-; P3=hypercoagulable) were sent to 34 laboratories (corresponding to 38 instruments). CAT was studied using 1 and 5 pM tissue factor and other dedicated reagents. Normalisation with the local RP in use in the laboratory could also be performed. Interlaboratory CVs were calculated for each plasma before and after normalisation. Regarding endogenous thrombin potential, a good discrimination between the 3 plasmas was achieved in all laboratories but there was no overlap after normalisation only. CVs were generally not reduced with the use of local RP but were generally improved with normalisation using the external RP, often becoming lower than 10%. Regarding P2 however, the benefit of normalisation was poor, and there were analytical difficulties as well, some laboratories being unable to get a useable signal. We confirm that normalisation of CAT results with a suitable external RP is useful in "real life" practice as it often permits an acceptable level of interlaboratory variability. In case of frank hypocoagulability, further improvements are required to get reliable, potentially clinically relevant results. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Thrombin generation induced by tissue factor plus ADP in human platelet rich plasma: A potential new measurement to assess the effect of the concomitant use of an oral factor Xa inhibitor edoxaban and P2Y12 receptor antagonists.

    PubMed

    Honda, Yuko; Morishima, Yoshiyuki

    2015-05-01

    Patients with atrial fibrillation undergoing percutaneous coronary intervention may require combination therapy with anticoagulants and antiplatelet agents. The objectives of this study were to establish an assay which can evaluate the effects of both anticoagulants and P2Y12 receptor antagonists and determine the effects of edoxaban, a direct factor Xa inhibitor, and P2Y12 receptor antagonists (clopidogrel and ticagrelor) alone and when combined. Human platelet-rich plasma (PRP) from healthy subjects was stimulated with adenosine diphosphate (ADP) plus tissue factor. Thrombin generation was measured by means of calibrated automated thrombography. Combination of 10μM ADP and low concentration (0.25 pM) tissue factor induced reproducible thrombin generation in human PRP. Edoxaban (40 and 80ng/mL), active metabolite of clopidogrel (AM-clopidogrel, 10 and 20μg/mL), and ticagrelor (3μg/mL) alone inhibited ADP plus tissue factor-induced thrombin generation. Edoxaban suppressed all 5 parameters (lag time, peak, time to peak, endogenous thrombin potential, and maximum rate), whereas AM-clopidogrel and ticagrelor inhibited 4 and 3 parameters, respectively. Concomitant treatment with edoxaban and AM-clopidogrel or ticagrelor produced an additive inhibition of thrombin generation compared to the single treatments. The thrombin generation assay induced by ADP plus tissue factor can detect the activities of both edoxaban and P2Y12 receptor antagonists. Combination of edoxaban and a P2Y12 receptor antagonist shows additive inhibition. These results suggest that ADP plus tissue factor-induced thrombin generation may be a useful measurement to assess the combination effects of anticoagulants and P2Y12 receptor antagonists in a single assay. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. THROMBIN GENERATION AND BLEEDING IN HEMOPHILIA A

    PubMed Central

    Brummel-Ziedins, Kathleen E.; Whelihan, Matthew F.; Gissel, Matthew; Mann, Kenneth G.; Rivard, Georges E.

    2012-01-01

    Introduction Hemophilia A displays phenotypic heterogeneity with respect to clinical severity. Aim To determine if tissue factor (TF)-initiated thrombin generation profiles in whole blood in the presence of corn trypsin inhibitor (CTI) are predictive of bleeding risk in hemophilia A. Methods We studied factor(F) VIII deficient individuals (11 mild, 4 moderate and 12 severe) with a well-characterized five-year bleeding history that included hemarthrosis, soft tissue hematoma and annual FVIII concentrate usage. This clinical information was used to generate a bleeding score. The bleeding scores (range 0–32) were separated into three groups (bleeding score groupings: 0, 0 and ≤9.6, >9.6), with the higher bleeding tendency having a higher score. Whole blood collected by phlebotomy and contact pathway suppressed by 100μg/mL CTI was stimulated to react by the addition of 5pM TF. Reactions were quenched at 20min by inhibitors. Thrombin generation, determined by ELISA for thrombin – antithrombin was evaluated in terms of clot time (CT), maximum level (MaxL) and maximum rate (MaxR) and compared to the bleeding score. Results Data are shown as the mean±SD. MaxL was significantly different (p<0.001) between the groups: 504±114nM, 315±117nM, and 194±91nM; with higher thrombin concentrations in the groups with lower bleeding scores. MaxR was higher in the groups with a lower bleeding score; 97±51nM/min, 86±60nM/min and 39±16nM/min (p=0.09). No significant difference was detected in CT among the groups, 5.6±1.3min, 4.7±0.7min, 5.6±1.3min. Conclusions Our empirical study in CTI-inhibited whole blood shows that the MaxL of thrombin generation appears to correlate with the bleeding phenotype of hemophilia A. PMID:19563500

  20. Low paediatric thrombin generation is caused by an attenuation of prothrombin conversion.

    PubMed

    Kremers, Romy M W; Wagenvoord, Rob J; de Laat, H Bas; Monagle, Paul; Hemker, H Coenraad; Ignjatovic, Vera

    2016-06-02

    Thrombin generation (TG) is decreased in children. TG is determined by two underlying processes: the conversion of prothrombin to thrombin and the inactivation of thrombin. Therefore, lower TG capacity in children can either be caused by a reduction of prothrombin conversion, an increase of thrombin inactivation, or both. In 36 children and 8 adults, TG and the factors that determine thrombin inactivation (antithrombin, α2Macroglobulin (α2M) and fibrinogen) were measured. Prothrombin conversion, thrombin inhibitor complex formation, and the overall thrombin decay capacity were determined. In silico modelling was performed to determine the contribution prothrombin conversion and thrombin inactivation to deviant paediatric TG. Both the amount of prothrombin converted and the maximal prothrombin conversion rate are significantly reduced in children as compared to adults. This is partly due to the prothrombin levels being lower and partly to a lower prothrombin conversion rate. The overall thrombin decay capacity is not significantly different in children, but α2Macroglobulin plays a more important role than it does in adults. In silico experiments demonstrate that reduced prothrombin conversion and to a lesser extent elevated α2M levels provide an explanation for low TG in children. Young age has a dual effect on prothrombin conversion. Lower plasma prothrombin levels result in decreased prothrombin conversion but the rate of prothrombin conversion is also decreased, i. e. the development of prothrombinase is lower than in adults.

  1. Measurement of dabigatran in standardly used clinical assays, whole blood viscoelastic coagulation, and thrombin generation assays.

    PubMed

    van Ryn, Joanne; Grottke, Oliver; Spronk, Henri

    2014-09-01

    Dabigatran, a direct thrombin inhibitor, is increasingly used clinically as one of the new oral anticoagulants. This review summarizes the assays available to measure its activity and includes the relative sensitivity of the different assays for this agent. In addition to plasma-based clotting tests, assays commonly used in surgical/emergency settings, such as activated clotting time and thromboelastometry/thromboelastography, are reviewed. In addition, the thrombin generation assay is discussed as an important method to determine the potential risk of thrombosis or bleeding and its relevance to the measurement of direct thrombin inhibitors. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Thrombin

    PubMed Central

    Di Cera, Enrico

    2008-01-01

    Thrombin is a Na+-activated, allosteric serine protease that plays opposing functional roles in blood coagulation. Binding of Na+ is the major driving force behind the procoagulant, prothrombotic and signaling functions of the enzyme, but is dispensable for cleavage of the anticoagulant protein C. The anticoagulant function of thrombin is under the allosteric control of the cofactor thrombomodulin. Much has been learned on the mechanism of Na+ binding and recognition of natural substrates by thrombin. Recent structural advances have shed light on the remarkable molecular plasticity of this enzyme and the molecular underpinnings of thrombin allostery mediated by binding to exosite I and the Na+ site. This review summarized our current understanding of the molecular basis of thrombin function and allosteric regulation. The basic information emerging from recent structural, mutagenesis and kinetic investigation of this important enzyme is that thrombin exists in three forms, E*, E and E:Na+, that interconvert under the influence of ligand binding to distinct domains. The transition between the Na+-free slow from E and the Na+-bound fast form E:Na+ involves the structure of the enzyme as a whole, and so does the interconversion between the two Na+-free forms E* and E. E* is most likely an inactive form of thrombin, unable to interact with Na+ and substrate. The complexity of thrombin function and regulation has gained this enzyme pre-eminence as the prototypic allosteric serine protease. Thrombin is now looked upon as a model system for the quantitative analysis of biologically important enzymes. PMID:18329094

  3. Altered Flow Changes Thrombin Generation Rate of Circulating Platelets.

    PubMed

    Yin, Wei; Bond, Kyle; Rouf, Farzana; Rubenstein, David A

    2015-12-01

    Shear stress affects platelet participation in coagulation. Many numerical models have been developed to describe coagulation kinetics. However, most of those models used rate constants determined under static conditions. Little is known about the effects of flow on coagulation rate constants. In the present study, platelets were exposed to constant or pulsatile shear stress/rate, with or without prothrombin, factor Xa, and factor Va. Thrombin generation was measured using a modified prothrombinase assay, and the overall thrombin generation rate was solved using typical Michaelis-Menten kinetics. Platelet surface P-selectin and phosphatidylserine (PS) expression was measured using flow cytometry. The results demonstrated that the concentration of factor Va had a dominant effect on thrombin generation rate under flow. In comparison, the expression of PS was less sensitive to altered flow. The lumped overall rate constant for prothrombin conversion to thrombin was significantly affected by the shear forces that were applied to the coagulation complex. Constant shear stress/rate induced faster thrombin generation compared to pulsatile shear stress/rate, but elevated shear stress/rate did not necessarily enhance thrombin generation. Therefore, the overall thrombin generation rate is dynamic and must be described as a function of shear stress/rate, shear exposure time and the immediate availability of coagulation proteins.

  4. Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis

    PubMed Central

    Danforth, Christopher M.; Orfeo, Thomas; Everse, Stephen J.; Mann, Kenneth G.; Brummel-Ziedins, Kathleen E.

    2012-01-01

    In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are studied. In this study we have defined the consequences of normal range variation of components of the coagulation proteome by using a mechanism-based computational approach that translates coagulation factor concentration data into a representation of an individual's thrombin generation potential. A novel graphical method is used to integrate standard measures that characterize thrombin generation in both empirical and computational models (e.g max rate, max level, total thrombin, time to 2 nM thrombin (“clot time”)) to visualize how normal range variation in coagulation factors results in unique thrombin generation phenotypes. Unique ensembles of the 8 coagulation factors encompassing the limits of normal range variation were used as initial conditions for the computational modeling, each ensemble representing “an individual” in a theoretical healthy population. These “individuals” with unremarkable proteome composition was then compared to actual normal and “abnormal” individuals, i.e. factor ensembles measured in apparently healthy individuals, actual coagulopathic individuals or artificially constructed factor ensembles representing individuals with specific factor deficiencies. A sensitivity analysis was performed to rank either individual factors or all possible pairs of factors in terms of their contribution to the overall distribution of thrombin generation phenotypes. Key findings of these analyses include: normal range variation of coagulation factors yields thrombin generation phenotypes indistinguishable from individuals with some, but not all, coagulopathies examined; coordinate variation of certain pairs of factors within their normal ranges

  5. Alpha-1 proteinase inhibitor M358R reduces thrombin generation when displayed on the surface of cells expressing tissue factor.

    PubMed

    Gierczak, Richard F; Pepler, Laura; Bhagirath, Vinai; Liaw, Patricia C; Sheffield, William P

    2014-11-01

    The M358R variant of alpha-1-proteinase inhibitor (API) is a potent soluble inhibitor of thrombin. Previously we engineered AR-API M358R, a membrane-bound form of this protein and showed that it inhibited exogenous thrombin when expressed on transfected cells lacking tissue factor (TF). To determine the suitability of AR-API M358R for gene transfer to vascular cells to limit thrombogenicity, we tested the ability of AR-API M358R to inhibit endogenous thrombin generated in plasma via co-expression co-expressing it on the surface of cells expressing TF. Transfected AR-API M358R formed inhibitory complexes with thrombin following exposure of recalcified, defibrinated plasma to TF on T24/83 cells, but discontinuously monitored thrombin generation was unaffected. Similarly, AR-API M358R expression did not reduce continuously monitored thrombin generation by T24/83 cell suspensions exposed to recalcified normal plasma in a Thrombogram-Thrombinoscope-type thrombin generation assay (TGA); in contrast, 1 μM hirudin variant 3 or soluble API M358R abolished thrombin generation. Gene transfer of TF to HEK 293 conferred the ability to support TF-dependent thrombin generation on HEK 293 cells. Co-transfection of HEK 293 cells with a 9:1 excess of DNA encoding AR-API M358R to that encoding TF reduced peak thrombin generation approximately 3-fold compared to controls. These in vitro results suggest that surface display of API M358R inhibits thrombin generation when the tethered serpin is expressed in excess of TF, and suggest its potential to limit thrombosis in appropriate vascular beds in animal models. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Low molecular weight heparins prevent thrombin-induced thrombo-embolism in mice despite low anti-thrombin activity. Evidence that the inhibition of feed-back activation of thrombin generation confers safety advantages over direct thrombin inhibition.

    PubMed

    Momi, S; Nasimi, M; Colucci, M; Nenci, G G; Gresele, P

    2001-03-01

    Thrombin-induced thromboembolism in mice is a model in which the feed-back clotting activation produced by the injected enzyme greatly contributes to fibrin accumulation in lungs and to mortality. Using this model we have previously shown that activated human protein C (aPC), by interrupting endogenous clotting activation at a high level (factors Va and VIIIa), prevents mortality inducing only a minor hemostatic impairment. With the same model we have now compared the antithrombotic and prohemorrhagic effects of two low molecular weight heparins (LMWHs), reviparin and tinzaparin, which are expected to inhibit preferentially the positive feed-back triggered by thrombin (anti Xa activity), with those of unfractionated heparin (UFH) and PEG-hirudin, which inhibit mainly or exclusively thrombin activity (anti IIa activity). Pulmonary thromboembolism was induced in mice by i.v. injection of bovine thrombin (1,000U/kg). Drugs (from 0.12 to 1.2 mg/kg) were given as bolus injection 2 min prior to thrombin challenge and mortality was assessed within 15 min. The bleeding time was assessed by a tail tip transection model. Activated partial thromboplastin time (aPTT), thrombin clotting time (TcT), fibrinogen assay and anti Xa activity determination were performed in citrated plasma from saline- or drug-treated animals. All drugs protected mice from thrombin-induced mortality in a dose-dependent way. At comparable antithrombotic dosages, the anti IIa activity generated in plasma (assessed by TcT) was highest with UFH, intermediate with tinzaparin and very low with reviparin. Accordingly, the fibrinogen drop, which is caused mainly by the injected thrombin, was prevented by the heparins to an extent that was fairly well related to their anti IIa activity. aPTT and bleeding time, used as measures of hemorrhagic risk, were markedly more prolonged by UFH than by reviparin. Tinzaparin, instead, had an intermediate effect. Interestingly, PEG-hirudin, at equipotent antithrombotic

  7. Dynamics of Thrombin Generation and Flux from Clots during Whole Human Blood Flow over Collagen/Tissue Factor Surfaces.

    PubMed

    Zhu, Shu; Lu, Yichen; Sinno, Talid; Diamond, Scott L

    2016-10-28

    Coagulation kinetics are well established for purified blood proteases or human plasma clotting isotropically. However, less is known about thrombin generation kinetics and transport within blood clots formed under hemodynamic flow. Using microfluidic perfusion (wall shear rate, 200 s(-1)) of corn trypsin inhibitor-treated whole blood over a 250-μm long patch of type I fibrillar collagen/lipidated tissue factor (TF; ∼1 TF molecule/μm(2)), we measured thrombin released from clots using thrombin-antithrombin immunoassay. The majority (>85%) of generated thrombin was captured by intrathrombus fibrin as thrombin-antithrombin was largely undetectable in the effluent unless Gly-Pro-Arg-Pro (GPRP) was added to block fibrin polymerization. With GPRP present, the flux of thrombin increased to ∼0.5 × 10(-12) nmol/μm(2)-s over the first 500 s of perfusion and then further increased by ∼2-3-fold over the next 300 s. The increased thrombin flux after 500 s was blocked by anti-FXIa antibody (O1A6), consistent with thrombin-feedback activation of FXI. Over the first 500 s, ∼92,000 molecules of thrombin were generated per surface TF molecule for the 250-μm-long coating. A single layer of platelets (obtained with αIIbβ3 antagonism preventing continued platelet deposition) was largely sufficient for thrombin production. Also, the overall thrombin-generating potential of a 1000-μm-long coating became less efficient on a per μm(2) basis, likely due to distal boundary layer depletion of platelets. Overall, thrombin is robustly generated within clots by the extrinsic pathway followed by late-stage FXIa contributions, with fibrin localizing thrombin via its antithrombin-I activity as a potentially self-limiting hemostatic mechanism. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Anticoagulants and the Propagation Phase of Thrombin Generation

    PubMed Central

    Orfeo, Thomas; Gissel, Matthew; Butenas, Saulius; Undas, Anetta; Brummel-Ziedins, Kathleen E.; Mann, Kenneth G.

    2011-01-01

    The view that clot time-based assays do not provide a sufficient assessment of an individual's hemostatic competence, especially in the context of anticoagulant therapy, has provoked a search for new metrics, with significant focus directed at techniques that define the propagation phase of thrombin generation. Here we use our deterministic mathematical model of tissue-factor initiated thrombin generation in combination with reconstructions using purified protein components to characterize how the interplay between anticoagulant mechanisms and variable composition of the coagulation proteome result in differential regulation of the propagation phase of thrombin generation. Thrombin parameters were extracted from computationally derived thrombin generation profiles generated using coagulation proteome factor data from warfarin-treated individuals (N = 54) and matching groups of control individuals (N = 37). A computational clot time prolongation value (cINR) was devised that correlated with their actual International Normalized Ratio (INR) values, with differences between individual INR and cINR values shown to derive from the insensitivity of the INR to tissue factor pathway inhibitor (TFPI). The analysis suggests that normal range variation in TFPI levels could be an important contributor to the failure of the INR to adequately reflect the anticoagulated state in some individuals. Warfarin-induced changes in thrombin propagation phase parameters were then compared to those induced by unfractionated heparin, fondaparinux, rivaroxaban, and a reversible thrombin inhibitor. Anticoagulants were assessed at concentrations yielding equivalent cINR values, with each anticoagulant evaluated using 32 unique coagulation proteome compositions. The analyses showed that no anticoagulant recapitulated all features of warfarin propagation phase dynamics; differences in propagation phase effects suggest that anticoagulants that selectively target fXa or thrombin may

  9. Computational analysis of the effects of reduced temperature on thrombin generation: the contributions of hypothermia to coagulopathy.

    PubMed

    Mitrophanov, Alexander Y; Rosendaal, Frits R; Reifman, Jaques

    2013-09-01

    that can be used to simulate the effects of changing temperature on the kinetics of biochemical systems and applied this strategy to analyze the effects of hypothermia on thrombin generation. We found that thrombin generation can be noticeably impaired in subjects with different blood plasma composition even in moderate hypothermia. Our work provides mechanistic support to the notion that thrombin generation impairment may be a key factor in coagulopathy induced by hypothermia and complicated by blood plasma dilution.

  10. Effect of BAX499 aptamer on tissue factor pathway inhibitor function and thrombin generation in models of hemophilia

    PubMed Central

    Gissel, Matthew; Orfeo, Thomas; Foley, Jonathan H; Butenas, Saulius

    2012-01-01

    Summary Introduction In hemophilia, thrombin generation is significantly suppressed due to decreased factor (F)X activation. Clinical studies and experiments with transgenic mice have suggested that the severity of hemophilia is substantially reduced by tissue factor pathway inhibitor (TFPI) deficiency. Methods We evaluated the effect of TFPI antagonist aptamer BAX499 (formerly ARC19499) on TFPI function in purified systems and on thrombin generation and clot formation in plasma and blood. Results BAX499 effectively neutralized TFPI inhibition of FXa and FXa dependent inhibition of TF/FVIIa by TFPI. BAX499 did not inhibit FXa or TF/FVIIa when used up to 500 nM. In the synthetic coagulation proteome with TFPI at its mean physiologic concentration, BAX499 at 1 – 10 nM increased thrombin generation triggered with 5 pM relipidated TF in a concentration-dependent manner. In severe hemophilia A or B models using the synthetic coagulation proteome, the addition of BAX499 at 5 nM increased thrombin generation to the levels observed in normal control. Thrombin generation measured in induced hemophilia B plasma required ~100 nM BAX499 to restore thrombin levels to those seen in untreated plasma. In induced hemophilia B whole blood, BAX499 repaired the clotting time but failed to appreciably impact the propagation phase of thrombin generation. Conclusion These data suggest that inhibition of TFPI by BAX499 may have potential for hemophilia treatment but requires further study in blood-based hemophilia systems. PMID:22951415

  11. Ex vivo thrombin generation patterns in septic patients with and without disseminated intravascular coagulation.

    PubMed

    Carlier, Laurence; Hunault, Gilles; Lerolle, Nicolas; Macchi, Laurent

    2015-01-01

    The thrombin generation test (TGT) describes the ability of the plasma to generate thrombin. Its usefulness in septic patients has yet to be assessed. Patients admitted for severe sepsis in a medical intensive care unit were sampled for TGT on day 0, 3, 6, and 10. TGT data were compared to "classical" hemostastic tests and to outcome parameters, notably disseminated intravascular coagulation (DIC) according to International Society for Thrombosis and Hemostasis criteria as well as survival. A total of 102 patients were recruited of whom 11 received therapeutic anticoagulation and showed profoundly-altered TGT parameters. In comparison to healthy subjects, the 67 septic patients without DIC exhibited longer Lag times, higher Rate Indices, no change in peak or amount of thrombin generated, although the return to baseline was prolonged. In the 24 DIC patients, Lag time and Rate Index did not differ from healthy subjects (Rate Index being significantly lower than in Sepsis patients). The decreases in peak and amount of thrombin generated were not significant. Return to baseline was prolonged comparatively to Sepsis patients. Due to a large overlap of TGT values between groups, the ability of TGT parameters to diagnose DIC or predict survival was respectively poor or absent. The thrombin Generation Test displayed particular patterns in septic patients and in septic DIC patients. The wide overlap between patients in TGT values prevents the usefulness of this test in clinical practice. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Characterization of the thrombin generation potential of leukemic and solid tumor cells by calibrated automated thrombography

    PubMed Central

    Marchetti, Marina; Diani, Erika; ten Cate, Hugo; Falanga, Anna

    2012-01-01

    Background Thrombin, the final enzyme of blood coagulation, is a multifunctional serine protease also involved in the progression of cancer. Tumor cells may activate blood coagulation proteases through the expression of procoagulant activities. However, specific information about the thrombin generation potential of malignant tissues is lacking. In this study we applied a single global coagulation test, the calibrated automated thrombogram assay, to characterize the specific procoagulant phenotypes of different tumor cells. Design and Methods Malignant hematologic cells (i.e. NB4, HEL, and K562) or solid tumor cells (i.e. MCF-7 breast cancer and H69 small cell lung cells) were selected for the study. The calibrated automated thrombo-gram assay was performed in normal plasma and in plasma samples selectively deficient in factor VII, XII, IX or X, in the absence or presence of a specific anti-tissue factor antibody. Furthermore, cell tissue factor levels were characterized by measuring antigen, activity and mRNA expression. Results In normal plasma, NB4 induced the highest thrombin generation, followed by MCF-7, H69, HEL, and K562 cells. The anti-tissue factor antibody, as well as deficiencies of factors VII, IX and XII affected the thrombin generation potential of malignant cells to different degrees, allowing differentiation of the two different pathways of blood clotting activation – by tissue factor or contact activation. The thrombin generation capacity of NB4 and MCF-7 cells was tissue factor-dependent, as it was highly sensitive to inhibition by anti-tissue factor antibody and factor VII deficiency, while the thrombin generation capacity of H69, HEL and K562 was contact activation-dependent, as no thrombin was generated by these cells in factor XII-deficient plasma. Conclusions This study demonstrates that the calibrated automated thrombogram assay is capable of quantifying, characterizing, and comparing the thrombin generation capacity of different tumor

  13. Preoperative thrombin generation is predictive for the risk of blood loss after cardiac surgery: a research article.

    PubMed

    Bosch, Yvonne; Al Dieri, Raed; ten Cate, Hugo; Nelemans, Patty; Bloemen, Saartje; Hemker, Coenraad; Weerwind, Patrick; Maessen, Jos; Mochtar, Baheramsjah

    2013-06-12

    In this study the value of thrombin generation parameters measured by the Calibrated Automated Thrombography for prediction of blood loss after cardiac surgery with cardiopulmonary bypass was investigated. Thirty male patients undergoing first-time coronary artery bypass grafting were enrolled. Blood samples were taken pre-bypass before heparinisation (T1) and 5 min after protamine administration (T2). Thrombin generation was measured both in platelet-rich plasma and in platelet-poor plasma. Besides thrombin generation measurements, activated clotting time, haematocrit, haemoglobin, platelet number, fibrinogen, antithrombin, D-dimers, prothrombin time and activated partial thromboplastin time were determined. Blood loss was measured and the amount of transfusion products was recorded postoperatively until 20 hours after surgery. Patients were divided into two groups based on the median volume of postoperative blood loss (group 1: patients with median blood loss <930 ml; group 2: patients with median blood loss ≥930 ml). On T1, patients of group 2 had a significantly lower endogenous thrombin potential and peak thrombin (p<0.001 and p=0.004 respectively) in platelet-rich plasma, a significantly lower endogenous thrombin potential (p=0.004) and peak thrombin (p=0.014) in platelet-poor plasma, and a lower platelet count (p=0.002). On T2 both endogenous thrombin potential and peak thrombin remain significantly lower (p=0.011 and p=0.010) in group 2, measured in platelet-rich plasma but not in platelet-poor plasma. In addition, platelet number remains lower in group 2 after protamine administration (p=0.002). The key finding is that the Calibrated Automated Thrombography assay, performed preoperatively, provides information predictive for blood loss after cardiac surgery.

  14. Influence of single nucleotide polymorphisms on thrombin generation in factor V Leiden heterozygotes.

    PubMed

    Segers, O; Simioni, P; Tormene, D; Castoldi, E

    2014-03-03

    Carriership of the factor V (FV) Leiden mutation increases the risk of venous thromboembolism (VTE) ~4-fold, but the individual risk of each FV Leiden carrier depends on several co-inherited risk and protective factors. Under the hypothesis that thrombin generation might serve as an intermediate phenotype to identify genetic modulators of VTE risk, we enrolled 188 FV Leiden heterozygotes (11 with VTE) and determined the following parameters: thrombin generation in the absence and presence of activated protein C (APC); plasma levels of prothrombin, factor X, antithrombin, protein S and tissue factor pathway inhibitor; and the genotypes of 24 SNPs located in the genes encoding these coagulation factors and inhibitors. Multiple regression analysis was subsequently applied to identify the (genetic) determinants of thrombin generation. The endogenous thrombin potential (ETP) showed a striking inter-individual variability among different FV Leiden carriers and, especially when measured in the presence of APC, correlated with VTE risk. Several SNPs in the F2 (rs1799963, rs3136516), F10 (rs693335), SERPINC1 (rs2227589), PROS1 (Heerlen polymorphism) and TFPI (rs5940) genes significantly affected the ETP-APC and/or the ETP+APC in FV Leiden carriers. Most of these SNPs have shown an association with VTE risk in conventional epidemiological studies, suggesting that the genetic dissection of thrombin generation leads to the detection of clinically relevant SNPs. In conclusion, we have identified several SNPs that modulate thrombin generation in FV Leiden heterozygotes. These SNPs may help explain the large variability in VTE risk observed among different FV Leiden carriers.

  15. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation

    PubMed Central

    Stopa, Jack D.; Neuberg, Donna; Puligandla, Maneka; Furie, Bruce; Zwicker, Jeffrey I.

    2017-01-01

    BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies. RESULTS: Following oral administration of 1,000 mg isoquercetin to healthy adults, the measured peak plasma quercetin concentration (9.2 μM) exceeded its IC50 for inhibition of PDI by isoquercetin in vitro (2.5 ± 0.4 μM). Platelet-dependent thrombin generation decreased by 51% in the healthy volunteers compared with baseline (P = 0.0004) and by 64% in the anti-phospholipid antibody cohort (P = 0.015) following isoquercetin ingestion. To understand how PDI affects thrombin generation, we evaluated substrates of PDI identified using an unbiased mechanistic-based substrate trapping approach. These studies identified platelet factor V as a PDI substrate. Isoquercetin blocked both platelet factor Va and thrombin generation with an IC50 of ~5 μM. Inhibition of PDI by isoquercetin ingestion resulted in a 53% decrease in the generation of platelet factor Va (P = 0.001). Isoquercetin-mediated inhibition was reversed with addition of exogenous factor Va. CONCLUSION: These studies show that oral administration of isoquercetin inhibits PDI activity in plasma and diminishes platelet-dependent thrombin generation predominantly by blocking the generation of platelet factor Va. These pharmacodynamic and mechanistic observations represent an important step in the development of a novel class of antithrombotic agents targeting PDI. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01722669) FUNDING: National Heart

  16. Mechanistic Modeling of the Effects of Acidosis on Thrombin Generation

    DTIC Science & Technology

    2015-08-01

    coagulopathy .1–3 Acidosis arises when trauma is accompanied by severe hemor- rhage and shock, and the resulting hypoperfusion leads to the accumulation of...potentially be used to discriminate between physiological and acidotic thrombin generation— a question related to the problem of coagulopathy diag...associated coagulopathy can have several causes, including plasma dilution and hypothermia. Our results suggest that the effect of acidosis on

  17. Systems Biology of Coagulation Initiation: Kinetics of Thrombin Generation in Resting and Activated Human Blood

    PubMed Central

    Chatterjee, Manash S.; Denney, William S.; Jing, Huiyan; Diamond, Scott L.

    2010-01-01

    Blood function defines bleeding and clotting risks and dictates approaches for clinical intervention. Independent of adding exogenous tissue factor (TF), human blood treated in vitro with corn trypsin inhibitor (CTI, to block Factor XIIa) will generate thrombin after an initiation time (Ti) of 1 to 2 hours (depending on donor), while activation of platelets with the GPVI-activator convulxin reduces Ti to ∼20 minutes. Since current kinetic models fail to generate thrombin in the absence of added TF, we implemented a Platelet-Plasma ODE model accounting for: the Hockin-Mann protease reaction network, thrombin-dependent display of platelet phosphatidylserine, VIIa function on activated platelets, XIIa and XIa generation and function, competitive thrombin substrates (fluorogenic detector and fibrinogen), and thrombin consumption during fibrin polymerization. The kinetic model consisting of 76 ordinary differential equations (76 species, 57 reactions, 105 kinetic parameters) predicted the clotting of resting and convulxin-activated human blood as well as predicted Ti of human blood under 50 different initial conditions that titrated increasing levels of TF, Xa, Va, XIa, IXa, and VIIa. Experiments with combined anti-XI and anti-XII antibodies prevented thrombin production, demonstrating that a leak of XIIa past saturating amounts of CTI (and not “blood-borne TF” alone) was responsible for in vitro initiation without added TF. Clotting was not blocked by antibodies used individually against TF, VII/VIIa, P-selectin, GPIb, protein disulfide isomerase, cathepsin G, nor blocked by the ribosome inhibitor puromycin, the Clk1 kinase inhibitor Tg003, or inhibited VIIa (VIIai). This is the first model to predict the observed behavior of CTI-treated human blood, either resting or stimulated with platelet activators. CTI-treated human blood will clot in vitro due to the combined activity of XIIa and XIa, a process enhanced by platelet activators and which proceeds in the

  18. Systems biology of coagulation initiation: kinetics of thrombin generation in resting and activated human blood.

    PubMed

    Chatterjee, Manash S; Denney, William S; Jing, Huiyan; Diamond, Scott L

    2010-09-30

    Blood function defines bleeding and clotting risks and dictates approaches for clinical intervention. Independent of adding exogenous tissue factor (TF), human blood treated in vitro with corn trypsin inhibitor (CTI, to block Factor XIIa) will generate thrombin after an initiation time (T(i)) of 1 to 2 hours (depending on donor), while activation of platelets with the GPVI-activator convulxin reduces T(i) to ∼20 minutes. Since current kinetic models fail to generate thrombin in the absence of added TF, we implemented a Platelet-Plasma ODE model accounting for: the Hockin-Mann protease reaction network, thrombin-dependent display of platelet phosphatidylserine, VIIa function on activated platelets, XIIa and XIa generation and function, competitive thrombin substrates (fluorogenic detector and fibrinogen), and thrombin consumption during fibrin polymerization. The kinetic model consisting of 76 ordinary differential equations (76 species, 57 reactions, 105 kinetic parameters) predicted the clotting of resting and convulxin-activated human blood as well as predicted T(i) of human blood under 50 different initial conditions that titrated increasing levels of TF, Xa, Va, XIa, IXa, and VIIa. Experiments with combined anti-XI and anti-XII antibodies prevented thrombin production, demonstrating that a leak of XIIa past saturating amounts of CTI (and not "blood-borne TF" alone) was responsible for in vitro initiation without added TF. Clotting was not blocked by antibodies used individually against TF, VII/VIIa, P-selectin, GPIb, protein disulfide isomerase, cathepsin G, nor blocked by the ribosome inhibitor puromycin, the Clk1 kinase inhibitor Tg003, or inhibited VIIa (VIIai). This is the first model to predict the observed behavior of CTI-treated human blood, either resting or stimulated with platelet activators. CTI-treated human blood will clot in vitro due to the combined activity of XIIa and XIa, a process enhanced by platelet activators and which proceeds in the

  19. Thrombin generation by exposure of blood to endotoxin: a simple model to study disseminated intravascular coagulation.

    PubMed

    Stief, T W

    2006-04-01

    Pathologic disseminated intravascular coagulation (PDIC) is a serious complication in sepsis. In an in-vitro system consisting of incubation of fresh citrated blood with lipopolysaccharides (LPS) or glucans and subsequent plasma recalcification plasmatic thrombin was quantified. Five hundred microliters of freshly drawn citrated blood of healthy donors were incubated with up to 800 ng/mL LPS (Escherichia coli) or up to 80 microg/mL Zymosan A (ZyA; Candida albicans) for 30 minutes at room temperature (RT). The samples were centrifuged, and 30 microL plasma were recalcified with 1 volume or less of CaCl(2) (25 micromoles Ca(2+)/mL plasma). After 0 to 12 minutes (37 degrees C), 20 microL 2.5 M arginine, pH 8.6, were added. Thirty microliters 0.9 mM HD-CHG-Ala-Arg-pNA in 2.3 M arginine were added, and the absorbance increase at 405 nm was determined. Fifty microliters plasma were also incubated with 5 microL 250 mM CaCl2 for 5, 10, or 15 minutes (37 degrees C). Fifty microliters 2.5 M arginine stops coagulation, and 50 microL 0.77 mM HD-CHG-Ala-Arg-pNA in 2.3 M arginine starts the thrombin detection. The standard was 1 IU/mL thrombin in 7% human albumin instead of plasma. Arginine was also added in the endotoxin exposure time (EET) or in the plasma coagulation reaction time (CRT). Tissue factor (TF)-antigen and soluble CD14 were determined. LPS at blood concentrations greater than 10 ng/mL or ZyA at greater than 1 microg/mL severalfold enhance thrombin generation, when the respective plasmas are recalcified. After 30 minutes EET at RT, the thrombin activity at 12 minutes CRT generated by the addition of 200 ng/mL LPS or 20 microg/mL ZyA is approximately 200 mIU/mL compared to approximately 20 mIU/mL without addition of endotoxin, or compared to about 7 mIU/mL thrombin at 0 minutes CRT. Arginine added to blood or to plasma inhibits thrombin generation; the inhibitory concentration 50% (IC 50) is approximately 15 mM plasma concentration. Endotoxin incubation of blood

  20. Thrombin Generation Capacity of Prothrombin Complex Concentrate in an In Vitro Dilutional Model

    PubMed Central

    Grottke, Oliver; Rossaint, Rolf; Henskens, Yvonne; van Oerle, Rene; ten Cate, Hugo; Spronk, Henri M. H.

    2013-01-01

    Background The use of PCC for the treatment of trauma-induced coagulopathy potentially increase the risk of thromboembolism and disseminated intravascular coagulation, which is addressed to an imbalance of both pro- and anticoagulants. As PCCs differ in composition, we used an in vitro dilutional approach to assess the overall thrombin generation of five different PCCs through various laboratory assays. Methods The vitamin K-dependent coagulation factors, heparin, and antithrombin were assessed in five commercially available PCCs. The procoagulant potential of the PCCs was assessed in plasma and whole blood from 4 healthy donors by means of classical coagulation assays, thrombin generation assay and thromboelastometry. In order to reflect coagulopathy, whole blood was diluted to 80, 60, 40, and 20% with Ringer’s lactate solution. Results The five different PCCs were characterised by comparable levels of factors II, VII, IX and X (all around 20–30 IU/mL), whereas the heparin (0 to 17.6 IU/mL) and antithrombin (0.06 to 1.29 IU/mL) levels were remarkably different between manufactures. In vitro dilution of blood induced a prolongation of the PT and aPTT, and attenuation of thrombin generation and ExTem induced thromboelastometry. Overall, non- or low-heparin containing PCCs restored the in vitro dilutional coagulopathy, whereas PCCs containing heparin have an anticoagulant effect. The thrombin generation assay showed to be the most sensitive method for assessment of PCC effects. Conclusions This study shows that most available PCCs are not balanced regarding their pro- and anticoagulants. The effect of measured differences in thrombin generation among different PCCs requires further investigations to elaborate the clinical meaning of this finding in the treatment of trauma induced coagulopathy. PMID:23696866

  1. Protein Z efficiently depletes thrombin generation in disseminated intravascular coagulation with poor prognosis.

    PubMed

    Lee, Nuri; Kim, Ji-Eun; Gu, Ja-Yoon; Yoo, Hyun Ju; Kim, Inho; Yoon, Sung-Soo; Park, Seonyang; Han, Kyou-Sup; Kim, Hyun Kyung

    2016-01-01

    Disseminated intravascular coagulation (DIC) is characterized by consumption of coagulation factors and anticoagulants. Thrombin generation assay (TGA) gives useful information about global hemostatic status. We developed a new TGA system that anticoagulant addition can deplete thrombin generation in plasma, which may reflect defective anticoagulant system in DIC. TGAs were measured on the calibrated automated thrombogram with and without thrombomodulin or protein Z in 152 patients who were suspected of having DIC, yielding four parameters including lag time, endogenous thrombin potential, peak thrombin and time-to-peak in each experiment. Nonsurvivors showed significantly prolonged lag time and time-to-peak in TGA-protein Z system, which was performed with added protein Z. In multivariate Cox regression analysis, lag time and time-to-peak in TGA system were significant independent prognostic factors. In TGA-protein Z system, lag time and time-to-peak were revealed as independent prognostic factors of DIC. Protein Z addition could potentiate its anticoagulant effect in DIC with poor prognosis, suggesting the presence of defective protein Z system. The prolonged lag time and time-to-peak in both TGA and TGA-protein Z systems are expected to be used as independent prognostic factors of DIC.

  2. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4.

    PubMed

    Semeraro, Fabrizio; Ammollo, Concetta T; Morrissey, James H; Dale, George L; Friese, Paul; Esmon, Naomi L; Esmon, Charles T

    2011-08-18

    The release of histones from dying cells is associated with microvascular thrombosis and, because histones activate platelets, this could represent a possible pathogenic mechanism. In the present study, we assessed the influence of histones on the procoagulant potential of human platelets in platelet-rich plasma (PRP) and in purified systems. Histones dose-dependently enhanced thrombin generation in PRP in the absence of any trigger, as evaluated by calibrated automated thrombinography regardless of whether the contact phase was inhibited. Activation of coagulation required the presence of fully activatable platelets and was not ascribable to platelet tissue factor, whereas targeting polyphosphate with phosphatase reduced thrombin generation even when factor XII (FXII) was blocked or absent. In the presence of histones, purified polyphosphate was able to induce thrombin generation in plasma independently of FXII. In purified systems, histones induced platelet aggregation; P-selectin, phosphatidylserine, and FV/Va expression; and prothrombinase activity. Blocking platelet TLR2 and TLR4 with mAbs reduced the percentage of activated platelets and lowered the amount of thrombin generated in PRP. These data show that histone-activated platelets possess a procoagulant phenotype that drives plasma thrombin generation and suggest that TLR2 and TLR4 mediate the activation process.

  3. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

    PubMed Central

    Semeraro, Fabrizio; Ammollo, Concetta T.; Morrissey, James H.; Dale, George L.; Friese, Paul; Esmon, Naomi L.

    2011-01-01

    The release of histones from dying cells is associated with microvascular thrombosis and, because histones activate platelets, this could represent a possible pathogenic mechanism. In the present study, we assessed the influence of histones on the procoagulant potential of human platelets in platelet-rich plasma (PRP) and in purified systems. Histones dose-dependently enhanced thrombin generation in PRP in the absence of any trigger, as evaluated by calibrated automated thrombinography regardless of whether the contact phase was inhibited. Activation of coagulation required the presence of fully activatable platelets and was not ascribable to platelet tissue factor, whereas targeting polyphosphate with phosphatase reduced thrombin generation even when factor XII (FXII) was blocked or absent. In the presence of histones, purified polyphosphate was able to induce thrombin generation in plasma independently of FXII. In purified systems, histones induced platelet aggregation; P-selectin, phosphatidylserine, and FV/Va expression; and prothrombinase activity. Blocking platelet TLR2 and TLR4 with mAbs reduced the percentage of activated platelets and lowered the amount of thrombin generated in PRP. These data show that histone-activated platelets possess a procoagulant phenotype that drives plasma thrombin generation and suggest that TLR2 and TLR4 mediate the activation process. PMID:21673343

  4. Tissue factor-driven thrombin generation and inflammation in atherosclerosis.

    PubMed

    ten Cate, Hugo

    2012-05-01

    The transmembrane receptor tissue factor is a prominent protein expressed at macrophages and smooth muscle cells within human atherosclerotic lesions. While many coagulation proteins are detectable in atherosclerosis, a locally active thrombin and fibrin generating molecular machinery may be instrumental in manipulating cellular functions involved in atherogenesis. These include inflammation, angiogenesis and cell proliferation. Indeed, many experimental studies in mice show a correlation between hypercoagulability and increased atherosclerosis. In mice, the amount of atherosclerosis and/or the plaque phenotype, appear to be modifiable by specific anticoagulant interventions. While attempts to vary tissue factor level in the vasculature does not directly reduce plaque burden, the overexpression of tissue factor pathway inhibitor attenuates thrombogenicity and neo intima formation in mice. Moreover, inhibition of factor Xa or thrombin with novel selective agents, including rivaroxaban and dabigatran, inhibits inflammation associated with atherosclerosis in apoE(-/-) mice. The potential to modify a complex chronic disease like atherosclerosis with novel selective anticoagulants merits further clinical study.

  5. Evaluation of Thrombin Generation Assay in Patients With Hemophilia.

    PubMed

    Haghpanah, Sezaneh; Bazrafshan, Asghar; Silavizadeh, Samir; Dehghani, Javad; Afrasiabi, Abdolreza; Karimi, Mehran

    2016-05-01

    We evaluated the correlation between thrombin generation (TG) parameters with bleeding symptoms and disease severity in patients with hemophilia. In this cross-sectional study, 59 patients with hemophilia without inhibitors and regardless of their severity were randomly selected from southern Iran and TG assays were conducted. Bleeding score (BS) was calculated by performing a clinical evaluation using Tosetto questionnaire. Only lag time showed a statistically significant correlation with BS (rs = .316,P= .016). All TG parameters except peak showed association with disease severity (P< .05). Endogenous thrombin potential showed a significant correlation with factor activity level (rs = .459,P< .001). Both lag time and start tail showed significant negative correlations with factor activity level (rs = -0.488,P< .001 andrs = - .289,P< .026, respectively). Although most of the TG parameters evaluated were not significantly correlated with the BS of patients with hemophilia, the majority of TG parameters were significantly associated with factor activity level and disease severity.

  6. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction?

    PubMed

    Dale, Brian; Eikelboom, John W; Weitz, Jeffrey I; Young, Ed; Paikin, Jeremy S; Coppens, Michiel; Whitlock, Richard P; Connolly, Stuart J; Ginsberg, Jeffrey S; Hirsh, Jack

    2013-02-01

    Compared with warfarin, dabigatran is associated with less intracranial hemorrhage, but an increased risk of myocardial infarction. To explore these phenomena, we compared their effects on thrombin generation. Thrombin generation in plasma from 10 patients taking therapeutic doses of warfarin (mean INR 2.6) was compared with that in plasma containing 250 ng/mL dabigatran. Although lag times were similar when thrombin generation was induced by recalcification or with a range of tissue factor concentrations, there was a greater reduction in peak thrombin generation and endogenous thrombin potential in plasma from warfarin-treated patients than in dabigatran-containing plasma. Similar results were obtained when thrombin generation was determined in plasma samples from 18 warfarin or 36 dabigatran treated patients entered into the RE-LY trial. Warfarin suppresses thrombin generation more efficiently than dabigatran. Greater suppression of normal hemostatic mechanisms in the brain and pathological thrombosis at sites of atherosclerotic plaque disruption may explain the higher rate of intracranial bleeding and lower rate of myocardial infarction with warfarin compared with dabigatran.

  7. PLASMA GENERATOR

    DOEpatents

    Foster, J.S. Jr.

    1958-03-11

    This patent describes apparatus for producing an electricity neutral ionized gas discharge, termed a plasma, substantially free from contamination with neutral gas particles. The plasma generator of the present invention comprises a plasma chamber wherein gas introduced into the chamber is ionized by a radiofrequency source. A magnetic field is used to focus the plasma in line with an exit. This magnetic field cooperates with a differential pressure created across the exit to draw a uniform and uncontaminated plasma from the plasma chamber.

  8. Argatroban-coupled Affi-Gel matrix for the purification of thrombin from plasma.

    PubMed

    Lefkowitz, Jerry B

    2005-10-01

    Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay. None of the available purification methods easily deals with this subject. The procedure described in the present paper uses a readily available pharmaceutical agent, argatroban, to construct an affinity matrix. Argatroban has a high affinity for thrombin and its thrombin binding is reversible. Prothrombin derived from a Ba(2+) precipitate of human plasma is used as the starting material. The crude prothrombin can be bulk activated to thrombin using taipan-snake (Oxyuranus scutellatus) venom and bound to the argatroban-coupled matrix without further processing steps. The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis. This purification scheme is rapid, yielding purified thrombin within 2 days.

  9. Coagulopathy by Hypothermia and Acidosis: Mechanisms of Thrombin Generation and Fibrinogen Availability

    DTIC Science & Technology

    2009-07-01

    can- not be immediately corrected by pH neutralization alone. Conclusions: Hypothermia and acidosis impair thrombin generation and fibrinogen...formation have been re- viewed recently.6,7 At the same time , thrombin generation is subject to inhibition from antithrombin III, thrombomodulin...of hypothermia was primarily located in the FVIIa/ tissue factor pathway. Conversely, acidosis of pH 7.1 mod- erately inhibited thrombin generation in

  10. Comparison of markers of coagulation activation and thrombin generation test in uncomplicated pregnancies.

    PubMed

    Joly, Berangere; Barbay, Virginie; Borg, Jeanne-Yvonne; Le Cam-Duchez, Veronique

    2013-09-01

    Pregnancy is a well-established risk factor for venous thromboembolism, and is associated with a state of hypercoagulability or parameters of thrombin generation. Currently, there is a lack of consensual data on thrombin generation during pregnancy. This study aimed to find a sensitive and specific biological marker of coagulation activation and to identify parameters of thrombin generation. The population included 101 women with uncomplicated pregnancies. The objective of this study was to correlate thrombin generation test (measured at 5pM tissue factor, 4μM lipids and without thrombomodulin), with fibrinogen and markers of blood coagulation activation: D-dimer, prothrombin fragments 1+2 (F1+2), thrombin-antithrombin complexes (TAT) and fibrin monomer complexes (FMC) in these women. Internal quality control was performed in each set of experiments. Fibrinogen, D-dimer, F1+2, and TAT concentrations increased significantly throughout pregnancy, and were correlated with term of pregnancy. In our study, thrombin generation seemed to increase early on, and then remained stable throughout normal pregnancy, in contrast with other markers of blood coagulation activation, excepting FMC. The latter are subject to large inter-individual variations, especially during second trimester. No correlation was demonstrated between thrombin generation parameters and other activation markers. While markers of coagulation activation significantly increased during pregnancy, thrombin generation increased only early on and remains stable during pregnancy. Finding a sensitive and specific biological marker for vascular pregnancy complications, such as FMC and thrombin generation levels, requires further investigation. © 2013.

  11. Thrombin generation and international normalized ratio in inherited thrombophilia patients receiving thromboprophylactic therapy.

    PubMed

    Luna-Záizar, Hilda; González-Moncada, Ana Isabel; Padilla-López, Emily Lizbeth; Ramírez-Anguiano, Ana Cristina; Pacheco-Moisés, Fermín Paul; Velasco-Ramírez, Sandra Fabiola; Padilla-Romo, María Guadalupe Zavelia; Borjas-Gutierrez, Cesar; Jaloma-Cruz, Ana Rebeca

    2015-12-01

    Thrombin generation assay (TGA) is useful as a global functional test for assessing bleeding or thrombotic risk and its modification with therapy. We investigated TGA to assess anticoagulation status compared with the international normalized ratio (INR) system in patients with primary thrombophilia receiving and not undergoing thromboprophylaxis. We studied 50 patients with at least one thrombotic event and a confirmed diagnosis of inherited thrombophilia. Thrombin generation was measured in platelet-poor plasma by calibrated automated thrombography (CAT). Patients in optimal anticoagulation (INR: 2.0-3.0) showed an endogenous thrombin potential (ETP) of 14-56% of normal and a peak of 18-55% of normal. A significant inverse relationship between INR and thrombin generation parameters (ETP, peak and velocity index) and a linear correlation for lag time was found in patients treated with vitamin-K antagonists (VKA). Receiver-operating characteristics (ROC) analysis showed that the optimal cutoff for ETP was 1600.2 nM · min (111.6% of normal, with a sensitivity of 96.6% and a specificity of 92.9%) and for the peak was 298.3 nM (112.1% of normal, with a sensitivity of 96.4% and a specificity of 100%). According to this analysis, ETP was able to identify patients with increased thrombotic and hemorrhagic risk, correlating with severe clinical complications. TGA showed excellent sensitivity and specificity for assessing anticoagulation status in patients with primary thrombophilia receiving VKA, with significant advantages with regard to INR. Clinical data strongly support ETP as a valuable indicator of thrombotic or hemorrhagic risk in patients receiving or not receiving thromboprophylaxis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis.

    PubMed

    Matsumoto, Tomoko; Nogami, Keiji; Shima, Midori

    2013-10-01

    Normal haemostasis is maintained by a controlled balance between coagulation and fibrinolysis, involving thrombin and plasmin the respective key enzymes. Simultaneous evaluation of both enzymes facilitates, therefore, an overall understanding of normal and pathological haemostasis. Combined thrombin and plasmin generation (T/P-G) assays have been recently described, and we have adapted the technique to investigate the interplay between coagulation and fibrinolysis in patients with various haemostatic disorders. Our modified T/P-G was initiated by the addition of a mixture of optimised lower concentrations of tissue factor and tissue-type plasminogen activator. Thrombin generation (TG) and plasmin generation (PG) were monitored simultaneously using individual fluorescent substrates in separate microtitre wells. The relationship between coagulation and fibrinolysis was demonstrated by analysing the effects of thrombin inhibitors, activated protein C and thrombomodulin. The most evident impairments in TG were observed with plasma samples deficient of coagulation factors participating in the prothrombinase complex. Defects in PG were observed with deficiencies of factor (F)V, FX, fibrinogen, and plasminogen. TG appeared to be a prerequisite for the initiation of PG, and overall PG was governed by fibrinogen concentration. TG in patients with haemophilia A correlated with levels of FVIII activity, but there was no significant relationship between PG and FVIII:C, confirming that the abnormal haemostasis in haemophilia A results in a severe imbalance between coagulation and fibrinolysis. The findings demonstrate that global haemostasis depends on a sensitive balance between coagulation and fibrinolysis, and that the modified T/P-G assay could provide an enhanced understanding of haemorrhage and thrombosis in clinical practice.

  13. Thrombin generation test for evaluation of antiplatelet treatment in patients with coronary artery disease after percutaneous coronary intervention.

    PubMed

    Berezovskaya, Gelena; Smirnova, Olga; Malev, Eduard; Khromov-Borisov, Nikita; Klokova, Elena; Karpenko, Mikhail; Papayan, Lyudmila; Petrishchev, Nikolay

    2017-04-04

    To study the possibility of using thrombin generation tests in platelet-rich and platelet-poor plasma for evaluation of dual antiplatelet therapy efficacy in patients with coronary artery disease (CAD), following percutaneous coronary intervention. Venous blood was analyzed from CAD patients aged 53-75 years who had undergone percutaneous coronary intervention with stenting within one year and had been receiving standard doses of clopidogrel and aspirin (75 and 75-100 mg per day, respectively). The control group comprised age- and sex-matched subjects without clinical signs of CAD who were not receiving these drugs. Thrombin generation tests were performed in platelet-rich and platelet-poor plasma. Intravascular platelet activation, induced platelet aggregation, and routine coagulation were evaluated. Antiplatelet treatment did not influence results of routine coagulation tests or intravascular platelet activation. The dual antiplatelet therapy affects collagen-induced platelet aggregation (44 ± 2.5 vs. 7.9 ± 2.6%, р = 10(-7)) and leads to decreases in endogenous thrombin potential (1900 ± 85 vs. 1740 ± 95 nM∙min, p = 0.0045), maximum thrombin concentration (134 ± 9.5 vs. 106 ± 6.5 nM, p = 4∙10(-6)), and increases in time to peak thrombin (27 ± 1.5 vs. 31 ± 2 min, p = 0.0012). Decreases in thrombin generation rate showed the highest statistical significance (13 ± 2 vs. 7.9 ± 0.8 nM/min, p = 10(-8)). Antiplatelet treatment did not alter thrombogram parameters for platelet-poor plasma.

  14. Kinetic Modeling Sheds Light on the Mode of Action of Recombinant Factor VIIa on Thrombin Generation

    DTIC Science & Technology

    2011-01-01

    Haemost 2004;2:402–13. [20] Brummel Ziedins K, Rivard GE, Pouliot RL, Butenas S, Gissel M, Parhami-Seren B, et al. Factor VIIa replacement therapy in...coagulopathy in a porcine trauma model. J Trauma 2010;68:1151–7. [25] Gallistl S, Cvirn G, Muntean W . Recombinant factor VIIa does not induce...VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX, XI. J Thromb Haemost 2006;4:192–200. [27] Streif W , Paes B, Berry L, Andrew

  15. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

    PubMed Central

    Tucker, Erik I.; Marzec, Ulla M.; White, Tara C.; Hurst, Sawan; Rugonyi, Sandra; McCarty, Owen J. T.; Gailani, David; Hanson, Stephen R.

    2009-01-01

    The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)–dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti–human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and β-thromboglobulin (βTG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface. PMID:18945968

  16. Inhibition of tissue factor pathway inhibitor increases the sensitivity of thrombin generation assay to procoagulant microvesicles.

    PubMed

    Gheldof, Damien; Mullier, François; Chatelain, Bernard; Dogné, Jean-Michel; Chatelain, Christian

    2013-07-01

    Patients with cancer have a seven-fold to 10-fold increased risk of developing venous thromboembolism (VTE). Circulating microvesicles could be a predictive biomarker for VTE in cancer. Thrombin generation assay (TGA) is a useful technique to detect procoagulant activity of microvesicles. However, TGA suffers from a lack of sensitivity due to the presence of tissue factor pathway inhibitor (TFPI) in plasma. The aim of the study was to improve the sensitivity of TGA to tissue factor by limiting the interference of TFPI. Serial dilutions of MDA-MB231 cells were incubated for 45 min at 37°C to generate microvesicles. Samples were then centrifuged and supernatants that contain microvesicles were used for TGA. Normal pooled plasma was incubated with inhibitor of TFPI or was diluted twice to decrease plasma level of TFPI. Lagtime was used as a surrogate marker of TGA to detect procoagulant activity of microvesicles. Inhibition of TFPI decreased twice the cell concentration needed for a significant reduction of lagtime and decreased 2.4-fold the intraassay variability. Plasma dilution had no impact on the TGA sensitivity when TGA was triggered by microvesicles derived from MDA-MB-231. Thrombin generation is a very sensitive method to study the procoagulant activity of tissue factor bearing microvesicles. The sensitivity can be increased by inhibition of TFPI with specific monoclonal antibody against its Kunitz domain I. A two times plasma dilution is an interesting cheaper alternative to study the procoagulant activity of microvesicles by TGA with a good sensitivity, especially when low plasma quantities are available.

  17. Factor XIa and Thrombin Generation Are Elevated in Patients with Acute Coronary Syndrome and Predict Recurrent Cardiovascular Events

    PubMed Central

    Loeffen, Rinske; van Oerle, René; Leers, Mathie P. G.; Kragten, Johannes A.; Crijns, Harry; Spronk, Henri M. H.; ten Cate, Hugo

    2016-01-01

    Objective In acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS. Methods We measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis. Results Thrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310–885) vs. 380(235–540) μg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2–20.9] and 4.5 [1.1–18.9]). Conclusion ACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events. PMID:27419389

  18. Effect of heparin on TAFI-dependent inhibition of fibrinolysis: relative importance of TAFIa generated by clot-bound and fluid phase thrombin.

    PubMed

    Colucci, Mario; Pentimone, Anna; Binetti, Bianca M; Cramarossa, Marialisa; Piro, Donatella; Semeraro, Nicola

    2002-08-01

    Heparin has been proposed to enhance thrombolysis by inhibiting thrombin-dependent generation of activated TAFI (thrombin activatable fibrinolysis inhibitor), a carboxypeptidase that inhibits fibrinolysis. We evaluated the effect of heparin in an in vitro thrombolysis model consisting of a radiolabelled blood clot submerged in defibrinated plasma. Fibrinolysis was induced by adding t-PA (250 ng/ml) and calcium to the plasma bath. Control experiments indicated that thrombin generation induced by recalcification caused significant TAFI activation and inhibited clot lysis. Heparin (up to 1 U/ml), added to the plasma bath, failed to enhance clot lysis. Thrombin generation in the fluid phase was totally inhibited by heparin at concentrations > 0.5 U/ml. In contrast, thrombin generation on the clot surface was not inhibited by heparin (1 U/ml). TAFIa generation did occur in heparin-containing samples (1 U/ml) and amounted to about 10% of TAFIa formed in control samples. This low amount of TAFIa did exert antifibrinolytic activity as indicated by the observation that the addition of a specific TAFIa inhibitor (PTI) along with heparin enhanced clot lysis. Hirudin (10 micrograms/ml), at variance with heparin, inhibited clot-bound thrombin and enhanced clot lysis. These data show that heparin is unable to stimulate fibrinolysis through a TAFI-dependent mechanism, most likely because of its inefficiency in inhibiting thrombin generation on the clot surface. Moreover, they suggest that clot-bound thrombin plays a major role in TAFI-mediated inhibition of fibrinolysis through "localized" TAFIa generation.

  19. The role of whole blood in thrombin generation in contact with various titanium surfaces.

    PubMed

    Thor, Andreas; Rasmusson, Lars; Wennerberg, Ann; Thomsen, Peter; Hirsch, Jan-Michael; Nilsson, Bo; Hong, Jaan

    2007-02-01

    Understanding of the thrombotic response (activation of the intrinsic coagulation system followed by platelet activation) from blood components upon contact with a titanium dental implant is important and not fully understood. The aims of this study were to evaluate: (1) the thrombogenic response of whole blood, platelet-rich plasma (PRP) and platelet-poor plasma (PPP) in contact with a highly thrombogenic surface as titanium, (2) the thrombogenic response of clinically used surfaces as hydroxyapatite (HA), machined titanium (mTi), TiO2 grit-blasted titanium (TiOB) and fluoride ion-modified grit-blasted titanium (TiOB-F). An in vitro slide chamber model, furnished with heparin, was used in which whole blood, PRP or PPP came in contact with slides of the test surfaces. After incubation (60 min rotation at 22 rpm in a 37 degrees C water bath), blood/plasma was mixed with EDTA or citrate, further centrifuged at +4 degrees C (2200 g at 10 min). Finally, plasma was collected pending analysis. Whole blood in contact with Ti alloy resulted in the binding of platelets to the material surface and in the generation of thrombin-antithrombin (TAT) complexes. With whole blood TAT levels increased 1000-fold compared with PRP and PPP, in which both almost no increase of TAT could be detected. In addition, the platelet activation showed a similar pattern with a 15-fold higher release of beta-TG in whole blood. In the in vitro chamber model with the clinically relevant materials, the fluoride-modified surface (TiOB-F) showed pronounced TAT generation compared with TiOB, mTi and HA. Similar results were achieved for platelet consumption and activation markers of the intrinsic coagulation system. Taken together these results implicate first that whole blood is necessary for sufficient thrombin generation and platelet activation during placement of implants. Second, a fluoride ion modification seems to augment the thrombogenic properties of titanium.

  20. Reduced peak, but no diurnal variation, in thrombin generation upon melatonin supplementation in tetraplegia. A randomised, placebo-controlled study.

    PubMed

    Iversen, Per Ole; Dahm, Anders; Skretting, Grethe; Mowinckel, Marie-Christine; Stranda, Annicke; Østerud, Bjarne; Sandset, Per Morten; Kostovski, Emil

    2015-11-01

    Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis. Moreover, they have blunted plasma variations in melatonin and altered diurnal variation of several haemostatic markers, compared with able-bodied. However, whether healthy individuals and tetraplegic patients, with or without melatonin, display abnormalities in thrombin generation during a 24-hour (h) cycle, is unknown. We therefore used the Calibrated Automated Thrombogram (CAT) assay to examine diurnal variations and the possible role of melatonin in thrombin generation. Six men with long-standing complete tetraplegia were included in a randomised placebo-controlled cross-over study with melatonin supplementation (2 mg, 4 consecutive nights), whereas six healthy, able-bodied men served as controls. Ten plasma samples were collected frequently during a 24-h awake/sleep cycle. No significant diurnal variation of any of the measured CAT indices was detected in the three study groups. Whereas endogenous thrombin potential (ETP) was independent (p > 0.05) of whether the tetraplegic men received melatonin or placebo, melatonin decreased (p = 0.005) peak values in tetraplegia compared with those given placebo. Able-bodied men had lower (p = 0.019) ETP and Lag-Time (p = 0.018) compared with tetraplegics receiving placebo. Neither the Time-to-Peak nor the Start-Tail was affected (p > 0.05) by melatonin in tetraplegia. In conclusion, indices of thrombin generation are not subjected to diurnal variation in healthy able-bodied or tetraplegia, but peak thrombin generation is reduced in tetraplegic men receiving oral melatonin.

  1. THROMBIN GENERATION AND PROCOAGULANT MICROPARTICLE (MP) PROFILES AFTER ACUTE TRAUMA: A PROSPECTIVE COHORT STUDY

    PubMed Central

    Park, Myung S.; Xue, Ailing; Spears, Grant M.; Halling, Timothy M.; Ferrara, Michael J.; Kuntz, Melissa M.; Dhillon, Sabtir K.; Jenkins, Donald H.; Harmsen, William S.; Ballman, Karla V.; Heit, John A.

    2015-01-01

    Objective The two sides of Trauma Induced Coagulopathy (TIC), the hypo- and the hyper- coagulable states, are poorly understood. To identify potential mechanisms for venous thromboembolism and bleeding after acute trauma, we estimated changes in circulating procoagulant MPs and thrombin activity during hospitalization for trauma. Methods Whole blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24 and 72 hours after injury, and discharge. Platelet poor plasma was harvested and stored at −80°C until analysis. Thrombin generation was determined using the calibrated automated thrombogram (CAT), reported as lagtime (minutes), peak height (nM thrombin) and time to reach peak height (ttPeak - minutes). The concentration of total procoagulant MPs (number/uL]) was measured by flow cytometry. Data are presented as median [interquartile range]. Results Among 443 trauma patients (1734 samples; ISS=13.0 [6.0, 22.0], hospital LOS=4.0 [2.0, 10.0] days, age=48 [28, 65] years, 70.7% male, 95% with blunt mechanism, mortality 3.2%), no discernable patterns in thrombin generation or MP concentration were observed over time. The peak height and MPs were significantly different from healthy volunteers and were 337 [285, 395] nM and 400 [211, 772] per uL plasma, respectively. Extreme (defined as highest or lowest 5%) values reflecting a possible “hypercoagulable state” (lagtime ≤ 1.98, peak height ≥ 486.2, ttPeak ≤ 3.61, and total procoagulant MP ≥ 2278) were reached within 12 hours after acute trauma, while extreme values representing a possible “hypocoagulable state” (lagtime ≥ 18.6, peak height ≤ 17.8 and ttPeak ≥ 29.45) were not reached until 1-3 days. Conclusion Although there was no predictable pattern of coagulopathy observed in each patient after trauma, those who reached extreme values did so relatively early after injury. These findings should be taken into account when designing risk model tools involving coagulation

  2. Therapeutic Correction of Thrombin Generation in Dilution-Induced Coagulopathy: Computational Analysis Based on a Data Set of Healthy Subjects

    DTIC Science & Technology

    2012-01-01

    Thrombophilia Study. For every simulated thrombin curve, we calculated and analyzed five standard thrombin generation parameters. RESULTS: The three...model of in vitro thrombin accumulation to generate and analyze thrombin curves for the 472 control subjects in the Leiden Thrombophilia Study (LETS).15... Thrombophilia Study (LETS). Thromb Haemost. 1997;78: 631Y635. 16. Brummel-Ziedins KE, Orfeo T, Rosendaal FR, Undas A, Rivard GE, Butenas S, Mann KG

  3. Thrombin generation during collection of blood from donors taking oral contraceptives.

    PubMed

    Skjønsberg, O H; Kierulf, P; Engebretsen, L F; Gjønnes, G; Godal, H C

    1987-01-01

    Thrombin generation, as evidenced by plasma fibrinopeptide A (FPA) concentrations, was studied during blood collection from donors taking oral contraceptives (OC). 450 ml blood were drawn into Fenwal PVC bags from 26 OC users and 28 nonusers. Blood samples for determination of FPA, beta-thromboglobulin (BTG), thrombotest (TT), prekallikrein (PKK), antithrombin-III (AT-III) and factor VIII procoagulant activity (FVIII:C) were drawn from the bags immediately after ending blood donation and following storage for 24 h at 4 degrees C. The FPA concentrations following donation were significantly higher in the OC than in the control group (p less than 0.05). The levels of PKK were also higher in blood obtained from OC users (p less than 0.001), as was the FVIII:C level, the latter difference, however, was not significant (p = 0.06). No cold-promoted activation of factor VII, as evidenced from TT, was detected following storage at 4 degrees C, neither was any change observed in the FPA, PKK and AT-III levels. The BTG concentrations increased significantly during storage, most pronounced in the control group (p less than 0.05). The decay of FVIII:C was similar in the two groups, averaging 24.7%. No correlation was observed between the FPA levels and the other parameters determined. We conclude that thrombin generation is more pronounced during routine blood collection from donors taking OC.

  4. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation.

    PubMed

    Thomas, Christopher P; Morgan, Lloyd T; Maskrey, Benjamin H; Murphy, Robert C; Kühn, Hartmut; Hazen, Stanley L; Goodall, Alison H; Hamali, Hassan A; Collins, Peter W; O'Donnell, Valerie B

    2010-03-05

    Here, a group of specific lipids, comprising phosphatidylethanolamine (PE)- or phosphatidylcholine (PC)-esterified 12S-hydroxyeicosatetraenoic acid (12S-HETE), generated by 12-lipoxygenase was identified and characterized. 12S-HETE-PE/PCs were formed within 5 min of activation by thrombin, ionophore, or collagen. Esterified HETE levels generated in response to thrombin were 5.85 +/- 1.42 (PE) or 18.35 +/- 4.61 (PC), whereas free was 65.5 +/- 17.6 ng/4 x 10(7) cells (n = 5 separate donors, mean +/- S.E.). Their generation was stimulated by triggering protease-activated receptors-1 and -4 and signaling via Ca(2+) mobilization secretory phospholipase A2, platelet-activating factor-acetylhydrolase, src tyrosine kinases, and protein kinase C. Stable isotope labeling showed that they form predominantly by esterification that occurs on the same time scale as free acid generation. Unlike free 12S-HETE that is secreted, esterified HETEs remain cell-associated, with HETE-PEs migrating to the outside of the plasma membrane. 12-Lipoxygenase inhibition attenuated externalization of native PE and phosphatidylserine and HETE-PEs. Platelets from a patient with the bleeding disorder, Scott syndrome, did not externalize HETE-PEs, and liposomes supplemented with HETE-PC dose-dependently enhanced tissue factor-dependent thrombin generation in vitro. This suggests a role for these novel lipids in promoting coagulation. Thus, oxidized phospholipids form by receptor/agonist mechanisms, not merely as an undesirable consequence of vascular and inflammatory disease.

  5. Relationship between short activated partial thromboplastin times, thrombin generation, procoagulant factors and procoagulant phospholipid activity.

    PubMed

    Mina, Ashraf; Favaloro, Emmanuel J; Koutts, Jerry

    2012-04-01

    Short activated partial thromboplastin times (APTTs) are associated with thrombosis. However, what short APTTs actually represent in terms of possible mechanistic pathways is not well characterized. We have assessed thrombin generation as compared with levels of procoagulant factor (fibrinogen, V, VIII, IX, XI and XII) activities, von Willebrand factor level and activity using collagen binding, as well as procoagulant phospholipid activity, in 113 consecutive samples exhibiting a short APTT compared with an equal number of age-matched and sex-matched samples yielding a normal APTT. We found a significant difference in peak thrombin generation, velocity index and area under the curve between the two groups, and that thrombin generation markers correlated with the APTT, procoagulant phospholipid activity and several procoagulant clotting factors. We conclude that short APTTs represent a procoagulant milieu, as represented by heightened thrombin generation and several other heightened procoagulant activities, which may help explain the association with thrombosis.

  6. PLASMA GENERATOR

    DOEpatents

    Wilcox, J.M.; Baker, W.R.

    1963-09-17

    This invention is a magnetohydrodynamic device for generating a highly ionized ion-electron plasma at a region remote from electrodes and structural members, thus avoiding contamination of the plasma. The apparatus utilizes a closed, gas-filled, cylindrical housing in which an axially directed magnetic field is provided. At one end of the housing, a short cylindrical electrode is disposed coaxially around a short axial inner electrode. A radial electrical discharge is caused to occur between the inner and outer electrodes, creating a rotating hydromagnetic ionization wave that propagates aiong the magnetic field lines toward the opposite end of the housing. A shorting switch connected between the electrodes prevents the wave from striking the opposite end of the housing. (AEC)

  7. The impact of major surgery on blood coagulation factors and thrombin generation.

    PubMed

    Horne, McDonald K; Merryman, Paula K; Cullinane, Ann M; Nghiem, Khanh; Alexander, H Richard

    2007-09-01

    We studied the blood coagulation system of 14 patients with metastatic malignancies before and after they had undergone major surgery. In addition to measuring a battery of coagulation factors, we assessed the function of the system with assays of whole blood thrombin generation. With the exceptions of factor VIII (fVIII), which increased, and fibrinogen and fIX, which did not change, the activities of all the pro- and anticoagulant proteins were significantly lower postoperatively. However, the thrombin generating capacity of the system was relatively preserved. Although the integral of thrombin activity over time was lower after surgery, the mean peak thrombin concentration was unchanged and the time to clot formation was shortened. Similar changes could be reproduced by lowering the concentrations of pro- and anticoagulant factors together in control blood samples. Therefore, simultaneous reductions in pro- and anticoagulant proteins postoperatively worked to maintain the functional integrity of the blood coagulation system. 2007 Wiley-Liss, Inc

  8. Computational Analysis of Intersubject Variability and Thrombin Generation in Dilutional Coagulopathy

    DTIC Science & Technology

    2012-11-01

    healthy subjects in the Leiden Thrombophilia Study. Individual thrombin curves were calculated for undiluted blood and for different dilution...performing computa- tional thrombin generation analyses on a data set obtained as a part of the Leiden Thrombophilia Study (LETS).24 Computer modeling...the results. Thromb Res 2007; 119:663-5. 24. van der Meer FJ, Koster T, Vandenbroucke JP, Briët E, Rosendaal FR. The Leiden thrombophilia study (LETS

  9. African-Caribbean ethnicity is associated with a hypercoagulable state as measured by thrombin generation.

    PubMed

    Roberts, Lara N; Patel, Raj K; Chitongo, Paradzai; Bonner, Lynda; Arya, Roopen

    2013-01-01

    African-Caribbean ethnicity is associated with an increased risk of both first and recurrent venous thromboembolism (VTE). The aim of this study was to evaluate thrombin generation in African-Caribbeans compared with whites in patients with deep vein thrombosis (DVT) and healthy volunteers. Thrombin generation was measured in a case-control study of 80 patients who had completed anticoagulation therapy for a first DVT (50 white and 30 African-Caribbean) and 66 controls. Peak thrombin with and without thrombomodulin was significantly higher in African-Caribbeans with DVT compared with whites with DVT (P < 0.001 for both comparisons) and African-Caribbean controls (P < 0.001, 0.003, respectively). Endogenous thrombin potential (ETP) with and without thrombomodulin was significantly higher in African-Caribbeans with DVT than whites with DVT (P ≤ 0.001 for both comparisons). Maximum velocity and ETP ratio were increased in African-Caribbeans with DVT compared with whites with DVT (P < 0.001 and 0.030, respectively) and African-Caribbean controls (P < 0.001 and 0.019, respectively). Within the control group, peak thrombin was significantly increased in African-Caribbeans compared with whites (P = 0.017). ETP, peak thrombin with thrombomodulin and maximum velocity were also increased in African-Caribbeans compared with white controls (P = 0.045 for all comparisons). African-Caribbeans with DVT had significantly higher factor VIII levels compared with whites with DVT and controls. African-Caribbean ethnicity confers a hypercoagulable state as measured by thrombin generation. This supports epidemiological findings of increased risk of first and recurrent VTE. Thrombin generation requires adjustment for ethnicity in studies undertaken in ethnically diverse populations.

  10. Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge

    PubMed Central

    Mahmud, Shawn A.; Lambert, Michele P.; Poncz, Mortimer; Slungaard, Arne

    2007-01-01

    Pharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affects APC generation. Mice completely deficient in PF4 (mPF4−/−) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C–deficient (PC+/−) mice. Transgenic mice overexpressing human PF4 (hPF4+) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen in PC+/− mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4+ and PC+/−/hPF4+ mice had improved survival. Further, infusion of hPF4+ platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting. PMID:17540840

  11. Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge.

    PubMed

    Kowalska, M Anna; Mahmud, Shawn A; Lambert, Michele P; Poncz, Mortimer; Slungaard, Arne

    2007-09-15

    Pharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affects APC generation. Mice completely deficient in PF4 (mPF4(-/-)) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C-deficient (PC(+/-)) mice. Transgenic mice overexpressing human PF4 (hPF4(+)) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen in PC(+/-) mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4(+) and PC(+/-)/hPF4(+) mice had improved survival. Further, infusion of hPF4(+) platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting.

  12. Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation

    PubMed Central

    Dallaku, Kastriot; Shakur, Haleema; Edwards, Phil; Beaumont, Danielle; Roberts, Ian; Huque, Sumaya; Delius, Maria; Mansmann, Ulrich

    2017-01-01

    Background. Postpartum haemorrhage (PPH) is a potentially life-threatening complication for women, and the leading cause of maternal mortality. Tranexamic acid (TXA) is an antifibrinolytic used worldwide to treat uterine haemorrhage and to reduce blood loss in general surgery. TXA may have effects on thrombin generation, platelet function and coagulation factors as a result of its inhibition on the plasmin. Methods. WOMAN ETAPlaT is a sub-study of the World Maternal Antifibrinolitic trial (WOMAN trial). All adult women clinically diagnosed with PPH after a vaginal delivery or caesarean section, are eligible for inclusion in the study. Blood samples will be collected at the baseline and 30 minutes after the first dose of study treatment is given. Platelet function will be evaluated in whole blood immediately after sampling with Multiplate® tests (ADPtest and TRAPtest). Thrombin generation, fibrinogen, D-dimer, and coagulation factors vW, V and VIII will be analysed using platelet poor plasma. Results. Recruitment to WOMAN ETAPlaT started on 04 November 2013 and closed on 13 January 2015, during this time  188 patients were recruited. The final participant follow-up was completed on 04 March 2015. This article introduces the statistical analysis plan for the study, without reference to unblinded data.   Conclusion. The data from this study will provide evidence for the effect of TXA on thrombin generation, platelet function and coagulation factors in women with PPH. Trial registration: ClinicalTrials.gov Identifier: NCT00872469; ISRCTN76912190 PMID:28413832

  13. Effects of tranexamic acid on platelet function and thrombin generation (ETAPlaT): WOMAN trial sub-study

    PubMed Central

    2016-01-01

    Background. Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid (TXA) has the potential to reduce bleeding and a large randomized placebo controlled trial of its effect in women with PPH (The WOMAN trial) is underway. TXA might also affect coagulation factors and platelets.  Objectives. To examine the effect of TXA on thrombin generation, platelet function, fibrinogen, D-dimer and coagulation factors in women with PPH.  Methods. We will conduct a sub-study within the WOMAN trial. Women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion. Blood samples will be collected at baseline and 30 minutes after the first dose of study treatment. Using platelet poor plasma we will measure thrombin generation, fibrinogen, D-dimer, factor V and VIII, and Von Willebrand factor. Platelet function will be evaluated in whole blood using Multiplate® tests. Outcomes. The primary outcome is the effect of TXA on thrombin generation. Secondary outcomes include the effect of TXA on platelet function, fibrinogen, D-dimer and coagulation factors. PMID:28090594

  14. Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation.

    PubMed

    Dallaku, Kastriot; Shakur, Haleema; Edwards, Phil; Beaumont, Danielle; Roberts, Ian; Huque, Sumaya; Delius, Maria; Mansmann, Ulrich

    2016-12-15

    Background. Postpartum haemorrhage (PPH) is a potentially life-threatening complication for women, and the leading cause of maternal mortality. Tranexamic acid (TXA) is an antifibrinolytic used worldwide to treat uterine haemorrhage and to reduce blood loss in general surgery. TXA may have effects on thrombin generation, platelet function and coagulation factors as a result of its inhibition on the plasmin. Methods. WOMAN ETAPlaT is a sub-study of the World Maternal Antifibrinolitic trial (WOMAN trial). All adult women clinically diagnosed with PPH after a vaginal delivery or caesarean section, are eligible for inclusion in the study. Blood samples will be collected at the baseline and 30 minutes after the first dose of study treatment is given. Platelet function will be evaluated in whole blood immediately after sampling with Multiplate® tests (ADPtest and TRAPtest). Thrombin generation, fibrinogen, D-dimer, and coagulation factors vW, V and VIII will be analysed using platelet poor plasma. Results. Recruitment to WOMAN ETAPlaT started on 04 November 2013 and closed on 13 January 2015, during this time  188 patients were recruited. The final participant follow-up was completed on 04 March 2015. This article introduces the statistical analysis plan for the study, without reference to unblinded data.   Conclusion. The data from this study will provide evidence for the effect of TXA on thrombin generation, platelet function and coagulation factors in women with PPH. Trial registration: ClinicalTrials.gov Identifier: NCT00872469; ISRCTN76912190.

  15. Assessment of immunoglobulin concentrates on thrombogenic activity by thrombin generation assay, prekallikrein activator assay, and size-exclusion chromatography.

    PubMed

    Seifner, Alexandra; Beck, Gerhard; Bayer, Patrick; Eichmeir, Stephanie; Lackner, Friedrich; Rögelsperger, Olga; Weber, Katharina; Wollein, Gabriele

    2014-02-01

    Immunoglobulin G (IgG) concentrates have recently been found to be contaminated with procoagulant impurities causing thromboembolic events (TEEs) in vivo. In this study the question was raised whether a thrombin generation assay (TGA) will be able to characterize IgG samples from the Austrian market with regard to their thrombogenic potential. A total of 44 IgG concentrates have been assayed by TGA employing pooled normal plasma and Factor (F)XI-deficient plasma (FXIdp). Furthermore, the prekallikrein activator assay including determination of blank values, size-exclusion chromatography, and further test systems required for batch release testing of IgG concentrates according to the European Pharmacopeia (Pharm. Eur.) were carried out. All samples complied with acceptance criteria stated in the Plarm. Eur. and/or prescribed by the marketing approval. One intravenous immunoglobulin (IVIG) involved in TEEs exceeded a threshold level of 350 nmol peak thrombin, which was not exceeded after change of manufacture and by all the other IVIGs tested. Two hyperimmune globulins revealed elevated peak thrombin levels of up to 810 nmol in FXI and up to 285 nmol in FXIdp. The study indicates that the TGA is able to reliably predict procoagulant activities probably associated with the presence of FXIa and potential thrombogenicity. Comparison of thrombin generation with product-specific acceptance criteria as well as variables from other test systems as amidolytic activity and molecular size can help to monitor IgG quality and manufacturing changes with regard to thrombogenicity. © 2013 American Association of Blood Banks.

  16. Cancer cells BXPC3 and MCF7 differentially reverse the inhibition of thrombin generation by apixaban, fondaparinux and enoxaparin.

    PubMed

    Rousseau, Aurélie; Van Dreden, Patrick; Mbemba, Elisabeth; Elalamy, Ismail; Larsen, Annette; Gerotziafas, Grigoris T

    2015-12-01

    Cancer cells may alter the efficiency of the antithrombotic agents. To explore this possibility, the present study compared the capacity of the LMWH enoxaparin and the specific inhibitors of Xa (apixaban and fondaparinux) to inhibit thrombin generation triggered by pancreas adenocarcinoma cells (BXPC3) and human breast carcinoma cells (MCF7). Samples of platelet poor (PPP) or platelet rich plasma (PRP) spiked with apixaban, fondaparinux or enoxaparin were added in micro wells carrying cancer cells and assessed for thrombin generation. In the control experiment thrombin generation was triggered with tissue factor reagent. The three antithrombotics inhibited thrombin generation in a concentration dependent manner. The BXPC3 and MCF7 cells reversed in a different intensity the effect of the studied agents. According to the histological type of the cancer the antithrombotic efficiency of apixaban was preserved or partially reversed. Fondaparinux, was more vulnerable to the presence of cancer cells as compared to apixaban. The effect of BXCP3 or MCF7 cells on the antithrombotic potency of enoxaparin was of similar magnitude as that on apixaban. The type of cancer cells is determinant for the antithrombotic efficiency of the specific factor Xa inhibitors. In contrast it does not significantly influence the potency of enoxaparin. The present study shows that the impact of the type of cancer cells on the antithrombotic activity of the specific Xa inhibitors should not be neglected. This has to be taken into consideration for the design of dose-finding studies of the direct orally active FXa inhibitors in patients with different histological types of cancer. Copyright © 2015. Published by Elsevier Ltd.

  17. Concentrated lyophilized plasma used for reconstitution of whole blood leads to higher coagulation factor activity but unchanged thrombin potential compared with fresh-frozen plasma.

    PubMed

    Iapichino, Giacomo E; Ponschab, Martin; Cadamuro, Janne; Süssner, Susanne; Gabriel, Christian; Dieplinger, Benjamin; Egger, Margot; Schlimp, Christoph J; Bahrami, Soheyl; Schöchl, Herbert

    2017-07-01

    During massive hemorrhage, it is recommended to transfuse red blood cells, platelet concentrate, and fresh-frozen plasma in a ratio close to 1:1:1. To avoid the thawing process of fresh frozen plasma, lyophilized plasma (LP) is increasingly used. Evidence is limited on the activity of coagulation factors in reconstituted blood using LP and concentrated LP versions. Whole blood from ten healthy volunteers was separated into red blood cell, fresh frozen plasma, and platelet concentrate units. Aliquots of red blood cells and plasma concentrate were mixed with either fresh frozen plasma (200 mL) or LP at reconstitution ratios of 2:1:1, 1:1:1, and 1:1:2. LP was used either at the recommended standard volume of 200 mL (LP200) or was more concentrated at volumes of 100 and 50 mL (LP100 and LP50, respectively). The hemostatic capacity of each reconstituted whole blood sample was tested with blood cell counts, standard coagulation tests, factor activity, thrombin generation, and viscoelastic assays. Hematocrit, platelet counts, and fibrinogen levels of the three ratios were similar between FFP200 and LP200 units but were lower compared with the corresponding ratios in LP100 and LP50 units. The activity of procoagulant and anticoagulant factors increased linearly with the increasing plasmatic fraction and, at 1:1:2 ratio, was significantly higher in LP50 units compared with FFP200 and LP200 units. Thrombin generation was similar throughout the four plasma groups at any ratio. Decreasing the dilution volume of LP facilitates reaching higher hematocrit and coagulation protein levels without a relevant increase in thrombin generation. This is due to preserved balance between procoagulant and anticoagulant factors in the concentrated LP preparations. © 2017 AABB.

  18. Profile of thrombin generation in children with acute lymphoblastic leukemia treated by Berlin-Frankfurt-Münster (BFM) protocols.

    PubMed

    Lejhancova-Tousovska, Katerina; Zapletal, Ondrej; Vytiskova, Sona; Strbackova, Petra; Sterba, Jaroslav

    2012-03-01

    Treatment with L-asparaginase is associated with coagulation disturbances with deep venous thrombosis being the most common clinical consequence. Use of the calibrated automated thrombogram allows precise estimation of thrombin generated in vitro. We show the first data on thrombin generation, measured by calibrated automated thrombography (CAT), in children with acute lymphoblastic leukemia treated with L-asparaginase. Thrombin generation was measured by means of CAT in 23 children treated for acute lymphoblastic leukemia. Samples were obtained at predefined time points during the induction and reinduction phase of acute lymphoblastic leukemia-intercontinental Berlin-Frankfurt-Münster (BFM) 2000 or Associazione Italiana Ematologica Oncologia Pedaitrica Interim BFM 2000 protocols. Antihrombin and fibrinogen were measured on the same sample. Twenty-eight sets of thrombin generation measurements were collected from 23 patients. We observed no significant effect of antithrombin deficiency and/or hypofibrinogenemia on thrombin generation. Endogenous thrombin generation and peak thrombin were significantly higher during induction than in the reinduction phase (P < 0.001). Four patients with severe infection experienced an increase in thrombin generation, reaching maximum in a median of 7.5 days after the onset of infection. Two of those patients developed deep venous thrombosis at the time of peaked endogenous thrombin generation. Thrombin generation in children with acute lymphoblastic leukemia treated according to BFM protocols is significantly higher during the induction phase compared with reinduction and is not substantially affected by hypofibrinogenemia and/or antithrombin deficiency. Severe infection during the induction phase enhances thrombin generation with subsequent risk of thrombosis.

  19. Developing individualized coagulation profiling of disease risk: thrombin generation dynamic models of the pro and anticoagulant balance.

    PubMed

    Brummel-Ziedins, Kathleen E

    2014-05-01

    Global assays and computational models have advanced research into the realm of individualized profiling of hemostatic states. This brief review will describe one computational approach which utilizes an integrated method that evaluates the dynamics of thrombin generation by defining interactions of the pro and anticoagulant proteins, enzymes and cofactors based upon individualized concentrations of select factors. This plasma composition based computational modeling can provide a mechanism based bridge between empirical global assays of coagulation and individualized risk prediction. Copyright © 2014. Published by Elsevier Ltd.

  20. From laboratory to clinical practice: Dabigatran effects on thrombin generation and coagulation in patient samples.

    PubMed

    Helin, Tuukka A; Lemponen, Marja; Hjemdahl, Paul; Rönquist-Nii, Yuko; Lassila, Riitta; Joutsi-Korhonen, Lotta

    2015-07-01

    Dabigatran (Dabi) is not routinely monitored. However, in emergency cases quantitative assessment is required and laboratories must provide suitable tests at all hours. Little is known about Dabi effects on thrombin generation. Patient samples (n=241) were analyzed for functional Dabi concentrations (Dabi-TT) using a combination of the Hemoclot Thrombin Inhibitors assay (HTI®) and, for samples with low levels, undiluted thrombin time (TT). Results were compared to prothrombin time (PT) and activated partial thromboplastin time (APTT). In 49 samples Dabi effects were further investigated with Calibrated Automated Thrombogram (CAT®) for thrombin generation and with Russell's viper venom time (RVVT), prothrombinase-induced clotting time (PiCT®), chromogenic Anti-IIa® and ecarin clotting assay (ECA®). Fibrinogen and D dimer were assessed to reflect the coagulation status of the patient. A subset of these samples (n=21) were also analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Dabi-TT correlated with RVVT (R(2)=0.49), PiCT® (R(2)=0.73), ECA® (R(2)=0.89), Anti-IIa® (R(2)=0.90) and LC-MS/MS (R(2)=0.81). APTT correlated curvi-linearly with Dabi-TT (R(2)=0.71), but was normal in many cases (18/70) despite Dabi-TT>40ng/mL. There was no association between Dabi-TT and fibrinogen or D dimer levels. Increasing Dabi concentrations prolonged lag time (R(2)=0.54) and, surprisingly, elevated the ETP and Peak of CAT® (p<0.001). Thrombin-specific tests measure Dabi accurately, whereas coagulation time based assays depend more on other factors. The enhanced thrombin generation in Dabi-treated patients may predict clinically relevant hypercoagulability and warrants further investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. The effect of fibrin(ogen) on thrombin generation and decay.

    PubMed

    Kremers, R M W; Wagenvoord, R J; Hemker, H C

    2014-09-02

    Defibrination causes a ~30% decrease of thrombin generation (TG) which can be restored by adding native fibrinogen in its original concentration (3 mg/ml). The fibrinogen variant γA/γ', which binds thrombin with high affinity, is over four times more efficient in this respect than the more common γA/γA form. By using high tissue factor concentrations we accelerated prothrombin conversion so as to obtain a descending part of the TG curve that was governed by thrombin decay only. From that part we calculated the antithrombin (AT)- and α2-macroglobulin-dependent decay constants at a series of concentrations of native, γA/γA and γA/γ' fibrinogen. We found that the increase of TG in the presence of fibrinogen is primarily due to a dose-dependent decrease of thrombin inactivation by α2-macroglobulin, where the γA/γ' form is much more active than the γA/γA form. AT-dependent decay is somewhat decreased by γA/γ' fibrinogen but hardly by the γA/γA form. We assume that binding of thrombin to fibrin(ogen) interferes with its binding to inhibitors. Attenuation of decay only in part explains the stimulating effect of fibrinogen on TG, as fibrinogen stimulates prothrombin conversion, regardless of the fibrinogen variant.

  2. Thrombin generation as objective parameter of treatment response in patients with severe haemophilia A and high-titre inhibitors.

    PubMed

    Luna-Záizar, H; Beltrán-Miranda, C P; Esparza-Flores, M A; Soto-Padilla, J; Bergés-García, A; Rodríguez-Zepeda, M D C; Pompa-Garza, M T; Jaloma-Cruz, A R

    2014-01-01

    In Mexico, 15% of haemophilia A (HA) patients develop inhibitory alloantibodies in response to replacement therapy with factor VIII (FVIII), requiring bypass therapy such as activated prothrombin complex concentrate (APCC). Because bypass therapy has not been broadly available in Mexico even in recent years, this study aimed to evaluate the thrombin generation assay (TGA) in assessing the response to FVIII or APCC treatment in patients with severe HA positive to inhibitors. We studied 189 patients with severe HA. Clinical severity was verified by one-stage APTT-based clotting assay. Inhibitors to FVIII were investigated by the Nijmegen-Bethesda (N-B) method, and type of inhibition was assessed through serial plasma dilutions. Thrombin generation was measured with the calibrated automated thrombogram in inhibitor-positive plasmas previously spiked and incubated with FVIII or APCC. Data were analysed using anova, Student or Fisher's exact tests. We detected 47 (24.9%) subjects with high-titre (5-1700 N-B U mL(-1)) and 25 (13.2%) subjects with low-titre inhibitor antibodies (0.6-4.7 N-B U mL(-1)). We found an association between kinetic behaviour and clinical response to FVIII (P = 0.0049) or vs. FVIII response evaluated with TGA (P = 0.0007). Global concordance between clinical and in vitro response was 70%. By evaluating the capacity of thrombin formation in a plasma sample, TGA predicts the response to FVIII or APCC therapy and allows individual optimization of resources in patients with severe HA and high-titre inhibitors. The inhibition pattern of the antibodies to FVIII:C correlated with the TGA parameters and showed an association with the clinical response to FVIII. © 2013 John Wiley & Sons Ltd.

  3. Ex vivo reversal of effects of rivaroxaban evaluated using thromboelastometry and thrombin generation assay

    PubMed Central

    Schenk, B.; Würtinger, P.; Streif, W.; Sturm, W.; Fries, D.; Bachler, M.

    2016-01-01

    Background In major bleeding events, the new direct oral anticoagulants pose a great challenge for physicians. The aim of the study was to test for ex vivo reversal of the direct oral anticoagulant rivaroxaban with various non-specific reversal agents: prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and fibrinogen concentrate (FI). Methods Blood was obtained from healthy volunteers and from patients treated with rivaroxaban. Blood samples from healthy volunteers were spiked with rivaroxaban to test the correlation between rivaroxaban concentration and coagulation tests. Patient blood samples were spiked with various concentrations of the above-mentioned agents and analysed using thromboelastometry and thrombin generation. Results When added in vitro, rivaroxaban was significantly (P<0.05) correlated with ROTEM® thromboelastometry EXTEM (extrinsic coagulation pathway) clotting time (CT), time to maximal velocity (MaxV−t), and with all measured thrombin generation parameters. In vivo, CT, MaxV−t, lag time, and peak thrombin generation (Cmax) were significantly correlated with rivaroxaban concentrations. Regarding reversal of rivaroxaban, all tested agents significantly (P<0.05) reduced EXTEM CT, but to different extents: rFVIIa by 68%, aPCC by 47%, PCC by 17%, and FI by 9%. Only rFVIIa reversed EXTEM CT to baseline values. Both PCC (+102%) and aPCC (+232%) altered overall thrombin generation (area under the curve) and increased Cmax (+461% for PCC, +87.5% for aPCC). Conclusions Thromboelastometry and thrombin generation assays do not favour the same reversal agents for rivaroxaban anticoagulation. Controlled clinical trials are urgently needed to establish doses and clinical efficacy of potential reversal agents. Clinical trial registration EudracCT trial no. 213-00474-30. PMID:27623677

  4. Efficient thrombin generation requires molecular phosphatidylserine, not a membrane surface.

    PubMed

    Majumder, Rinku; Weinreb, Gabriel; Lentz, Barry R

    2005-12-27

    Activation of prothrombin to thrombin is catalyzed by a "prothrombinase" complex, traditionally viewed as factor X(a) (FX(a)) in complex with factor V(a) (FV(a)) on a phosphatidylserine (PS)-containing membrane surface, which is widely regarded as required for efficient activation. Activation involves cleavage of two peptide bonds and proceeds via one of two released intermediates or through "channeling" (activation without the release of an intermediate). We ask here whether the PS molecule itself and not the membrane surface is sufficient to produce the fully active human "prothrombinase" complex in solution. Both FX(a) and FV(a) bind soluble dicaproyl-phosphatidylserine (C6PS). In the presence of sufficient C6PS to saturate both FX(a) and FV(a2) (light isoform of FV(a)), these proteins form a tight (Kd = 0.6 +/- 0.09 nM at 37 degrees C) soluble complex. Complex assembly occurs well below the critical micelle concentration of C6PS, as established in the presence of the proteins by quasi-elastic light scattering and pyrene fluorescence. Ferguson analysis of native gels shows that the complex migrates with an apparent molecular mass only slightly larger than that expected for one FX(a) and one FV(a2), further ruling out complex assembly on C6PS micelles. Human prothrombin activation by this complex occurs at nearly the same overall rate (2.2 x 10(8) M(-1) s(-1)) and via the same reaction pathway (50-60% channeling, with the rest via the meizothrombin intermediate) as the activation catalyzed by a complex assembled on PS-containing membranes (4.4 x 10(8) M(-1) s(-1)). These results question the accepted role of PS membranes as providing "dimensionality reduction" and favor a regulatory role for platelet-membrane-exposed PS.

  5. Comparison of thrombin generation assay with conventional coagulation tests in evaluation of bleeding risk in patients with rare bleeding disorders.

    PubMed

    Zekavat, Omid R; Haghpanah, Sezaneh; Dehghani, Javad; Afrasiabi, Abdolreza; Peyvandi, Flora; Karimi, Mehran

    2014-09-01

    Based on the premise that the capacity of plasma to generate thrombin in vitro is a comprehensive and precise functional test of the clotting system, we designed a cross-sectional, single-center study involving 83 patients with rare bleeding disorders (RBDs) to compare the usefulness of the thrombin generation (TG) assay versus conventional tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT) in predicting bleeding risk in patients with RBD in southern Iran. The TG parameters consisted of endogenous thrombin potential, lag time, peak, time to peak (ttPeak), and start tail. The area under the receiver-operating characteristic (ROC) curve showed statistically significant associations between bleeding risk and lag time, ttPeak, and start tail. We determined cutoff values for these 3 TG parameters and obtained a negative predictive value of 86% to 90% in patients with RBD who had a bleeding score (BS) ≤13. The ROC curves for the association of PT and aPTT with BS did not indicate any significant association. Correlation analysis supported the results of ROC curve analysis, only lag time, ttPeak, and start tail showed significant positive correlations with BS (P < .05). Disease severity based on plasma factor activity was significantly associated with prolonged lag time and ttPeak and with prolonged PT (P <.05). We suggest that TG assay is a potentially more useful tool for predicting the bleeding risk in patients with RBD. However, the small sample size in different RBD subgroups precluded subgroup analysis. Prospective multicenter studies with larger numbers of patients are therefore advisable.

  6. Association between Stable Coronary Artery Disease and In Vivo Thrombin Generation.

    PubMed

    Valente-Acosta, Benjamin; Baños-González, Manuel Alfonso; Peña-Duque, Marco Antonio; Martínez-Ríos, Marco Antonio; Quintanar-Trejo, Leslie; Aptilon-Duque, Gad; Flores-García, Mirthala; Cruz-Robles, David; Cardoso-Saldaña, Guillermo; de la Peña-Díaz, Aurora

    2016-01-01

    Background. Thrombin has been implicated as a key molecule in atherosclerotic progression. Clinical evidence shows that thrombin generation is enhanced in atherosclerosis, but its role as a risk factor for coronary atherosclerotic burden has not been proven in coronary artery disease (CAD) stable patients. Objectives. To evaluate the association between TAT levels and homocysteine levels and the presence of coronary artery disease diagnosed by coronary angiography in patients with stable CAD. Methods and Results. We included 95 stable patients admitted to the Haemodynamics Department, including 63 patients with significant CAD and 32 patients without. We measured the thrombin-antithrombin complex (TAT) and homocysteine concentrations in all the patients. The CAD patients exhibited higher concentrations of TAT (40.76 μg/L versus 20.81 μg/L, p = 0.002) and homocysteine (11.36 μmol/L versus 8.81 μmol/L, p < 0.01) compared to the patients without significant CAD. Specifically, in patients with CAD+ the level of TAT level was associated with the severity of CAD being 36.17 ± 24.48 μg/L in the patients with bivascular obstruction and 42.77 ± 31.81 μg/L in trivascular coronary obstruction, p = 0.002. Conclusions. The level of in vivo thrombin generation, quantified as TAT complexes, is associated with the presence and severity of CAD assessed by coronary angiography in stable CAD patients.

  7. Association between Stable Coronary Artery Disease and In Vivo Thrombin Generation

    PubMed Central

    Baños-González, Manuel Alfonso; Peña-Duque, Marco Antonio; Martínez-Ríos, Marco Antonio; Quintanar-Trejo, Leslie; Aptilon-Duque, Gad; Flores-García, Mirthala; Cruz-Robles, David; Cardoso-Saldaña, Guillermo

    2016-01-01

    Background. Thrombin has been implicated as a key molecule in atherosclerotic progression. Clinical evidence shows that thrombin generation is enhanced in atherosclerosis, but its role as a risk factor for coronary atherosclerotic burden has not been proven in coronary artery disease (CAD) stable patients. Objectives. To evaluate the association between TAT levels and homocysteine levels and the presence of coronary artery disease diagnosed by coronary angiography in patients with stable CAD. Methods and Results. We included 95 stable patients admitted to the Haemodynamics Department, including 63 patients with significant CAD and 32 patients without. We measured the thrombin-antithrombin complex (TAT) and homocysteine concentrations in all the patients. The CAD patients exhibited higher concentrations of TAT (40.76 μg/L versus 20.81 μg/L, p = 0.002) and homocysteine (11.36 μmol/L versus 8.81 μmol/L, p < 0.01) compared to the patients without significant CAD. Specifically, in patients with CAD+ the level of TAT level was associated with the severity of CAD being 36.17 ± 24.48 μg/L in the patients with bivascular obstruction and 42.77 ± 31.81 μg/L in trivascular coronary obstruction, p = 0.002. Conclusions. The level of in vivo thrombin generation, quantified as TAT complexes, is associated with the presence and severity of CAD assessed by coronary angiography in stable CAD patients. PMID:27597926

  8. The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency.

    PubMed

    Livnat, Tami; Shenkman, Boris; Martinowitz, Uri; Zivelin, Ariella; Dardik, Rima; Tamarin, Ilia; Mansharov, Rachel; Budnik, Ivan; Salomon, Ophira

    2015-08-01

    The phenotype of bleeding in patients with severe FXI deficiency is unpredictable and unlike other bleeding disorders, it is not directly correlated with levels of FXI. In this study we analyzed whether the global coagulation assays can serve as a clinical tool in predicting bleeding tendency in patients with severe FXI deficiency undergoing surgery, taking into account the large inter-individual variability of FXI levels and genotypes. Thrombin generation (TG) was measured in 39 platelet-poor plasma with or without tissue factor (TF) and in the presence or absence of corn trypsin inhibitor (CTI). Rotation thromboelastometry (ROTEM) was performed with fresh whole blood of 26 patients applying NATEM and INTEM tests. TG induced by recalcification can distinguish between bleeding and non-bleeding patients with severe FXI deficiency particularly among those with FXI activity of 2-20IU/dl. The addition of TF or TF and CTI to the TG assay masked the ability to differentiate between XI activity, genotype as well as bleeding and non-bleeding patients. ROTEM assays failed to distinguish bleeding from non-bleeding patients but could do so between different FXI activity levels and genotypes. In conclusion, in the current study we found a sensitive tool to distinguish between bleeding and non-bleeding patients. In order to recommend TG as a predictive tool for treatment tailoring, a larger patient group is required.

  9. Monitoring Low Molecular Weight Heparins at Therapeutic Levels: Dose-Responses of, and Correlations and Differences between aPTT, Anti-Factor Xa and Thrombin Generation Assays

    PubMed Central

    Thomas, Owain; Lybeck, Emanuel; Strandberg, Karin; Tynngård, Nahreen; Schött, Ulf

    2015-01-01

    Background Low molecular weight heparins (LMWH’s) are used to prevent and treat thrombosis. Tests for monitoring LMWH’s include anti-factor Xa (anti-FXa), activated partial thromboplastin time (aPTT) and thrombin generation. Anti-FXa is the current gold standard despite LMWH’s varying affinities for FXa and thrombin. Aim To examine the effects of two different LMWH’s on the results of 4 different aPTT-tests, anti-FXa activity and thrombin generation and to assess the tests’ concordance. Method Enoxaparin and tinzaparin were added ex-vivo in concentrations of 0.0, 0.5, 1.0 and 1.5 anti-FXa international units (IU)/mL, to blood from 10 volunteers. aPTT was measured using two whole blood methods (Free oscillation rheometry (FOR) and Hemochron Jr (HCJ)) and an optical plasma method using two different reagents (ActinFSL and PTT-Automat). Anti-FXa activity was quantified using a chromogenic assay. Thrombin generation (Endogenous Thrombin Potential, ETP) was measured on a Ceveron Alpha instrument using the TGA RB and more tissue-factor rich TGA RC reagents. Results Methods’ mean aPTT at 1.0 IU/mL LMWH varied between 54s (SD 11) and 69s (SD 14) for enoxaparin and between 101s (SD 21) and 140s (SD 28) for tinzaparin. ActinFSL gave significantly shorter aPTT results. aPTT and anti-FXa generally correlated well. ETP as measured with the TGA RC reagent but not the TGA RB reagent showed an inverse exponential relationship to the concentration of LMWH. The HCJ-aPTT results had the weakest correlation to anti-FXa and thrombin generation (Rs0.62–0.87), whereas the other aPTT methods had similar correlation coefficients (Rs0.80–0.92). Conclusions aPTT displays a linear dose-respone to LMWH. There is variation between aPTT assays. Tinzaparin increases aPTT and decreases thrombin generation more than enoxaparin at any given level of anti-FXa activity, casting doubt on anti-FXa’s present gold standard status. Thrombin generation with tissue factor-rich activator is

  10. A highly sensitive thrombin generation assay for assessment of recombinant activated factor VII therapy in haemophilia patients with an inhibitor.

    PubMed

    Livnat, Tami; Martinowitz, Uri; Zivelin, Ariella; Rima, Dardik; Kenet, Gili

    2011-04-01

    Bypass agents are the common treatment for haemophilia patients who develop inhibitory antibodies. Laboratory assessment of the efficacy of bypassing agent therapy is a challenge. In the present work we modified the conditions triggering thrombin generation (TG) assay in order to find the most sensitive assay for detection of rFVIIa and its analogue NN1731 in haemophilic plasma. TG was measured in samples of normal plasma, plasma of haemophilia patient with inhibitors, as well as haemophilia induced plasma. Recalcification-induced TG was compared to tissue factor (TF) -induced TG in the presence and absence of rFVIIa and NN1731. Recalcification-induced TG (without TF) in haemophilic plasma yielded baseline flat curves, with increased TG as a consequence of spiking the plasma rFVIIa. Using our system, we observed both dose-dependence and time-dependence of rFVIIa effect on TG. Elevated concentrations of TF mask the difference between rFVIIa-treated and non-treated haemophilic plasma. NN1731 yielded normalisation of recalcification-induced TG curves (without TF) which may reflect high potency. In conclusion, we suggest that triggering TG by recalcification-only may be the most sensitive assay for determining the impact of bypassing agents in haemophilic plasma, and may serve as a caution surrogate safety marker in future studies.

  11. [Renal function and plasma dabigatran level measured at trough by diluted thrombin time assay].

    PubMed

    Martinuzzo, Marta E; Duboscq, Cristina; Viñuales, Estela S; Girardi, Beatriz; Penchasky, Diana; Ceresetto, José; Stemmelin, Germán; Otero, Victoria; Barrera, Luis H; López, Marina S; Otaso, Juan C; Hoyhamburu, José

    2017-01-01

    Dabigatran etexilate (direct thrombin inhibitor) is effective in preventing embolic stroke in patients with atrial fibrillation. It does not require laboratory control, but given the high renal elimination, its measurement in plasma is important in renal failure. The objectives of the study were to verify the analytical quality of the diluted thrombin time assay for measurement of dabigatran plasma concentration (cc), correlate cc with classic coagulation assays, prothrombin time (PT) and activated partial thromboplastin time (APTT), and evaluate them according to the creatinine clearance (CLCr). Forty plasma samples of patients (34 consecutive and 6 suspected of drug accumulation) receiving dabigatran at 150 (n = 19) or 110 (n = 21) mg/12 hours were collected. Blood samples were drawn at 10-14 hours of the last intake. Dabigatran concentration was determined by diluted thrombin time (HemosIl DTI, Instrumentation Laboratory (IL). PT and APTT (IL) were performed on two fotooptical coagulometers, ACL TOP 300 and 500 (IL). DTI presented intra-assay coefficient of variation < 5.4% and inter-assay < 6%, linearity range 0-493 ng/ml. Patients' cc: median 83 (4-945) ng/ml. Individuals with CLCr in the lowest tertile (22.6-46.1 ml/min) showed significantly higher median cc: 308 (49-945), compared to the average 72 (12-190) and highest tertile, 60 (4-118) ng/ml. Correlation between cc and APTT or PT were moderate, r2 = 0.59 and -0.66, p < 0.0001, respectively. DTI test allowed us to quantify plasma dabigatran levels, both in patients with normal or altered renal function, representing a useful tool in clinical situations such as renal failure, pre surgery or emergencies.

  12. Effect of new synthetic heparin mimetics on whole blood thrombin generation in vivo and in vitro in rats.

    PubMed

    Hérault, J P; Bernat, A; Gaich, C; Herbert, M

    2002-02-01

    The effect of new heparin mimetics (synthetic oligosaccharides) was studied in vitro with regard to thrombin generation (TG) in rat platelet rich plasma (PRP) and whole blood (WB) and in vivo on stasis-induced venous thrombosis in the rat. TG in PRP and in WB was highly dependent on platelet count and strongly influenced by the haematocrit. The peak of TG appeared to be significantly higher in WB than in PRP whereas the endogenous thrombin potential (ETP) was not significantly different under either condition. The effect of hirudin, the synthetic pentasaccharide SR90107/Org31540 (SP) and heparin were measured on TG in PRP and WB. We then compared the effect of two new synthetic heparin mimetics (SR121903A and SanOrg123781) with potent and comparable antithrombin (AT) mediated activity against factor Xa and thrombin. These two compounds were made of a pentasaccharide with a high affinity to AT, prolonged at the non-reducing end by an oligosaccharide chain recognised by thrombin. In SR121903A, the charge density and charge distribution was analogous to that of heparin whereas in SanOrg123781 the charges were only located on the last 5 saccharides of the non-reducing end of the molecule. In PRP and in WB, SR121903A acted on the lag time and on the AUC whereas SanOrg123781 inhibited thrombin formation with no effect on the lag time. SanOrg123781 was more potent in inhibiting TG than SR121903A. This difference was due to the structures of the compounds that differed in their ability to be neutralised by platelet factor 4. The antithrombotic effect of the two compounds was examined in a venous thrombosis model in rats. We observed that SanOrg123781 was more active than SR121903A and heparin. Taken together, these results indicate that the activity of oligosaccharides is greatly influenced by the global charge density of the molecule and show that SanOrg123781 is a potent and promising antithrombotic drug candidate.

  13. Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis

    PubMed Central

    Altman, Raul; Scazziota, Alejandra Silvia; Herrera, Maria de Lourdes; Gonzalez, Claudio

    2006-01-01

    Background Platelet activation is crucial in normal hemostasis. Using a clotting system free of external tissue factor, we investigated whether activated Factor VII in combination with platelet agonists increased thrombin generation (TG) in vitro. Methods and results TG was quantified by time parameters: lag time (LT) and time to peak (TTP), and by amount of TG: peak of TG (PTG) and area under thrombin formation curve after 35 minutes (AUC→35min) in plasma from 29 healthy volunteers using the calibrated automated thrombography (CAT) technique. TG parameters were measured at basal conditions and after platelet stimulation by sodium arachidonate (AA), ADP, and collagen (Col). In addition, the effects of recombinant activated FVII (rFVIIa) alone or combined with the other platelet agonists on TG parameters were investigated. We found that LT and TTP were significantly decreased (p < 0.05) and PTG and AUC→35min were significantly increased (p < 0.05) in platelet rich plasma activated with AA, ADP, Col, and rFVIIa compared to non-activated platelet rich plasma from normal subjects (p = 0.01). Furthermore platelet rich plasma activated by the combined effects of rFVIIa plus AA, ADP or Col had significantly reduced LT and TTP and increased AUC→35min (but not PTG) when compared to platelet rich plasma activated with agonists in the absence of rFVIIa. Conclusion Platelets activated by AA, ADP, Col or rFVIIa triggered TG. This effect was increased by combining rFVIIa with other agonists. Our intrinsic coagulation system produced a burst in TG independent of external tissue factor activity an apparent hemostatic effect with little thrombotic capacity. Thus we suggest a modification in the cell-based model of hemostasis. PMID:16630353

  14. Different Recovery Profiles of Coagulation Factors, Thrombin Generation, and Coagulation Function After Hemorrhagic Shock in Pigs

    DTIC Science & Technology

    2012-06-06

    Different recovery profiles of coagulation factors, thrombin generation, and coagulation function after hemorrhagic shock in pigs Wenjun Z. Martini ...Defense. Address for reprints: Wenjun Z. Martini , PhD, The US Army Institute of Surgical Research, 3698 Chambers Pass, Ft. Sam Houston, San Antonio, TX...ELEMENT NUMBER 6. AUTHOR(S) Martini W. Z., Cortez D. S., Dubick M. A., Blackbourne L. H., 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7

  15. Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors.

    PubMed

    Tripodi, Armando; Ammollo, Concetta T; Semeraro, Fabrizio; Colucci, Mario; Malchiodi, Elena; Verrua, Elisa; Ferrante, Emanuele; Arnaldi, Giorgio; Trementino, Laura; Padovan, Lidia; Chantarangkul, Veena; Peyvandi, Flora; Mantovani, Giovanna

    2017-05-01

    Patients with Cushing disease (CD) are at increased risk of venous thromboembolism (VTE). It was surmised, but not conclusively shown that the risk is related to plasma hypercoagulability secondary to the glucocorticoids effect. This study is aimed at detecting hypercoagulability in patients with CD. Case-control study of 48 CD patients and controls enrolled at two Italian clinics for whom we assessed the thrombin-forming-potential in the presence of optimal activation of protein C obtained by adding into the assay system its main endothelial activator, thrombomodulin. These experimental conditions mimic more closely than any other test the in vivo situation. We observed enhanced thrombin-generation in CD patients, as shown by the modification of thrombin-generation parameters [i.e., shortened lag-time and time-to-peak, increased thrombin peak and endogenous thrombin potential (ETP)]. Moreover, the ETP ratio (with/without thrombomodulin), recognized as an index of hypercoagulability, was increased in patients as compared to controls. We attempted to explain such hypercoagulability by measuring both procoagulant and anticoagulant factors, and some other non-coagulation parameters (i.e., neutrophil extracellular traps (NET), recently associated with the VTE risk and/or increased hypercoagulability. We showed that the hypercoagulability in patients with CD is associated with increased levels of factor VIII and NET-related variables. We detected plasma hypercoagulability in patients with CD and found experimental explanation for its occurrence. Whether this hypercoagulability can entirely explain the occurrence of VTE in patients with CD should be investigated by ad-hoc clinical trials. However, until these studies will be available the evidence supports the concept that patients with CD are candidates for antithrombotic prophylaxis.

  16. Characterization of the antithrombotic fingerprint of the branded and copies of the low-molecular-weight enoxaparin using thrombin generation assay.

    PubMed

    Gerotziafas, Grigoris T; Rouseau, Aurèlie; Mbemba, Elisabeth; Khartechi, Amir; Van Dreden, Patrick; Walenga, Janine; Fareed, Jawed; Elalamy, Ismail

    2015-11-01

    The patent protection of low-molecular-weight heparins (LMWHs) expired, so the definition of criteria for the biological similarity between LMWH copies and the original product is a real need. The present in vitro study compared copies and branded enoxaparin using the specific anti-Xa activity and the calibrated automated thrombogram assay. Samples of platelet-poor plasma (PPP) and platelet-rich plasma (PRP) from 15 healthy volunteers were spiked with branded enoxaparin (Lovenox) or its copies (Cutenox, Dilutol, Enoxa, Fibrinox, Loparin, Lupenox, Novex, Noxprin, and Versa). The specific anti-Xa activity was measured in PPP, and thrombin generation was assessed in PPP and PRP in the presence of tissue factor or pancreatic cancer cells BXPC3. The anti-Xa activity of enoxaparin copies ranged from 0.072 to 0.088 IU/μg, being lower as compared to the branded enoxaparin (0.095 anti-Xa IU/μg). The potency of each copy to inhibit thrombin generation varied in the 3 experimental systems. The presence of platelets or pancreatic cancer cells BXPC3 in human plasma induced significant modifications in the inhibitory efficiency of enoxaparin copies on thrombin generation, which distinguished them from the branded product. Enoxaparin copies showed significant variability regarding their inhibitory potency on thrombin generation. Platelets and cancer cells significantly increased the variability of the antithrombotic efficiency of the copies as compared to the branded enoxaparin. The present study underlines the need for the elaboration of additional functional criteria to evaluate the global antithrombotic capacity of enoxaparin copies in order to evaluate their potential sameness with the branded drug. © The Author(s) 2015.

  17. Free Fatty Acids Modulate Thrombin Mediated Fibrin Generation Resulting in Less Stable Clots

    PubMed Central

    Tanka-Salamon, Anna; Komorowicz, Erzsébet; Szabó, László; Tenekedjiev, Kiril

    2016-01-01

    Upon platelet activation, free fatty acids are released at the stage of thrombus formation, but their effects on fibrin formation are largely unexplored. Our objective was to characterize the kinetic effects of fatty acids on thrombin activity, as well as the structural and mechanical properties of the resultant fibrin clots. Thrombin activity on fibrinogen was followed by turbidimetry and detailed kinetic characterization was performed using a fluorogenic short peptide substrate. The viscoelastic properties of fibrin were measured with rotatory oscillation rheometer, whereas its structure was analyzed with scanning electron microscopy (SEM). In turbidimetric assays of fibrin generation, oleate and stearate at physiologically relevant concentrations (60–600 μM) produced a bell-shaped inhibitory dose response, increasing 10- to 30-fold the time to half-maximal clotting. Oleate inhibited thrombin activity on a short peptide substrate according to a mixed-type inhibitor pattern (a 9-fold increase of the Michaelis constant, Km and a 20% decrease of the catalytic constant), whereas stearate resulted in only a minor (15%) drop in the catalytic constant without any change in the Km. Morphometric analysis of SEM images showed a 73% increase in the median fiber diameter in the presence of stearate and a 20% decrease in the presence of oleate. Concerning the viscoelastic parameters of the clots, storage and loss moduli, maximal viscosity and critical shear stress decreased by 32–65% in the presence of oleate or stearate, but loss tangent did not change indicating decreased rigidity, higher deformability and decreased internal resistance to shear stress. Our study provides evidence that free fatty acids (at concentrations comparable to those reported in thrombi) reduce the mechanical stability of fibrin through modulation of thrombin activity and the pattern of fibrin assembly. PMID:27942000

  18. The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by the Hemoclot thrombin inhibitor assay in patient plasma samples.

    PubMed

    Hapgood, Greg; Butler, Jenny; Malan, Erica; Chunilal, Sanjeev; Tran, Huyen

    2013-08-01

    Dabigatran is an oral direct thrombin inhibitor that does not require routine laboratory monitoring. However, an assessment of its anticoagulant effect in certain clinical settings is desirable. We examined the relationship between dabigatran levels, as determined by the Hemoclot thrombin inhibitor assay (HTI), the thrombin time (TT) and the activated partial thromboplastin time (aPTT) using different reagents. We describe these parameters with the clinical outcomes of patients receiving dabigatran. Seventy-five plasma samples from 47 patients were analysed. The HTI assay was established to measure dabigatran level. aPTTs were performed using TriniCLOT aPTT S reagent (TC) and three additional aPTT reagents. From linear regression lines, we established the aPTT ranges corresponding to the therapeutic drug levels for dabigatran (90-180 ng/ml). The aPTT demonstrated a modest correlation with the dabigatran level (r= 0.80) but the correlation became less reliable at higher dabigatran levels. The therapeutic aPTT ranges for reagents were clinically and statistically different compared with our reference reagent (46-54 s (TC) vs 51-60 s (SP), 54-64 s (SS) and 61-71 s (Actin FS) (p<0.05)). The TT was sensitive to the presence of dabigatran with a level of 60 ng/ml resulting in a TT > 300 s. In conclusion, the aPTT demonstrated a modest correlation with the dabigatran level and was less responsive with supra-therapeutic levels. aPTT reagents differed in their responsiveness, suggesting individual laboratories must determine their own therapeutic range for their aPTT reagent. The TT is too sensitive to quantify dabigatran levels, but a normal TT suggests minimal or no plasma dabigatran.

  19. Effect of endovascular and open abdominal aortic aneurysm repair on thrombin generation and fibrinolysis.

    PubMed

    Abdelhamid, Mohamed F; Davies, Robert S M; Vohra, Rajiv K; Adam, Donald J; Bradbury, Andrew W

    2013-01-01

    Abdominal aortic aneurysm (AAA) is associated with a prothrombotic diathesis that may increase the risk of cardiovascular events. This diathesis is exacerbated in the short term by open aneurysm repair (OAR) and endovascular aneurysm repair (EVAR). However, the effect of EVAR and OAR on coagulation and fibrinolysis in the medium and long term is poorly understood. The purpose of this study was to investigate the medium-term effects of EVAR and OAR on thrombin generation, neutralization, and fibrinolysis. Prothrombin fragment (PF)1+2, thrombin antithrombin (TAT) complex, plasminogen activator inhibitor (PAI) activity, and tissue-plasminogen activator (t-PA) antigen were measured in eight age-matched controls (AMCs), 29 patients with AAA immediately before (preoperatively) and 12 months after EVAR (post-EVAR), and in 11 patients at a mean of 16 months after OAR (post-OAR). Preoperatively, PF1+2 levels were significantly higher in patients with AAAs than in AMC. PF1+2 levels post-EVAR and post-OAR were significantly lower than preoperative values and similar to AMC. There was no significant difference in TAT, PAI, or t-PA between AMC, AAA preoperatively, and post-EVAR. Post-OAR, PAI activity was significantly higher than in preoperative patients. AAA is associated with increased thrombin generation without upregulation of fibrinolysis. The prothrombotic, hypofibrinolytic diathesis observed in patients with AAA returns toward normal in the medium term after EVAR and OAR, although there is a trend toward decreased fibrinolysis post-OAR. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  20. Effect of low molecular weight heparins and fondaparinux upon thrombin generation triggered by human pancreatic cancer cells BXPC3.

    PubMed

    Gerotziafas, Grigoris T; Galea, Vassiliki; Mbemba, Elisabeth; Sassi, Mouna; Roman, Marie-Paule; Khaterchi, Amir; van Dreden, Patrick; Japcowitz, Max; Lotz, Jean Pierre; Bernaudin, Jean Francois; Fareed, Jawed; Hatmi, Mohamed; Elalamy, Ismail

    2014-01-01

    Low molecular weight heparins (LMWHs) and fondaparinux are widely used for prophylaxis and treatment of venous thromboembolic disease in cancer patients. However, the optimization of the antithrombotic treatment especially in patients with adenocarcinoma of the pancreas is a challenging issue. The understanding of the mechanism of action of the LMWHs and fondaparinux in cancer-induced hypercoagulability might help to optimize antithrombotic treatment. To this aim, we investigated the influence of BXPC3 pancreas adenocarcinoma cells on the antithrombotic activity of LMWHs and fondaparinux. Thrombin generation (TG) in normal platelet poor (PPP) and platelet rich plasma (PRP) spiked with clinically relevant concentrations of dalteparin, enoxaparin, nadroparin tinzaparin and fondaparinux was assessed with the Calibrated Automated Thrombogram assay. BXPC3 (5 cells/μl) were added to plasma. The mean rate index (MRI) of the propagation phase of TG and the endogenous thrombin potential (ETP) were analyzed. The IC50 of the studied compounds were determined and compared on the basis of anti-Xa and anti-IIa equivalent units. We demonstrate that the specific antithrombin (AT)-dependent anti-Xa activity of LMWHs and fondaparinux almost selectively inhibits the propagation phase of TG. The synergy between the anti-Xa and anti-IIa activities of LMWHs rather than the selective inhibition of FXa warrants abrogation of TG. The mean molecular weight and anti-Xa/anti-IIa ratio of the AT-dependent agents cannot predict the alteration of their capacity to inhibit TG. Tinzaparin was the most potent inhibitor of TG than the other LMWHs. Enoxaparin was more potent than nadroparin and dalteparin.

  1. Thrombin generation assay and transmission electron microscopy: a useful combination to study tissue factor-bearing microvesicles.

    PubMed

    Gheldof, Damien; Hardij, Julie; Cecchet, Francesca; Chatelain, Bernard; Dogné, Jean-Michel; Mullier, François

    2013-01-01

    Patients with cancer have a 7- to 10-fold increased risk of developing venous thromboembolism. Circulating microvesicles could be a useful predictive biomarker for venous thromboembolism in cancer. Validated and standardised techniques that could be used to determine the complete microvesicle phenotype are required. These were two-fold: a) to characterise tissue factor (TF)-bearing microvesicles released by cultured breast cancer cells MDA-MB-231 by flow cytometry (FCM), transmission electron microscopy (TEM) and thrombin generation assay (TGA); and b) to validate the sensitivity and variability intra/inter-assay of TGA as a useful method to study the procoagulant activity (PCA) of microvesicles. Cultured breast cancer cells MDA-MB-231 were incubated for 45 minutes at 37°C. Samples were then centrifuged or not at 4,500 g for 15 minutes, and cells and MVs or MV-containing supernatants were used for TEM, FCM and TGA. In activity assays, microvesicles (i.e. cell-depleted supernatants) were incubated with anti-TF antibodies or with annexin V to assess the contribution of TF and phospholipids to the PCA. Alternatively, supernatants were filtered through 0.1, 0.22, 0.45 or 0.65 µm membranes and subjected to TGA. The majority of the PCA was associated with microvesicles smaller than 0.1 µm, and the mean microvesicle size estimated by TEM after 10,000 g centrifugation was 121±54 nm with a majority of vesicles between 100 and 200 nm. Microvesicles derived from 5,000 MDA-MB-231cells/ml were sufficient to significantly increase the thrombin generation of normal pooled plasma. TEM, FCM and filtration coupled to TGA represent a useful combination to study the PCA of TF-bearing microvesicles, whatever their size. And it will be interesting to implement these techniques in patients.

  2. Thrombin-activated human platelets acutely generate oxidized docosahexaenoic-acid-containing phospholipids via 12-lipoxygenase.

    PubMed

    Morgan, Lloyd T; Thomas, Christopher P; Kühn, Hartmut; O'Donnell, Valerie B

    2010-10-01

    Arachidonate-containing oxidized phospholipids are acutely generated by 12-LOX (12-lipoxygenase) in agonist-activated platelets. In the present study, formation of structurally related lipids by oxidation of DHA (docosahexaenoic acid)-containing phospholipids is demonstrated using lipidomic approaches. Precursor scanning reverse-phase LC (liquid chromatography)-MS/MS (tandem MS) identified a new family of lipids that comprise phospholipid-esterified HDOHE (hydroxydocosahexaenoic acid). Two diacyl and two plasmalogen PEs (phosphatidylethanolamines) containing predominantly the 14-HDOHE positional isomer (18:0p/14-HDOHE-PE, 18:0a/14-HDOHE-PE, 16:0a/14-HDOHE-PE and 16:0p/14-HDOHE-PE) were structurally characterized using MS/MS and by comparison with biogenic standards. An involvement of 12-LOX was indicated as purified recombinant human 12-LOX also generated the 14-HDOHE isomer from DHA. Pharmacological studies using inhibitors and recombinant platelet 12-LOX indicate that they form via esterification of newly formed non-esterified HDOHE. HDOHE-PEs formed at significant rates (2-4 ng/4×10(7) cells) within 2-180 min of thrombin stimulation, and their formation was blocked by calcium chelation. In summary, a new family of oxidized phospholipid was identified in thrombin-activated human platelets.

  3. Solid expellant plasma generator

    NASA Technical Reports Server (NTRS)

    Stone, Nobie H. (Inventor); Poe, Garrett D. (Inventor); Rood, Robert (Inventor)

    2010-01-01

    An improved solid expellant plasma generator has been developed. The plasma generator includes a support housing, an electrode rod located in the central portion of the housing, and a mass of solid expellant material that surrounds the electrode rod within the support housing. The electrode rod and the solid expellant material are made of separate materials that are selected so that the electrode and the solid expellant material decompose at the same rate when the plasma generator is ignited. This maintains a point of discharge of the plasma at the interface between the electrode and the solid expellant material.

  4. Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase: A cohort study.

    PubMed

    Rozen, Laurence; Noubouossie, Denis; Dedeken, Laurence; Huybrechts, Sophie; Lê, Phu Quoc; Ferster, Alina; Demulder, Anne

    2017-02-01

    Asparaginase (Asp) and corticosteroid (CS) treatment in patients with acute lymphoblastic leukaemia (ALL) is associated with an increased risk of thrombotic events. Characterization of global haemostatic phenotypes of patients with ALL during Asp therapy. Thrombin generation (TG) was monitored in platelet-poor plasma of 56 children treated for a B lineage ALL (36 with native, 20 with PEG Asp) using 1 pM tissue factor and 4 μM phospholipids, with and without thrombomodulin. Protein C activity (PC), free protein S (PS), antithrombin (AT) and fibrinogen levels were also measured. Elevated endogenous thrombin potential (ETP) and peak of TG were noted at diagnosis, throughout the Induction phase and Late Intensification but was significantly less for PEG than for native Asp (P < 0.001), while age, sex, type of corticosteroid during Induction and molecular response had no significant effect. The reduction of ETP after addition of thrombomodulin was significantly lower in ALL children compared with that in controls, suggesting impairment in PS/PC pathway. Three patients experienced thrombosis: two treated with native and one with PEG Asp. The two patients with native Asp had, at the time of thrombosis, a prothrombotic profile. Treatment with Asp, in combination with CS, enhances TG in children with ALL, more significantly with native than PEG Asp, which is present early at diagnosis, persists during Induction and reappears during Late Intensification. This is consistent with the high incidence of thrombotic events described during these phases of therapy. The less pronounced effect of PEG Asp remains to be elucidated. © 2016 Wiley Periodicals, Inc.

  5. Thrombin generation in Cushing's Syndrome: do the conventional clotting indices tell the whole truth?

    PubMed

    Koutroumpi, S; Spiezia, L; Albiger, N; Barbot, M; Bon, M; Maggiolo, S; Gavasso, S; Simioni, P; Frigo, A; Mantero, F; Scaroni, C

    2014-02-01

    Cushing's Syndrome (CS) is associated with an increased mortality, where hypercoagulability seems to have a crucial role in both arterial and venous thrombosis. Parameters of in vitro thrombin generation (TG) such as lag time, peak thrombin and endogenous thrombin potential (ETP), that describe the time until thrombin burst, the peak amount of TG and the total amount of thrombin generated, respectively as well as classical clotting markers were evaluated in 33 CS patients compared to both a group of 28 patients matched for the features of Metabolic Syndrome (MetS) and 31 healthy individuals. CS and MetS patients had shorter lag time (p < 0.0001), higher peak and ETP (p < 0.0001) than healthy controls, though lag time was less shortened in CS (p < 0.0001) respect to MetS group. Prothrombin time (PT) was increased (p < 0.0001) in both CS and MetS patients, while partial thromboplastin time (PTT) was shorter (p < 0.0001) in CS compared to both MetS and healthy group (p < 0.0001). Factor VIII (FVIII), Antithrombin (AT), protein C and S were increased only in CS patients (p < 0.0001). lag time, AT and FVIII correlated to night salivary cortisol (r = + 0.59; p = 0.0005, r = + 0.40; p = 0.003, r = + 0.40; p = 0.04, respectively); PTT correlated inversely to urinary free cortisol (r = -0.45; p = 0.009). BMI correlated negatively to lag time (r = -0.40; p = 0.0001) and positively to peak and ETP (r = + 0.34; p = 0.001, r = + 0.28; p = 0.008, respectively). Obese and diabetic patients had shorter lag time (p = 0.0005; p = 0.0002, respectively), higher ETP (p = 0.0006; p = 0.007, respectively) and peak (p = 0.0003; p = 0.0005, respectively) as well as a more prolonged PT (p = 0.04; p = 0.009, respectively). Hypertensive individuals had higher ETP (p = 0.004), peak (p = 0.0008) and FVIII (p = 0.001). Our findings confirm a prothrombotic state in both CS and MetS patients, though lag time was less shortened in

  6. A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis.

    PubMed

    Lancé, Marcus D

    2015-01-01

    Thrombosis and hemorrhage are major contributors to morbidity and mortality. The traditional laboratory tests do not supply enough information to diagnose and treat patients timely and according to their phenotype. Global hemostasis tests might improve this circumstance. The viscoelastic tests (ROTEM/TEG) demonstrated to ameliorate treatment of acute hemorrhage in terms of decreased amount of transfusion and lowered costs. Thrombin generation measurement is indicative for thrombosis and might also become an important tool in managing hemorrhage. While the clot waveform analysis is less well known it could be of worth in staging sepsis patients, early detection of DIC and also in diagnosis and treatment monitoring of hemophiliac patients. Although in different degree all three methods still need more background, standardization and acceptance before a wide clinical application.

  7. High-intensity Interval Training Improves Mitochondrial Function and Suppresses Thrombin Generation in Platelets undergoing Hypoxic Stress.

    PubMed

    Wu, Li-Hua; Chang, Shao-Chiang; Fu, Tieh-Cheng; Huang, Ching-Hui; Wang, Jong-Shyan

    2017-06-23

    This study elucidates how high-intensity interval training (HIT) and moderate-intensity continuous training (MCT) affect mitochondrial functionality and thrombin generation (TG) in platelets following hypoxic exercise (HE, 100 W under 12% O2 for 30 min). Forty-five healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n = 15) or MCT (sustained 60%VO2max, n = 15) for 30 minutes/day, 5 days/week for 6 weeks, or to a control group (CTL, n = 15) that did not received exercise intervention. Before the intervention, HE (i) reduced the ATP-linked O2 consumption rate (OCR), the reserve capacity of OCR, and the activities of citrate synthase (CS) and succinate dehydrogenase (SDH), (ii) lowered mitochondrial membrane potential (MP) and elevated matrix oxidant burden (MOB) in platelets, and (iii) enhanced dynamic TG in platelet-rich plasma (PRP), which responses were attenuated by pretreating PRP with oligomycin or rotenone/antimycin A. However, 6-week HIT (i) increased mitochondrial OCR capacity with enhancing the CS and SDH activities and (ii) heightened mitochondrial MP with depressing MOB in platelets following HE, compared to those of MCT and CTL. Moreover, the HIT suppressed the HE-promoted dynamic TG in PRP. Hence, we conclude that the HIT simultaneously improves mitochondrial bioenergetics and suppresses dynamic TG in platelets undergoing hypoxia.

  8. Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives.

    PubMed

    Young, Guy; Sørensen, Benny; Dargaud, Yesim; Negrier, Claude; Brummel-Ziedins, Kathleen; Key, Nigel S

    2013-03-14

    Hemophilia is a bleeding disorder that afflicts about 1 in 5000 males. Treatment relies upon replacement of the deficient factor, and response to treatment both in clinical research and practice is based upon subjective parameters such as pain and joint mobility. Existing laboratory assays quantify the amount of factor in plasma, which is useful diagnostically and prognostically. However, these assays are limited in their ability to fully evaluate the patient's clot-forming capability. Newer assays, known as global assays, provide a far more detailed view of thrombin generation and clot formation and have been studied in hemophilia for about 10 years. They have the potential to offer a more objective measure of both the hemophilic phenotype as well as the response to treatment. In particular, in patients who develop inhibitors to deficient clotting factors and in whom bypassing agents are required for hemostasis, these assays offer the opportunity to determine the laboratory response to these interventions where traditional coagulation assays cannot. In this article we review the existing literature and discuss several controversial issues surrounding the assays. Last, a vision of future clinical uses of these assays is briefly described.

  9. In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel.

    PubMed

    Mazzeffi, Michael; Szlam, Fania; Jakubowski, Joseph A; Tanaka, Kenichi A; Sugidachi, Atsuhiro; Levy, Jerrold H

    2013-07-01

    Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model. The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values. PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline. Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Thrombin-induced reactive oxygen species generation in platelets: A novel role for protease-activated receptor 4 and GPIbα.

    PubMed

    Carrim, Naadiya; Arthur, Jane F; Hamilton, Justin R; Gardiner, Elizabeth E; Andrews, Robert K; Moran, Niamh; Berndt, Michael C; Metharom, Pat

    2015-12-01

    Platelets are essential for maintaining haemostasis and play a key role in the pathogenesis of cardiovascular disease. Upon ligation of platelet receptors through subendothelial matrix proteins, intracellular reactive oxygen species (ROS) are generated, further amplifying the platelet activation response. Thrombin, a potent platelet activator, can signal through GPIbα and protease-activated receptor (PAR) 1 and PAR4 on human platelets, and recently has been implicated in the generation of ROS. While ROS are known to have key roles in intra-platelet signalling and subsequent platelet activation, the precise receptors and signalling pathways involved in thrombin-induced ROS generation have yet to be fully elucidated. To investigate the relative contribution of platelet GPIbα and PARs to thrombin-induced reactive oxygen species (ROS) generation. Highly specific antagonists targeting PAR1 and PAR4, and the GPIbα-cleaving enzyme, Naja kaouthia (Nk) protease, were used in quantitative flow cytometry assays of thrombin-induced ROS production. Antagonists of PAR4 but not PAR1, inhibited thrombin-derived ROS generation. Removal of the GPIbα ligand binding region attenuated PAR4-induced and completely inhibited thrombin-induced ROS formation. Similarly, PAR4 deficiency in mice abolished thrombin-induced ROS generation. Additionally, GPIbα and PAR4-dependent ROS formation were shown to be mediated through focal adhesion kinase (FAK) and NADPH oxidase 1 (NOX1) proteins. Both GPIbα and PAR4 are required for thrombin-induced ROS formation, suggesting a novel functional cooperation between GPIbα and PAR4. Our study identifies a novel role for PAR4 in mediating thrombin-induced ROS production that was not shared by PAR1. This suggests an independent signalling pathway in platelet activation that may be targeted therapeutically. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation

    PubMed Central

    Whelihan, Matthew F.; Kiankhooy, Armin; Brummel-Ziedins, Kathleen

    2015-01-01

    Background Despite trauma-induced hypothermic coagulopathy being familiar in the clinical setting, empirical experimentation concerning this phenomenon is lacking. In this study we investigated the effects of hypothermia on thrombin generation, clot formation and global hemostatic functions in an in vitro environment using a whole blood model and thromboelastography (TEG) which can recapitulate hypothermia. Methods Blood was collected from healthy individuals through venipuncture and treated with corn trypsin inhibitor, to block the contact pathway. Coagulation was initiated with 5pM tissue factor at temperatures 37°C, 32°C, and 27°C. Reactions were quenched over time with soluble and insoluble components of each time point analyzed for thrombin generation, fibrinogen consumption, factor (f)XIII activation and fibrin deposition. Global coagulation potential was evaluated through TEG. Results Data showed that thrombin generation in samples at 37°C and 32°C had comparable rates while 27°C had a much lower rate (39.2 ± 1.1 and 43 ± 2.4 nM/min vs 28.6 ± 4.4 nM/min, respectively). Fibrinogen consumption and fXIII activation were highest at 37°C followed by 32°C and 27°C (13.8 ± 2.9 percent/min vs 7.8 ± 1.8 percent/min, respectively). Fibrin formation as seen through clot weights also followed this trend. TEG data showed clot formation was fastest in samples at 37°C and lowest at 27°C. Maximum clot strength was similar for each temperature. Also, percent lysis of clots was highest at 37°C followed by 32°C and then 27°C. Conclusions Induced hypothermic conditions directly affect the rate of thrombin generation and clot formation while global clot stability remains intact. PMID:24331944

  12. Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation.

    PubMed

    Whelihan, Matthew F; Kiankhooy, Armin; Brummel-Ziedins, Kathleen E

    2014-02-01

    Despite trauma-induced hypothermic coagulopathy being familiar in the clinical setting, empirical experimentation concerning this phenomenon is lacking. In this study, we investigated the effects of hypothermia on thrombin generation, clot formation, and global hemostatic functions in an in vitro environment using a whole blood model and thromboelastography, which can recapitulate hypothermia. Blood was collected from healthy individuals through venipuncture and treated with corn trypsin inhibitor, to block the contact pathway. Coagulation was initiated with 5pM tissue factor at temperatures 37°C, 32°C, and 27°C. Reactions were quenched over time, with soluble and insoluble components analyzed for thrombin generation, fibrinogen consumption, factor (f)XIII activation, and fibrin deposition. Global coagulation potential was evaluated through thromboelastography. Data showed that thrombin generation in samples at 37°C and 32°C had comparable rates, whereas 27°C had a much lower rate (39.2 ± 1.1 and 43 ± 2.4 nM/min vs 28.6 ± 4.4 nM/min, respectively). Fibrinogen consumption and fXIII activation were highest at 37°C, followed by 32°C and 27°C. Fibrin formation as seen through clot weights also followed this trend. Thromboelastography data showed that clot formation was fastest in samples at 37°C and lowest at 27°C. Maximum clot strength was similar for each temperature. Also, percent lysis of clots was highest at 37°C followed by 32°C and then 27°C. Induced hypothermic conditions directly affect the rate of thrombin generation and clot formation, whereas global clot stability remains intact. © 2013.

  13. Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo.

    PubMed

    Martínez de Lizarrondo, Sara; Roncal, Carmen; Calvayrac, Olivier; Rodríguez, Cristina; Varo, Nerea; Purroy, Ana; Lorente, Leonardo; Rodríguez, José A; Doeuvre, Loïc; Hervás-Stubbs, Sandra; Angles-Cano, Eduardo; Páramo, José A; Martínez-González, José; Orbe, Josune

    2012-06-01

    Thrombin induces CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) under inflammatory/prothrombotic conditions. Thrombin and CD40L could modulate endothelial MMP-10 expression in vitro and in vivo. Human endothelial cells were stimulated with thrombin (0.1-10 U/mL), CD40L (0.25-1 μg/mL), or their combination (thrombin/CD40L) to assess MMP-10 expression and microparticle generation. Thrombin/CD40L elicited higher MMP-10 mRNA (5-fold; P<0.001) and protein levels (4.5-fold; P<0.001) than either stimulus alone. This effect was mimicked by a protease-activated receptor-1 agonist and antagonized by hirudin, a-protease-activated receptor-1, α-CD40L, and α-CD40 antibodies. The synergistic effect was dependent on p38 mitogen-activated protein kinase and c-Jun N-terminal kinase-1 pathways. Thrombin also upregulated the expression of CD40 in endothelial cell surface increasing its availability, thereby favoring its synergistic effects with CD40L. In mice, thrombin/CD40L further increased the aortic MMP-10 expression. Septic patients with systemic inflammation and enhanced thrombin generation (n=60) exhibited increased MMP-10 and soluble CD40L levels associated with adverse clinical outcome. Endothelial and systemic activation by thrombin/CD40L and lipopolysaccharide also increased microparticles harboring MMP-10 and CD40L. Thrombin/CD40L elicited a strong synergistic effect on endothelial MMP-10 expression and microparticles containing MMP-10 in vitro and in vivo, which may represent a new link between inflammation/thrombosis with prognostic implications.

  14. In vitro comparison of the effect of two factor XI (FXI) concentrates on thrombin generation in major FXI deficiency.

    PubMed

    Pike, G N; Cumming, A M; Hay, C R M; Sempasa, B; Sutherland, M; Thachil, J; Burthem, J; Bolton-Maggs, P H B

    2016-05-01

    Bleeding risk in factor XI (FXI) deficiency following surgery may be reduced by treatment with either of two FXI concentrates, but indications for their use are unclear and treatment has been associated with thrombosis. To quantify and compare the effects of two different FXI concentrates on thrombin generation (TG) in major FXI deficiency (FXI:C < 15 IU dL(-1) ). Thrombin generation was measured in controls (n = 50), FXI-deficient individuals pre and post in vitro spiking with FXI concentrates (n = 10), and in ex vivo samples following treatment with FXI concentrate (n = 3). Thrombin generation was significantly impaired in FXI deficiency but improved following FXI replacement in vitro and in vivo. LFB Hemoleven(®) had greater effect on TG than BPL FXI concentrate in vitro (equivalent in vivo doses 10, 20 and 30 U kg(-1) ): higher endogenous thrombin potential (ETP) (P < 0.0001), peak height (P < 0.01) velocity (P < 0.0002) and shorter lag time and time to peak (both P < 0.003). Some measurements with LFB Hemoleven(®) exceeded the reference range. At lower dose (5 U kg(-1) ), BPL FXI concentrate normalized all TG parameters and LFB Hemoleven(®) normalized the ETP but exceeded the reference range with other parameters. Both FXI concentrates improve TG in vitro in major FXI deficiency but differ in dose response, and for both products, doses lower than previously recommended normalized TG in vitro. Comparison of in vitro spiked and ex vivo samples suggest that in vitro results could be used to estimate an expected in vivo response to FXI replacement. © 2015 John Wiley & Sons Ltd.

  15. A novel antidote-controlled anticoagulant reduces thrombin generation and inflammation and improves cardiac function in cardiopulmonary bypass surgery.

    PubMed

    Nimjee, Shahid M; Keys, J R; Pitoc, G A; Quick, G; Rusconi, C P; Sullenger, Bruce A

    2006-09-01

    Heparin and protamine are the standard anticoagulant-antidote regimen used in almost every cardiopulmonary bypass (CPB) procedure even though both are associated with an array of complications and toxicities. Here we demonstrate that an anticoagulant aptamer-antidote pair targeting factor IXa can replace heparin and protamine in a porcine CPB model and also limit the adverse effects on thrombin generation, inflammation, and cardiac physiology associated with heparin and protamine use. These results demonstrate that targeting clotting factors upstream of thrombin in the coagulation cascade can potentially reduce the perioperative pathologies associated with CPB and suggest that the aptamer-antidote pair to FIXa may improve the outcome of patients undergoing CPB. In particular, this novel anticoagulant-antidote pair may prove to be useful in patients diagnosed with heparin-induced thrombocytopenia or those who have been sensitized to protamine, particularly patients who have insulin-dependent diabetes.

  16. Feasibility of using thrombin generation assay (TGA) for monitoring of haemostasis during supplementation therapy in haemophilic patients without inhibitors.

    PubMed

    Ay, Y; Balkan, C; Karapinar, D Y; Akin, M; Bilenoğlu, B; Kavakli, K

    2012-11-01

    Monitoring factor replacement treatment and observing concordance with clinical haemostasis is crucial in vital haemorrhages and major surgeries in haemophilic patients. We aimed to investigate the value of the thrombin generation assay (TGA) and thromboelastography (TEG) for monitoring haemostasis in haemophilic patients during factor replacement treatment. The study group consisted of 29 patients (21 haemophilia A, 8 haemophilia B). All the patients FVIII-inhibitor were negative. A total of 35 bleeding episodes and/or surgical interventions were evaluated. aPTT, FVIII/FIX activity, TEG and TGA tests were conducted before and after factor therapy during the bleeding episode or surgical prophylaxis of haemophilic patients. Correlations among these tests were evaluated and compared with clinical responses. No correlation was found among aPTT, factor activities and clinical outcome. There were also no correlation found between TEG parameters and clinical outcome. The only significant correlation found between TGA parameters and clinical outcome was the correlation between peak thrombin. In conclusion, we found superiority of TGA-peak thrombin over other traditional tests for monitoring haemostasis in haemophilic patients in this study. © 2012 Blackwell Publishing Ltd.

  17. Feasibility of using thrombin generation assay (TGA) for monitoring bypassing agent therapy in patients with hemophilia having inhibitors.

    PubMed

    Ay, Yilmaz; Balkan, Can; Karapinar, Deniz Yilmaz; Akin, Mehmet; Bilenoglu, Basri; Kavakli, Kaan

    2013-01-01

    Monitoring bypassing agent therapy and observing concordance with clinical hemostasis is crucial in vital hemorrhages and major surgeries in patients with hemophilia having inhibitor. We aimed to investigate the value of the thrombin generation assay (TGA) and thromboelastography (TEG) for monitoring hemostasis in patients with hemophilia having inhibitor, during supplementation therapy with bypassing agents. The study group consisted of 7 patients with hemophilia having factor VIII inhibitor. All patients were male. The median age of the participants was 10 years. Age range was 6 to 32 years. The median inhibitor level was 10 Bethesda units (BU), with a range of 5 to 32 BU. A total of 17 bleeding episodes were evaluated. Both TEG and TGA tests were assessed in addition to clinical responses. Assessments were made prior to bypass agent therapy such as recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC) for bleeding episodes, during the first hour and 24 hours after either intervention in patients. No relation between clinical response and TGA or TEG parameters was found in patients. There was no difference between clinical responses after rFVIIa and aPCC treatments. However, after aPCC treatment, endogenous thrombin potential and peak thrombin levels and also TEG R, K, and alpha angle degrees were significantly higher. In conclusion, we found that the clinical effectiveness of bypass therapy in hemophilia cannot be assessed by TGA and TEG.

  18. Effects of Fibrinogen Concentrate on Thrombin Generation, Thromboelastometry Parameters, and Laboratory Coagulation Testing in a 24-Hour Porcine Trauma Model.

    PubMed

    Zentai, Christian; Solomon, Cristina; van der Meijden, Paola E J; Spronk, Henri M H; Schnabel, Jonas; Rossaint, Rolf; Grottke, Oliver

    2016-11-01

    In a 24-hour porcine model of liver injury, we showed that fibrinogen supplementation does not downregulate endogenous fibrinogen synthesis. Here we report data from the same study showing the impact of fibrinogen on coagulation variables. Coagulopathy was induced in 20 German land race pigs by hemodilution and blunt liver injury. Animals randomly received fibrinogen concentrate (100 mg/kg) or saline. Coagulation parameters were assessed and thromboelastometry (ROTEM) was performed. Fibrinogen concentrate significantly reduced the prolongations of EXTEM clotting time, EXTEM clot formation time, and prothrombin time induced by hemodilution and liver injury. A decrease in clot strength was also ameliorated. Endogenous thrombin potential was significantly higher in the fibrinogen group than in the control group, 20 minutes (353 ± 24 vs 289 ± 22 nmol/L·min; P < .05) and 100 minutes (315 ± 40 vs 263 ± 38 nmol/L·min; P < .05) after the start of infusion. However, no significant between-group differences were seen in other thrombin generation parameters or in d-dimer or thrombin-antithrombin levels. Fibrinogen-platelet binding was reduced following liver injury, with no significant differences between groups. No significant between-group differences were observed in any parameter at ∼12 and ∼24 hours. This study suggests that, in trauma, fibrinogen supplementation may shorten some measurements of the speed of coagulation initiation and produce a short-lived increase in endogenous thrombin potential, potentially through increased clotting substrate availability. Approximately 12 and 24 hours after starting fibrinogen concentrate/saline infusion, all parameters measured in this study were comparable in the 2 study groups. © The Author(s) 2015.

  19. Plasma motor generator system

    NASA Technical Reports Server (NTRS)

    Hite, Gerald E.

    1987-01-01

    The significant potential advantages of a plasma motor generator system over conventional systems for the generation of electrical power and propulsion for spacecraft in low Earth orbits warrants its further investigation. The two main components of such a system are a long insulated wire and the plasma generating hollow cathodes needed to maintain electrical contact with the ionosphere. Results of preliminary theoretical and experimental investigations of this system are presented. The theoretical work involved the equilibrium configurations of the wire and the nature of small oscillation about these equilibrium positions. A particularly interesting result was that two different configurations are allowed when the current is above a critical value. Experimental investigations were made of the optimal starting and running conditions for the proposed, low current hollow cathodes. Although optimal ranges of temperature, argon pressure and discharge voltage were identified, start up became progressively more difficult. This supposed depletion or contamination of the emissive surface could be countered by the addition of new emissive material.

  20. Plasma thrombin-cleaved osteopontin as a potential biomarker of acute atherothrombotic ischemic stroke.

    PubMed

    Ozaki, Saya; Kurata, Mie; Kumon, Yoshiaki; Matsumoto, Shirabe; Tagawa, Masahiko; Watanabe, Hideaki; Ohue, Shiro; Higaki, Jitsuo; Ohnishi, Takanori

    2017-01-01

    We investigated whether thrombin-cleaved osteopontin N-terminal is useful as a blood biomarker of acute atherothrombotic ischemic stroke. Acute ischemic stroke patients were prospectively evaluated with brain magnetic resonance imaging and cardiac evaluations for etiological diagnosis according to the Trial of Org 10172 in Acute Stroke Treatment classification. They were divided into the atherothrombotic and non-atherothrombotic groups. Thrombin-cleaved osteopontin N-terminal, osteopontin, matrix metalloproteinase-9, S100B, C-reactive protein and D-dimer levels were measured from blood samples collected at admission. After excluding patients who met the exclusion criteria or had stroke of other/undetermined etiology, 60 of the 100 patients initially enrolled were included in the final analysis. The ischemic stroke subtypes were atherothrombotic (n=28, 46.7%), cardioembolic (n=19, 31.7%) and lacunar (n=13, 21.7%). Thrombin-cleaved osteopontin N-terminal and matrix metalloproteinase-9 levels were significantly higher in the atherothrombotic than in the non-atherothrombotic group (median (interquartile range): 5.83  (0.0-8.6 ) vs. 0.0  (0.0-3.3) pmol l(-1), P=0.03 and 544   (322-749 ) vs. 343   (254-485) ng ml(-1), P=0.01, respectively). After adjustment for the prevalence of hypertension, diabetes and dyslipidemia, thrombin-cleaved osteopontin N-terminal levels of >5.47 pmol l(-1) (odds ratio, 16.81; 95% confidence interval, 3.53-80.10) and matrix metalloproteinase-9 levels of >605.5 ng ml(-1) (6.59; 1.77-24.60) were identified as independent predictors of atherothrombosis. Within 3 h from stroke onset, only thrombin-cleaved osteopontin N-terminal independently predicted atherothrombosis and thus may add valuable, time-sensitive diagnostic information in the early evaluation of ischemic stroke, especially the atherothrombotic subtype.

  1. The effect of omega-3 polyunsaturated fatty acids on fibrin and thrombin generation in healthy subjects and subjects with cardiovascular disease.

    PubMed

    McEwen, Bradley J; Morel-Kopp, Marie-Christine; Tofler, Geoffrey H; Ward, Christopher M

    2015-04-01

    Hypercoagulability plays a key role in the progression of cardiovascular disease (CVD). Although omega-3 polyunsaturated fatty acid (PUFA) intake has been inversely related to the risk of cardiovascular events, the mechanisms are not fully understood. The aim of this study was to investigate the effects of omega-3 on novel markers of global coagulation. The generation of fibrin and thrombin, measured via overall hemostasis potential (OHP) assay and calibrated automated thrombography, respectively, was determined in 40 healthy subjects and 16 patients with CVD at baseline and after 4 weeks of 640 mg/day omega-3 PUFA. In healthy subjects, fibrin generation was significantly reduced, as measured by overall coagulation potential (p = 0.013), OHP (p < 0.001), velocity of fibrin polymerization (p = 0.002), and significant increase in delay to fibrin generation (p = 0.002). The peak of generated thrombin was significantly reduced (p = 0.043). In subjects with CVD, omega-3 PUFA significantly reduced OHP and significantly increased the lag time to thrombin generation (both p < 0.001). Treatment with omega-3 PUFA had no effect on other fibrin and thrombin generation parameters in CVD patients. Four-week omega-3 PUFA supplementation reduced thrombotic potential in healthy subjects, as shown by reduced fibrin generation and peak thrombin. There was a greater effect on fibrin generation in healthy subjects compared with those with CVD.

  2. Influenza virus H1N1 activates platelets through FcγRIIA signaling and thrombin generation.

    PubMed

    Boilard, Eric; Paré, Guillaume; Rousseau, Matthieu; Cloutier, Nathalie; Dubuc, Isabelle; Lévesque, Tania; Borgeat, Pierre; Flamand, Louis

    2014-05-01

    Platelets play crucial functions in hemostasis and the prevention of bleeding. During H1N1 influenza A virus infection, platelets display activation markers. The platelet activation triggers during H1N1 infection remain elusive. We observed that H1N1 induces surface receptor activation, lipid mediator synthesis, and release of microparticles from platelets. These activation processes require the presence of serum/plasma, pointing to the contribution of soluble factor(s). Considering that immune complexes in the H1N1 pandemic were reported to play a pathogenic role, we assessed their contribution in H1N1-induced platelet activation. In influenza-immunized subjects, we observed that the virus scaffolds with immunoglobulin G (IgG) to form immune complexes that promote platelet activation. Mechanistically, this activation occurs through stimulation of low-affinity type 2 receptor for Fc portion of IgG (FcγRIIA), a receptor for immune complexes, independently of thrombin. Using a combination of in vitro and in vivo approaches, we found that the antibodies from H3N2-immunized mice activate transgenic mouse platelets that express FcγRIIA when put in the presence of H1N1, suggesting that cross-reacting influenza antibodies suffice. Alternatively, H1N1 can activate platelets via thrombin formation, independently of complement and FcγRIIA. These observations identify both the adaptive immune response and the innate response against pathogens as 2 intertwined processes that activate platelets during influenza infections.

  3. Thrombin Time

    MedlinePlus

    ... monitor unfractionated heparin therapy and to detect heparin contamination in a blood sample. While it is still ... thrombin time may sometimes be ordered when heparin contamination of a sample is suspected or when a ...

  4. G-Quadruplex Aptamers to Human Thrombin Versus Other Direct Thrombin Inhibitors: The Focus on Mechanism of Action and Drug Efficiency as Anticoagulants.

    PubMed

    Zavyalova, Elena; Ustinov, Nikita; Golovin, Andrey; Pavlova, Galina; Kopylov, Alexey

    2016-01-01

    Thrombin is a key enzyme of blood coagulation system which has multiple functions including pro- and anticoagulant, platelet aggregating and inflammatory activities. Unsurprisingly, this enzyme has been a target for anticoagulant drug development for decades. Among the most interesting direct thrombin inhibitors with intravenous administration route are the following ones: 1) hirudins, proteins with bivalent binding mode to the thrombin, 2) bivalirudin, the peptide with bivalent binding mode to the thrombin, 3) argatroban, the chemical that binds to the thrombin active site, and 4) G-quadruplex DNA aptamers, structured oligonucleotides with an affinity to protein-binding site of the thrombin. Efficiency of all these inhibitors has been studied in vivo in preclinical and clinical trials, as well as in vitro with various tests, allowing to compare them thoroughly. In the review three levels of comparison were used to highlight the features of each inhibitor: 1) thrombin inhibition constants as a characteristic of inhibitor potency in simple enzymatic system; 2) inhibition of fibrin fiber formation and thrombin generation in coagulation cascade as a characteristic of anticoagulant potency in human blood plasma; and 3) therapeutic doses used and therapeutic profiles obtained after intravenous administration into animals and humans. The data clearly demonstrate weak and strong aspects of thrombin binding aptamers providing a solid background for further novel anticoagulant development.

  5. Effect of iron ions on functional activity of thrombin.

    PubMed

    Azizova, O A; Shvachko, A G; Aseichev, A V

    2009-11-01

    The kinetics of thrombin inhibition by irons ions was studied in the thrombin time test with normal plasma. The kinetic and concentration characteristics for recovery of thrombin activity by desferal were evaluated at various periods of thrombin incubation with iron ions. The thrombin time test showed that incubation of thrombin with iron sulfate in a final concentration of 200 microM for 25-35 min is followed by the loss of thrombin activity. Pretreatment of iron-containing incubation system with desferal was shown to decelerate the process of thrombin inactivation. The kinetic characteristics for recovery of thrombin activity by 2 mM desferal were estimated at various periods after addition of iron sulfate in the inhibitory dose. The effect of reversibility was shown to depend on the time of thrombin preincubation with iron. Incomplete recovery of thrombin activity after increasing the time of incubation with iron (more than 30 min) was probably related to oxidative modification of thrombin.

  6. One-Step Facile Synthesis of Aptamer-Modified Graphene Oxide for Highly Specific Enrichment of Human A-Thrombin in Plasma.

    PubMed

    Xu, Yuan; Tan, Siyuan; Liang, Qionglin; Ding, Mingyu

    2017-09-13

    The enrichment of low-abundance proteins in complex biological samples plays an important role in clinical diagnostics and biomedical research. This work reports a novel one-step method for the synthesis of aptamer-modified graphene oxide (GO/Apt) nanocomposites, without introducing the use of gold, for the rapid and specific separation and enrichment of human α-thrombin from buffer solutions with highly concentrated interferences. The obtained GO/Apt nanocomposites had remarkable aptamer immobilization, up to 44.8 nmol/mg. Furthermore, GO/Apt nanocomposites exhibited significant specific enrichment efficiency for human α-thrombin (>90%), even under the presence of 3000-fold interference proteins, which was better than the performance of other nanomaterials. Finally, the GO/Apt nanocomposites were applied in the specific capturing of human α-thrombin in highly concentrated human plasma solutions with negligible nonspecific binding of other proteins, which demonstrated their prospects in rare protein analysis and biosensing applications.

  7. Effects of Fibrinogen Concentrate on Thrombin Generation, Thromboelastometry Parameters, and Laboratory Coagulation Testing in a 24-Hour Porcine Trauma Model

    PubMed Central

    Zentai, Christian; Solomon, Cristina; van der Meijden, Paola E. J.; Spronk, Henri M. H.; Schnabel, Jonas; Rossaint, Rolf

    2015-01-01

    Introduction: In a 24-hour porcine model of liver injury, we showed that fibrinogen supplementation does not downregulate endogenous fibrinogen synthesis. Here we report data from the same study showing the impact of fibrinogen on coagulation variables. Materials and Methods: Coagulopathy was induced in 20 German land race pigs by hemodilution and blunt liver injury. Animals randomly received fibrinogen concentrate (100 mg/kg) or saline. Coagulation parameters were assessed and thromboelastometry (ROTEM) was performed. Results: Fibrinogen concentrate significantly reduced the prolongations of EXTEM clotting time, EXTEM clot formation time, and prothrombin time induced by hemodilution and liver injury. A decrease in clot strength was also ameliorated. Endogenous thrombin potential was significantly higher in the fibrinogen group than in the control group, 20 minutes (353 ± 24 vs 289 ± 22 nmol/L·min; P < .05) and 100 minutes (315 ± 40 vs 263 ± 38 nmol/L·min; P < .05) after the start of infusion. However, no significant between-group differences were seen in other thrombin generation parameters or in d-dimer or thrombin–antithrombin levels. Fibrinogen–platelet binding was reduced following liver injury, with no significant differences between groups. No significant between-group differences were observed in any parameter at ∼12 and ∼24 hours. Conclusion: This study suggests that, in trauma, fibrinogen supplementation may shorten some measurements of the speed of coagulation initiation and produce a short-lived increase in endogenous thrombin potential, potentially through increased clotting substrate availability. Approximately 12 and 24 hours after starting fibrinogen concentrate/saline infusion, all parameters measured in this study were comparable in the 2 study groups. PMID:25948634

  8. Thrombin Inhibitors from Different Animals

    PubMed Central

    Tanaka-Azevedo, A. M.; Morais-Zani, K.; Torquato, R. J. S.; Tanaka, A. S.

    2010-01-01

    Venous and arterial thromboembolic diseases are still the most frequent causes of death and disability in high-income countries. Clinical anticoagulants are inhibitors of enzymes involved in the coagulation pathway, such as thrombin and factor Xa. Thrombin is a key enzyme of blood coagulation system, activating the platelets, converting the fibrinogen to the fibrin net, and amplifying its self-generation by the activation of factors V, VIII, and XI. Thrombin has long been a target for the development of oral anticoagulants. Furthermore, selective inhibitors of thrombin represent a new class of antithrombotic agents. For these reasons, a number of specific thrombin inhibitors are under evaluation for possible use as antithrombotic drugs. This paper summarizes old and new interests of specific thrombin inhibitors described in different animals. PMID:20976270

  9. Results of rotational thromboelastometry, coagulation activation markers and thrombin generation assays in orthopedic patients during thromboprophylaxis with rivaroxaban and enoxaparin: a prospective cohort study.

    PubMed

    Oswald, Elgar; Velik-Salchner, Corinna; Innerhofer, Petra; Tauber, Helmuth; Auckenthaler, Thomas; Ulmer, Hanno; Streif, Werner

    2015-03-01

    A prospective observational study was conducted in two clinical cohorts of patients to compare the effect of enoxaparin and rivaroxaban on rotational thromboelastometry (ROTEM), coagulation activation markers and thrombin generation. A total of 188 consecutive patients scheduled for major orthopedic surgery receiving 40-mg enoxaparin subcutaneously or 10-mg rivaroxaban orally were evaluated. Blood samples were taken before induction of anesthesia and on day 4 after surgery [postoperative day 4 (pod 4)]. The extrinsically (EXTEM) and the intrinsically (INTEM) activated ROTEM assay, antithrombin, prothrombin fragments (F1 + 2), thrombin-antithrombin complex (TAT) and D-dimers were measured, and the thrombodynamic ratio (TDR) was calculated. Thrombin generation was determined using calibrated automated thrombography. To compare the groups, changes (Δ) in baseline versus pod 4 were calculated. EXTEM clotting time (CT) increased more with rivaroxaban than with enoxaparin; values above the reference range were observed (median ΔEXTEM-CT 15 vs. 5 s, P ≤ 0.0001). The increase in INTEM-CT (values remained within the normal ranges) was slight with enoxaparin and significant with rivaroxaban; ΔINTEM-CT was comparable. EXTEM-TDR, unchanged with rivaroxaban, increased significantly with enoxaparin, whereas ΔINTEM-TDR was comparable. ΔAT, ΔF1 + 2 and ΔTAT were significantly lower in the rivaroxaban group. Endogenous thrombin potential (ETP), unchanged with rivaroxaban, decreased significantly with enoxaparin; the maximal rising slope (mean velocity rate index) decreased more with rivaroxaban. Data show that prolonged CT in the extrinsic ROTEM and thrombin generation assays reflecting initiation and propagation of thrombin may be useful for detecting treatment with rivaroxaban. The significance of observed differences in markers of coagulation needs to be investigated further.

  10. Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation

    PubMed Central

    Arellano-Rodrigo, Eduardo; Reverter, Joan Carles; Lopez-Farre, Antonio; Diaz-Ricart, Maribel; Badimon, Juan Jose; Escolar, Gines

    2017-01-01

    Introduction Mechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories. However, effects of DOACs on platelet activation and aggregation have not been explored in detail. We have investigated the effects of apixaban on platelet and fibrin components of thrombus formation under static and flow conditions. Methods We assessed the effects of apixaban (10, 40 and 160 ng/mL) on: 1) platelet deposition and fibrin formation onto a thrombogenic surface, with blood circulating at arterial shear-rates; 2) viscoelastic properties of forming clots, and 3) thrombin generation in a cell-model of coagulation primed by platelets. Results In studies with flowing blood, only the highest concentration of apixaban, equivalent to the therapeutic Cmax, was capable to significantly reduce thrombus formation, fibrin association and platelet-aggregate formation. Apixaban significantly prolonged thromboelastometry parameters, but did not affect clot firmness. Interestingly, results in a platelet-based model of thrombin generation under more static conditions, revealed a dose dependent persistent inhibitory action by apixaban, with concentrations 4 to 16 times below the therapeutic Cmax significantly prolonging kinetic parameters and reducing the total amount of thrombin generated. Conclusions Our studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban. Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis. PMID:28192448

  11. Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation.

    PubMed

    Pujadas-Mestres, Lluis; Lopez-Vilchez, Irene; Arellano-Rodrigo, Eduardo; Reverter, Joan Carles; Lopez-Farre, Antonio; Diaz-Ricart, Maribel; Badimon, Juan Jose; Escolar, Gines

    2017-01-01

    Mechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories. However, effects of DOACs on platelet activation and aggregation have not been explored in detail. We have investigated the effects of apixaban on platelet and fibrin components of thrombus formation under static and flow conditions. We assessed the effects of apixaban (10, 40 and 160 ng/mL) on: 1) platelet deposition and fibrin formation onto a thrombogenic surface, with blood circulating at arterial shear-rates; 2) viscoelastic properties of forming clots, and 3) thrombin generation in a cell-model of coagulation primed by platelets. In studies with flowing blood, only the highest concentration of apixaban, equivalent to the therapeutic Cmax, was capable to significantly reduce thrombus formation, fibrin association and platelet-aggregate formation. Apixaban significantly prolonged thromboelastometry parameters, but did not affect clot firmness. Interestingly, results in a platelet-based model of thrombin generation under more static conditions, revealed a dose dependent persistent inhibitory action by apixaban, with concentrations 4 to 16 times below the therapeutic Cmax significantly prolonging kinetic parameters and reducing the total amount of thrombin generated. Our studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban. Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis.

  12. Markers of thrombin generation during resurfacing and noncemented total hip arthroplasty: a pilot study.

    PubMed

    Su, Edwin P; Chatzoudis, Nikos; Sioros, Vasileios; Go, George; Sharrock, Nigel E

    2011-02-01

    Hip resurfacing arthroplasty (HRA) could be associated with an increased risk of deep vein thrombosis (DVT) compared to traditional noncemented THA because it involves greater dissection, increased kinking and distortion of the femoral vessels, takes longer to perform, and involves insertion of some cement into the femur. Does HRA lead to greater risk of thromboembolism compared with noncemented THA? We prospectively studied 20 patients receiving HRA and 20 receiving THA. All patients were younger than 67 years old and were similar in height, weight, American Society of Anesthesiologists status, and gender mix. Patients undergoing HRA were younger (mean, 50 versus 59 years), their surgery was longer (mean, 87 versus 65 minutes), and they required more crystalloid during surgery (mean, 2160 versus 1662 mL). Radial artery blood samples were taken at six events during surgery and assayed for prothrombin fragment F1 + 2 and thrombin-antithrombin III complex (TAT) using enzyme-linked immunosorbent assays. We observed no differences in the intraoperative increases in F1 + 2 and TAT between the two groups and no differences in surgical events. Based on these data, HRA and THA should have similar risk of thromboembolism as THA based on the parameters we measured. Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

  13. Plasma Generated Spherules

    NASA Astrophysics Data System (ADS)

    Ransom, C. J.

    2005-04-01

    Z-pinch plasma simulations have been performed that indicate the production of spherules under certain experimental parameters. (A. L. Peratt, private communication) While performing experiments dealing with the impact of plasma discharges on various materials, we observed that spherules were created at the surface of some of the materials. For specific materials and conditions, spherules were always produced. Both individual spherules and joined spherules were created. The size and shapes were nearly identical to items found by the Mars rover, Opportunity, and called ``blueberries.'' Sky & Telescope, June 2004, p. 20, among other sources indicated the blueberries were gray spherules composed of hematite. The experiments produced hematite spherules identical in appearance to those found on Mars. These experiments suggest how the newly discovered blueberries were formed on Mars while providing an explanation that does not depend on the presence of water.

  14. International Normalized Ratio (INR), coagulation factor activities and calibrated automated thrombin generation - influence of 24 h storage at ambient temperature.

    PubMed

    Christensen, T D; Jensen, C; Larsen, T B; Maegaard, M; Christiansen, K; Sørensen, B

    2010-04-01

    International Normalized Ratio (INR) measurements are used to monitor oral anticoagulation therapy with coumarins. Single coagulation factor activities and calibrated automated thrombin (CAT) generation are considered as more advanced methods for evaluating overall haemostatic capacity. The aims were to assess the variability of INR, coagulation factor activities, and CAT, during 24 h of storage of blood samples at ambient temperature. A total of 24 patients on stable coumarin treatment were followed prospectively for 6 weeks. INR was analyzed at 0, 6 and 24 h after blood sampling and 1-stage clotting activity of coagulation factors II, VII, IX, and X as well as CAT generation was recorded after 0 and 24 h respectively. Statistical analyses included Bland-Altman plot, 95% limits of agreement, and a variability test using a mixed effect model. The level of INR remained statistically unchanged from 0 to 6 and 24 h of storage. Coagulation factor activities and CAT revealed no significant difference induced by 24 h of storage, although the limits of agreement were wide. Patients' individual INR, coagulation factor activities, and CAT generation were not significantly influenced by 24 h storage of blood samples, but for the CAT generation analyses a trend toward time dependency was detected.

  15. Combined administration of FVIII and rFVIIa improves haemostasis in haemophilia A patients with high-responding inhibitors--a thrombin generation-guided pilot study.

    PubMed

    Livnat, T; Martinowitz, U; Azar-Avivi, S; Zivelin, A; Brutman-Barazani, T; Lubetsky, A; Kenet, G

    2013-09-01

    Treatment of haemophilia A patients with inhibitors is challenging, and may require individually tailored regimens. Whereas low titre inhibitor patients may respond to high doses of factor VIII (FVIII), high-responding inhibitor patients render replacement therapy ineffective and often require application of bypassing agents. Thrombin generation (TG) assays may be used to monitor haemostasis and/or predict patients' response to bypass agents. In this study we defined by TG, the potential contribution of FVIII to recombinant activated factor VII (rFVIIa)-induced haemostasis in inhibitor plasma. Based upon results, prospectively designed individual regimens of coadministration of rFVIIa and FVIII were applied. Plasma samples from 14 haemophilia patients with inhibitors (including high titre inhibitors) were tested. The response to increasing concentrations of FVIII, rFVIIa or both was assayed by TG. Eight patients, chosen following consent and at physician's discretion, comprised the combined FVIII-rFVIIa therapy clinical study cohort. Combined spiking with FVIII/rFVIIa improved TG induced by rFVIIa alone in all inhibitor plasmas. Combined rFVIIa and FVIII therapy was applied during bleeding or immune tolerance to eight patients, for a total of 393 episodes. Following a single combined dose, 90% haemostasis was documented and neither thrombosis nor any complications evolved. During study period decline of inhibitor levels and bleeding frequency were noted. Pre-analytical studies enabled us to prospectively tailor individual therapy regimens. We confirmed for the first time that the in vitro advantage of combining FVIII and rFVIIa, indeed accounts for improved haemostasis and may safely be applied to inhibitor patients. © 2013 John Wiley & Sons Ltd.

  16. Plasma Generator Using Spiral Conductors

    NASA Technical Reports Server (NTRS)

    Szatkowski, George N. (Inventor); Dudley, Kenneth L. (Inventor); Ticatch, Larry A. (Inventor); Smith, Laura J. (Inventor); Koppen, Sandra V. (Inventor); Nguyen, Truong X. (Inventor); Ely, Jay J. (Inventor)

    2016-01-01

    A plasma generator includes a pair of identical spiraled electrical conductors separated by dielectric material. Both spiraled conductors have inductance and capacitance wherein, in the presence of a time-varying electromagnetic field, the spiraled conductors resonate to generate a harmonic electromagnetic field response. The spiraled conductors lie in parallel planes and partially overlap one another in a direction perpendicular to the parallel planes. The geometric centers of the spiraled conductors define endpoints of a line that is non-perpendicular with respect to the parallel planes. A voltage source coupled across the spiraled conductors applies a voltage sufficient to generate a plasma in at least a portion of the dielectric material.

  17. Predictive role of gene polymorphisms affecting thrombin-generation pathway in variable efficacy of photodynamic therapy for neovascular age-related macular degeneration.

    PubMed

    Parmeggiani, Francesco; Gemmati, Donato; Costagliola, Ciro; Sebastiani, Adolfo; Incorvaia, Carlo

    2009-01-01

    Age-related macular degeneration (AMD) represents the leading cause of central blindness in developed countries. The majority of severe vision loss occurs in the neovascular form of AMD, generally characterized by the presence of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) and drugs acting against vascular endothelial growth factor are the most commonly employed treatments for AMD-related subfoveal CNV. The combined use of both these strategies is the most promising therapeutic approach towards this harmful disease. The therapeutic action of PDT-V depends to a photochemical perturbation of thrombo-coagulative processes within CNV. Predictive correlations between peculiar coagulation-balance gene polymorphisms and different levels of post-PDT-V benefit have been recently documented in Caucasian patients with neovascular AMD. Particularly, heterozygous A-allele carriers of factor V Leiden 1691 or prothrombin 20210 gene are characterized by a greater possibility to exhibit clinical benefit after PDT-V. Both mutations induce thrombophilia increasing the thrombin generation in plasma and, thus, they can consistently intensify the photothrombotic phase of the therapeutic CNV occlusion. In prospect, considering the different individual susceptibility to PDT-V, a preoperative assessment of the genotypic thrombophilic background could optimize the eligibility criteria of this intriguing treatment. This review summarizes some of the recent published patents on treatment of neovascular AMD, with a particular attention to PDT-V application in combined therapeutic modalities.

  18. Wakefield Generation in Plasma Channels

    NASA Astrophysics Data System (ADS)

    Volfbeyn, P.; Leemans, W. P.; Brussaard, G. J. H.; Esarey, E.; Wurtele, J. S.

    1999-11-01

    Laser wakefield generation in plasma channels is experimentally studied. Plasma channels, produced using the ignitor-heater method [1] in hydrogen and nitrogen, have been used to guide intense (> 5 x 10^17 W/cm^2), short (<70 fs) infrared (800 nm) laser pulses. Laser pulses injected into these channels produce a plasma wake with a phase velocity close to the speed of light. The transverse density profile of the channel determines the properties of the laser mode as well as of the plasma wave mode. The longitudinally integrated properties of the channel are measured with a Mach-Zehnder interferometer using 400 nm radiation. The probe and reference beam are combined directly on a CCD camera to provide two-dimensional interferograms and also through a spectrometer to allow Fourier domain interferometry. Progress on measuring the transverse channel profile and wakefield amplitudes will be presented. [1] P. Volfbeyn, E. Esarey and W.P. Leemans, Phys. Plasmas 6, 2269 (1999).

  19. Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera.

    PubMed

    Panova-Noeva, Marina; Marchetti, Marina; Spronk, Henri Maria; Russo, Laura; Diani, Erika; Finazzi, Guido; Finazzi, Good; Salmoiraghi, Silvia; Rambaldi, Alessandro; Rambaldi, Aueesandrd; Barbui, Tiziano; Barbui, Titiano; Ten Cate, Hugo; Ten Cate, Huao; Falanga, Anna

    2011-04-01

    The platelet contribution to the thrombophilic state of patients with myeloproliferative neoplasms (MPNs), i.e., essential thrombocythemia (ET) and polycythemia vera (PV), remains uncertain. In this study we aimed to characterize the thrombin generation (TG) potential expressed by platelets from these subjects, compare it to normal platelets, and identify what factors might be responsible for platelet TG. In a group of 140 MPN patients (80 ET and 60 PV) and 72 healthy subjects, we measured the global procoagulant potential of platelet-rich plasma (PRP) utilizing the TG assay by the calibrated automated thrombogram (CAT). To characterize the procoagulant contribution of platelets in PRP, the TG of both isolated platelets and platelet-poor plasma was measured, and the platelet surface expression of TF was determined. Finally, the activation status of platelets was assessed by the levels of P-selectin expressed on platelet surface. MPN patients had significantly increased PRP and isolated platelet TG potential compared to controls. This was associated to the occurrence of platelet activation. Patients carriers of the JAK2V617F mutation showed the highest values of TG and platelet surface TF and P-selectin. Platelet TG potential was significantly lower in hydroxyurea(HU) compared to non-HU-treated patients and was lowest in HU-treated JAK2V617F carriers. In subjects not receiving HU, platelet TG significantly increased by JAK2V617F allele burden increment (P < 0.05).This study demonstrates a platelet-dependent form of hypercoagulability in MPN patients, particularly in those carriers of the JAK2V617F mutation. The cytoreductive therapy with HU significantly affects this prothrombotic phenotype.

  20. Evaluation of the bone healing process utilizing platelet-rich plasma activated by thrombin and calcium chloride: a histologic study in rabbit calvaria.

    PubMed

    Betoni-Junior, Walter; Dechichi, Paula; Esteves, Jônatas Caldeira; Zanetta-Barbosa, Darceny; Magalhães, Aparecido Eurípedes Onório

    2013-02-01

    To evaluate the bone healing of defects filled with particulate bone graft in combination with platelet-rich plasma (PRP), added with a mixture of calcium chloride and thrombin or just calcium chloride. Two 5-mm bone defects were created in the calvaria of 24 rabbits. Each defect was filled with particulate bone graft and PRP. In one defect the PRP was activated by a mixture of calcium chloride and thrombin; in the other, PRP was activated by calcium chloride only. The animals were euthanized 1, 2, 4, and 8 weeks after the surgeries, and the calvaria was submitted to histologic processing for histomorphometric analysis. The qualitative analysis has shown that both defects presented the same histologic characteristics so that a better organized, more mature, and well-vascularized bone tissue was noticed in the eighth week. A good bone repair was achieved using either the mixture of calcium chloride and thrombin or the calcium chloride alone as a restarting agent of the coagulation process.

  1. Effect of two oral doses of 17beta-estradiol associated with dydrogesterone on thrombin generation in healthy menopausal women: a randomized double-blind placebo-controlled study.

    PubMed

    Rousseau, Alexandra; Robert, Annie; Gerotziafas, Grigoris; Torchin, Dahlia; Zannad, Faiez; Lacut, Karine; Libersa, Christian; Dasque, Eric; Démolis, Jean-Louis; Elalamy, Ismail; Simon, Tabassome

    2010-04-01

    Oral hormone therapy is associated with an increased risk of venous thrombosis. Drug agencies recommend the use of the lowest efficient dose to treat menopausal symptoms for a better risk/ratio profile, although this profile has not been totally investigated yet. The aim of the study was to compare the effect of the standard dose of 17beta-estradiol to a lower one on thrombin generation (TG). In a 2-month study, healthy menopausal women were randomized to receive daily 1mg or 2 mg of 17beta-estradiol (E1, n = 24 and E2, n = 26; respectively) with 10 mg dydrogesterone or placebo (PL, n = 22). Plasma levels factors VII, X, VIII and II were assessed before and after treatment as well as Tissue factor triggered TG, which allows the investigation of the different phases of coagulation process. The peak of thrombin was higher in hormone therapy groups (E1: 42.39 +/- 50.23 nm, E2: 31.08 +/- 85.86 nm vs. 10.52 +/- 40.63 nm in PL, P = 0.002 and P = 0.01). Time to reach the peak was also shortened (PL: 0.26 +/- 0.69 min vs. E1: -0.26 +/- 0.80 min, E2: -0.55 +/- 0.79 min, P <10(-3) for both comparisons) and mean rate index of the propagation phase of TG was significantly increased. Among the studied clotting factors, only the levels of FVII were significantly increased after treatment administration. The two doses of 17beta-estradiol induced in a similar degree an acceleration of the initiation and propagation phase of tissue factor triggered thrombin generation and a significant increase of FVII coagulant activity.

  2. An evaluation of platelet-rich plasma without thrombin activation with or without anorganic bone mineral in the treatment of human periodontal intrabony defects.

    PubMed

    Rodrigues, Silvia V; Acharya, Anirudh B; Thakur, Srinath L

    2011-01-01

    The efficacy of platelet-rich plasma (PRP) in periodontal regeneration is not well understood and the definite clinical viability of blood derived platelets lacks clarity. Also, the use of thrombin for platelet activation is disputed. Hence, the purpose of this study was to evaluate the efficacy of blood derived platelets without thrombin activation, alone or in combination with bovine anorganic bone mineral (ABM), in the treatment of human periodontal intrabony defects. PRP was prepared using a simple tabletop centrifuge and activated using calcium chloride without the addition of thrombin. This PRP was used alone (in Group A) and in combination with bovine ABM (in Group B) in the treatment of human periodontal angular defects. Both the control and the test groups showed definite improvement in clinical parameters. On comparison, however, there was a statistically significant improvement in the probing pocket depths and relative attachment level in Group B over Group A at 3 and 6 months intervals, whereas at the end of 9 months this difference was not statistically significant. There was no statistically significant difference between the groups with respect to the relative defect depth. Within the limitations of this study and the type of PRP used, i.e. without thrombin mediated activation, it can be concluded that both PRP and PRP combined with bovine ABM results in significant clinical improvement. Albeit statistically insignificant, there is a preponderance of better clinical results with the addition of ABM to PRP. Further studies need to be carried out on a larger sample size to confirm the results of the present study.

  3. Two distinct forms of Factor VIII coagulant protein in human plasma. Cleavage by thrombin, and differences in coagulant activity and association with von Willebrand factor.

    PubMed Central

    Weinstein, M J; Chute, L E

    1984-01-01

    We have characterized Factor VIII coagulant protein, present in normal human plasma, that reacts with a specific human 125I-labeled anti-human VIII:C antigen Fab antibody fragment. Two major Factor VIII coagulant antigen populations were present. The first, approximately 85% of the total antigen, was bound to von Willebrand factor and when tested in a standard one-stage assay had Factor VIII coagulant activity. The second antigenic population, eluting near fibrinogen when plasma was gel filtered, was not bound to von Willebrand protein, did not have Factor VIII coagulant activity unless activated, but did block anti-VIII:C Fab neutralization of clotting activity. The two antigenic populations were separable by cryoprecipitation and agarose gel electrophoresis. Although the two antigenic populations differed in their Factor VIII coagulant activity and in their binding to von Willebrand factor, the principal member of both populations is of mol wt 2.4 X 10(5). Both antigens, when proteolyzed by thrombin, were quickly converted to a 1 X 10(5)-mol wt form in association with the appearance of VIII:C activity. The 1 X 10(5)-mol wt antigen was further slowly degraded to an 8 X 10(4)-mol wt form while Factor VIII coagulant activity declined. These results demonstrate the presence of an inactive Factor VIII coagulant protein in plasma, not associated with von Willebrand factor, that can react with thrombin to yield Factor VIII coagulant activity. Images PMID:6421875

  4. Pulsed metallic-plasma generators.

    NASA Technical Reports Server (NTRS)

    Gilmour, A. S., Jr.; Lockwood, D. L.

    1972-01-01

    A pulsed metallic-plasma generator is described which utilizes a vacuum arc as the plasma source. The arc is initiated on the surface of a consumable cathode which can be any electrically conductive material. Ignition is accomplished by using a current pulse to vaporize a portion of a conductive film on the surface of an insulator separating the cathode from the ignition electrode. The film is regenerated during the ensuing arc. Over 100 million ignition cycles have been accomplished by using four 0.125-in. diameter zinc cathodes operating in parallel and high-density aluminum-oxide insulators. Among the applications being investigated for the generator are metal deposition, vacuum pumping, electric propulsion, and high-power dc arc interruption.

  5. Low thrombin generation during major orthopaedic surgery fails to predict the bleeding risk in inhibitor patients treated with bypassing agents.

    PubMed

    Mancuso, M E; Chantarangkul, V; Clerici, M; Fasulo, M R; Padovan, L; Scalambrino, E; Peyvandi, F; Tripodi, A; Santagostino, E

    2016-07-01

    In the presence of high-titre inhibitors, haemostatic bypassing agents are used to control bleeding and perform surgery. In this setting, no specific laboratory test is yet available to guide drug choice, monitor treatment efficacy and predict the risk of bleeding. The aims of this study, carried out in patients candidate to orthopaedic surgery, were to assess the dose-dependent increase in thrombin generation (TG) after infusion of bypassing agents and to evaluate whether or not a correlation existed between the haemostatic efficacy of bypassing therapies and perioperative TG values. TG was measured in 16 inhibitor patients, 10 of whom underwent 11 major orthopaedic procedures. In the non-bleeding state, TG significantly improved 30 min after whichever dose (P < 0.01), with no dose-response relationship when values obtained after different rFVIIa doses were compared. TG significantly improved 30 min after the preoperative bolus (P < 0.05), while during the postoperative period TG values measured before and after dosing did not differ. Moreover, postoperative TG values were similar or even more impaired (P ≤ 0.05) than those measured before preoperative dosing. No difference was found by comparing procedures with and without bleeding complications and yet no bleeding occurred in spite of persistently low TG values in one-third of procedures. This study fails to support a definite role for the TG assay as a reliable laboratory tool to monitor the haemostatic efficacy of bypassing therapies and as a predictor of the risk of bleeding in inhibitor patients using these agents during orthopaedic surgery. © 2016 John Wiley & Sons Ltd.

  6. Effects of thromboprophylactic doses of apixaban and rivaroxaban on coagulation and thrombin generation in association with total hip replacement.

    PubMed

    Helin, Tuukka A; Virtanen, Lauri; Manninen, Mikko; Leskinen, Jarkko; Leppilahti, Juhana; Joutsi-Korhonen, Lotta; Lassila, Riitta

    2017-05-01

    Factor Xa inhibitors (FXaI) apixaban and rivaroxaban are used for thromboprophylaxis after major elective orthopaedic surgery. Because few patient sample studies exist, we postoperatively assessed patients undergoing unilateral total hip arthroplasty, including 22 treated with apixaban (2.5 mg BID) and 20 treated with rivaroxaban (10 mg OD). We collected blood samples before and 3 h after drug intake at 4 time points, preoperatively, as well as on day 1, week 1 (day 2-8) and day 28 post-operation. APTT and PT were immediately analysed. Calibrated anti-FXa activity, Russel's Viper Venom Time (RVVT) and thrombin generation (TG; Calibrated Automated Thrombogram(®)) captured the effects of FXaI on coagulation and TG. APTT and PT remained within the reference interval throughout, and did not correlate with FXaI levels (PT R(2) = 0.44, APTT R(2) = 0.07). Mean apixaban concentration at the peak varied by eightfold (19-153 ng/mL), but rivaroxaban only by 1.5-fold (111-183 ng/mL). Rivaroxaban, but not apixaban prolonged RVVT at peak levels. Both FXaIs had a prolonged lag time of TG (p < 0.001). Rivaroxaban decreased ETP peak at all time points and reached a minimum at day 28 (540 nM/min at rivaroxaban 184 ng/mL, p < 0.001), while rivaroxaban trough levels were low and ETP values normal. However, with apixaban, after an initial decrease, ETP did not differ between peak and trough levels until decreasing on day 28 at peak (990 nM/min at apixaban 112 ng/mL, p = 0.005). In conclusion, due to different dosing and pharmacology rivaroxaban and apixaban distinctly inhibited TG under postoperative conditions.

  7. Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

    PubMed Central

    Nishimura, Toshihiko; Myles, Timothy; Piliposky, Adrian M.; Kao, Peter N.; Berry, Gerald J.

    2007-01-01

    Plasma procarboxypeptidase B (proCPB) is activated by the endothelial thrombin-prothrombomodulin complex. Activated (CPB) functions as a fibrinolysis inhibitor, but it may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild-type (WT) and proCPB-deficient mice (proCPB−/−). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB−/− mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB−/− mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by CPB. Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury. PMID:17105819

  8. Thalidomide-prednisone maintenance following autologous stem cell transplant for multiple myeloma: effect on thrombin generation and procoagulant markers in NCIC CTG MY.10.

    PubMed

    Kovacs, Michael J; Davies, Gwynivere A; Chapman, Judy-Anne W; Bahlis, Nizar; Voralia, Michael; Roy, Jean; Kouroukis, C Tom; Chen, Christine; Belch, Andrew; Reece, Donna; Zhu, Liting; Meyer, Ralph M; Shepherd, Lois; Stewart, Keith A

    2015-02-01

    Venous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide-prednisone to observation for 332 patients with MM post-autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty-three patients had biomarker data, including D-dimer, factor VIII and thrombin anti-thrombin (TAT) levels collected post-ASCT at baseline and 2 months after intervention investigating in-vivo thrombin generation. Differences between the time-points included a significant reduction over time in D-dimer, factor VIII and TAT levels in the observation group and sustained elevation of D-dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide-prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide-prednisone arm, with a trend to increase in D-dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide-prednisone maintenance therapy post-ASCT for MM.

  9. Dense Plasma Heating and Radiation Generation.

    DTIC Science & Technology

    The investigations under this grant consist of three parts: CO2 laser heating of dense preformed plasmas, interaction of a dense hot plasma with a...small solid pellet, and pulsed power systems and technology. The laser plasma heating experiment has demonstrated both beam guiding by the plasma and...plasma heating by the beam. These results will be useful in heating plasmas for radiation generation. Experiments have shown that the pellet-plasma

  10. Real-time measurement of free thrombin: evaluation of the usability of a new thrombin assay for coagulation monitoring during extracorporeal circulation.

    PubMed

    Krajewski, Stefanie; Krauss, Sabrina; Kurz, Julia; Neumann, Bernd; Schlensak, Christian; Wendel, Hans P

    2014-03-01

    In patients undergoing cardiac surgery with heart-lung machine support, adequate anticoagulation to mitigate blood clotting caused by the artificial surfaces of the extracorporeal circulation (ECC) system is essential. These patients routinely receive heparin, whose effectiveness is monitored by measurements of the activated clotting time (ACT). However, ACT values only poorly correlate with the actual hemostatic status. The aim of our study was to evaluate the detection of free thrombin in heparinized human blood as a monitor of anticoagulation during ECC. Human whole blood was anticoagulated with different concentrations of heparin (0.75, 1, 2 or 3 IU/ml) and circulated in the Chandler-loop model for up to 240 min at 37 °C. Next to ACT, ECC-mediated changes in free active thrombin, prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin-III (TAT) levels were measured before and during circulation. Platelet activation and cell count parameters were further investigated. Our study shows that detection of ECC-mediated changes in free thrombin is possible in blood anticoagulated with 0.75 or 1 IU/ml heparin, whereas no thrombin was detectable at higher heparin concentrations. Thrombin generation during 240 min of ECC is comparable to F 1+2 and TAT plasma levels during ECC. Thrombin is the key enzyme in the coagulation cascade and hence represents a promising marker for monitoring the coagulation status of patients. Although detection of free thrombin was not feasible at high heparin concentrations, the employed test represents an additional test to current laboratory methods investigating blood coagulation at low heparin concentrations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Natural inhibitors of thrombin.

    PubMed

    Huntington, James A

    2014-04-01

    The serine protease thrombin is the effector enzyme of blood coagulation. It has many activities critical for the formation of stable clots, including cleavage of fibrinogen to fibrin, activation of platelets and conversion of procofactors to active cofactors. Thrombin carries-out its multiple functions by utilising three special features: a deep active site cleft and two anion binding exosites (exosite I and II). Similarly, thrombin inhibitors have evolved to exploit the unique features of thrombin to achieve rapid and specific inactivation of thrombin. Exogenous thrombin inhibitors come from several different protein families and are generally found in the saliva of haematophagous animals (blood suckers) as part of an anticoagulant cocktail that allows them to feed. Crystal structures of several of these inhibitors reveal how peptides and proteins can be targeted to thrombin in different and interesting ways. Thrombin activity must also be regulated by endogenous inhibitors so that thrombi do not occlude blood flow and cause thrombosis. A single protein family, the serpins, provides all four of the endogenous thrombin inhibitors found in man. The crystal structures of these serpins bound to thrombin have been solved, revealing a similar exosite-dependence on complex formation. In addition to forming the recognition complex, serpins destroy the structure of thrombin, allowing them to be released from cofactors and substrates for clearance. This review examines how the special features of thrombin have been exploited by evolution to achieve inhibition of the ultimate coagulation protease.

  12. Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study

    PubMed Central

    Olson, N. C.; Butenas, S.; Lange, L. A.; Lange, E. M.; Cushman, M.; Jenny, N. S.; Walston, J.; Souto, J. C.; Soria, J. M.; Chauhan, G.; Debette, S.; Longstreth, W.T.; Seshadri, S.; Reiner, A.P.; Tracy, R. P.

    2016-01-01

    Background Relationships of thrombin generation (TG) with cardiovascular disease risk are under-evaluated in population-based cohorts. Objectives Evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common SNPs and incident cardiovascular disease and stroke. Patients/Methods We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n=5,411), both with and without inhibitory anti-FXIa antibody (pTG/FXIa−). We evaluated their associations with ~50K SNPs using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2-years. Results The minor allele for a SNP in the coagulation factor XII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β=−34.2 nM ± 3.5 nM; p=3.3×10−22; minor allele frequency (MAF) =0.23) and African-Americans (β=−31.1 nM ± 7.9 nM; p=9.0×10−5; MAF=0.42). Lower FXIa-independent pTG (pTG/FXIa−) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa− was associated with the ABO SNP rs657152 minor allele (β=16.3 nM; p=4.3×10−9; MAF=0.37). The risk factor-adjusted ischemic stroke hazard ratio (95% confidence interval) was 1.09 (1.01, 1.17; p=0.03) for pTG, 1.06 (0.98, 1.15; p=0.17) for pTG/FXIa−, and 1.11 (1.02, 1.21; p=0.02) for FXIa-dependent pTG (pTG/FXIa+), per 1-SD increment (n=834 ischemic strokes). In a multi-cohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β= −0.02; (SE=0.08); p=0.81). Conclusions These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke and indicate the importance of F12 SNPs on TG ex vivo and in vivo. PMID:26286125

  13. Thrombin inhibitors identified by computer-assisted multiparameter design

    PubMed Central

    Riester, Daniel; Wirsching, Frank; Salinas, Gabriela; Keller, Martina; Gebinoga, Michael; Kamphausen, Stefan; Merkwirth, Christian; Goetz, Ruediger; Wiesenfeldt, Martin; Stürzebecher, Jörg; Bode, Wolfram; Friedrich, Rainer; Thürk, Marcel; Schwienhorst, Andreas

    2005-01-01

    Here, we present a series of thrombin inhibitors that were generated by using powerful computer-assisted multiparameter optimization process. The process was organized in design cycles, starting with a set of randomly chosen molecules. Each cycle combined combinatorial synthesis, multiparameter characterization of compounds in a variety of bioassays, and algorithmic processing of the data to devise a set of compounds to be synthesized in the next cycle. The identified lead compounds exhibited thrombin inhibitory constants in the lower nanomolar range. They are by far the most selective synthetic thrombin inhibitors, with selectivities of >100,000-fold toward other proteases such as Factor Xa, Factor XIIa, urokinase, plasmin, and Plasma kallikrein. Furthermore, these compounds exhibit a favorable profile, comprising nontoxicity, high metabolic stability, low serum protein binding, good solubility, high anticoagulant activity, and a slow and exclusively renal elimination from the circulation in a rat model. Finally, x-ray crystallographic analysis of a thrombin–inhibitor complex revealed a binding mode with a neutral moiety in the S1 pocket of thrombin. PMID:15937115

  14. [New anticoagulants - direct thrombin inhibitors].

    PubMed

    Brand, B; Graf, L

    2012-11-01

    Direct thrombin-inhibitors inactivate not only free but also fibrin-bound thrombin. The group of parenteral direct thrombin-inhibitors includes the recombinant hirudins lepirudin and desirudin, the synthetic hirudin bivalirudin, and the small molecule argatroban. All these compounds do not interact with PF4/heparin-antibodies. Therefore, argatroban as well as bivalirudin are currently used to treat heparin-induced thrombocytopenia (HIT). The oral direct thrombin-inhibitor dabigatran etexilate is already licensed in many countries for the treatment of non-valvular atrial fibrillation. Dabigatran etexilate reveals a stable and predictable effect that allows a medication without dose adjustment or monitoring. The substance shows only few interactions with other drugs but strong inhibitors of p-glycoprotein can increase plasma levels of dabigatran substantially. After oral intake, the prodrug dabigatran etexilate is cleaved by esterase-mediated hydrolyses to the active compound dabigatran. Elimination of dabigatran is predominantly renal. Safety and efficacy of dabigatran etexilate were tested in an extensive clinical study program. Non-inferiority compared to current standard treatments was shown for prophylaxis of venous thromboembolic events after total knee and hip replacement, for stroke prevention in atrial fibrillation, and for treatment of acute venous thromboembolism. In daily practice, Dabigatran etexilate competes against the new direct factor Xa-inhibitors. In the absence of direct comparative clinical trials, it is not yet clear if one class of substances has distinct advantages over the other.

  15. Presence of plasma proteins facilitates the uptake of /sup 125/I-thrombin by the rabbit thoracic aorta endothelium in vitro

    SciTech Connect

    Hatton, M.W.; Moar, S.L.

    1986-07-01

    Various purified proteins, protein derivatives and two polysaccharides were added individually to a physiological medium in order to effect uptake of /sup 125/I-thrombin by the rabbit aorta endothelium. Over a wide range of concentration (0.004-40 mg/ml), the presence of either purified rabbit or bovine albumin during thrombin uptake encouraged an increase (70-110%) in /sup 125/I-thrombin binding by the endothelium and subendothelium compared to uptake by aorta segments in the absence of added protein. Pretreatment of aorta segments with albumin before incubation with /sup 125/I-thrombin in the absence of albumin did not encourage thrombin uptake to the same extent as having /sup 125/I-thrombin and albumin together. Purified human transferrin, rabbit IgG, chicken ovalbumin or denatured bovine casein could replace albumin to produce a similar enhancement of thrombin uptake. Replacing active concentrations of albumin by either reduced-carboxymethylated albumin, defatted albumin, plasmin-treated or thermolysin-treated albumin also caused an increase (50-130%) in thrombin binding, whereas replacement by acid-hydrolysed albumin or with polyglutamic acid was either ineffective or even inhibitory. Lysine-modified or arginine-modified albumins caused a small enhancement (14-32%) and no enhancement of thrombin uptake, respectively. Dextran, at low concentration (0.04-0.4 mg/ml) did not influence thrombin uptake, and at higher concentration (4-40 mg/ml) caused a decrease in uptake by both the endothelium and subendothelial layers. Low concentration of dextran sulphate inhibited thrombin uptake to 20-30% of control values. These data express the importance of accompanying protein in the response of the vascular endothelium during binding of thrombin. The possibility that other protein-cell interactions may be similarly influenced by macromolecular solutes is also discussed.

  16. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice.

    PubMed

    Kopec, Anna K; Joshi, Nikita; Towery, Keara L; Kassel, Karen M; Sullivan, Bradley P; Flick, Matthew J; Luyendyk, James P

    2014-11-01

    Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. Robust coagulation cascade activation is common in obese patients with NAFLD. We identified a critical temporal relationship between thrombin generation and the manifestation of hepatic steatosis, inflammation, and injury in C57BL/6J mice fed a high-fat diet (HFD) for 1, 2, and 3 months. Mice fed a HFD exhibited dramatic increases in hepatocellular injury and inflammation over time. Hepatic fibrin deposition preceded an increase in serum alanine aminotransferase, and the most dramatic changes in liver histopathology occurred in conjunction with a detectable increase in plasma thrombin-antithrombin levels at 3 months. To directly determine whether thrombin activity promotes NAFLD pathogenesis, mice were fed a HFD and simultaneously treated with the direct thrombin inhibitor dabigatran etexilate for 3 months. Notably, dabigatran treatment significantly reduced hepatic fibrin deposition, hepatic inflammation, hepatocellular injury, and steatosis in mice fed a HFD. Of interest, dabigatran treatment also significantly attenuated HFD-induced body weight gain. Gene expression analysis suggested that thrombin potentially drives NAFLD pathogenesis by altering the expression of genes associated with lipid metabolism and bile acid synthesis. Collectively, the results suggest that thrombin activity is central to HFD-induced body weight gain, liver injury, and inflammation and provide the proof-of-principle evidence that pharmacological thrombin inhibition could be effective in limiting NAFLD and associated pathologies.

  17. Proton driven plasma wakefield generation in a parabolic plasma channel

    NASA Astrophysics Data System (ADS)

    Golian, Y.; Dorranian, D.

    2016-11-01

    An analytical model for the interaction of charged particle beams and plasma for a wakefield generation in a parabolic plasma channel is presented. In the suggested model, the plasma density profile has a minimum value on the propagation axis. A Gaussian proton beam is employed to excite the plasma wakefield in the channel. While previous works investigated on the simulation results and on the perturbation techniques in case of laser wakefield accelerations for a parabolic channel, we have carried out an analytical model and solved the accelerating field equation for proton beam in a parabolic plasma channel. The solution is expressed by Whittaker (hypergeometric) functions. Effects of plasma channel radius, proton bunch parameters and plasma parameters on the accelerating processes of proton driven plasma wakefield acceleration are studied. Results show that the higher accelerating fields could be generated in the PWFA scheme with modest reductions in the bunch size. Also, the modest increment in plasma channel radius is needed to obtain maximum accelerating gradient. In addition, the simulations of longitudinal and total radial wakefield in parabolic plasma channel are presented using LCODE. It is observed that the longitudinal wakefield generated by the bunch decreases with the distance behind the bunch while total radial wakefield increases with the distance behind the bunch.

  18. Plasma plume MHD power generator and method

    DOEpatents

    Hammer, James H.

    1993-01-01

    Highly-conducting plasma plumes are ejected across the interplanetary magnetic field from a situs that is moving relative to the solar wind, such as a spacecraft or an astral body, such as the moon, having no magnetosphere that excludes the solar wind. Discrete plasma plumes are generated by plasma guns at the situs extending in opposite directions to one another and at an angle, preferably orthogonal, to the magnetic field direction of the solar wind plasma. The opposed plumes are separately electrically connected to their source by a low impedance connection. The relative movement between the plasma plumes and the solar wind plasma creates a voltage drop across the plumes which is tapped by placing the desired electrical load between the electrical connections of the plumes to their sources. A portion of the energy produced may be used in generating the plasma plumes for sustained operation.

  19. A model for the unique role of factor Va A2 domain extension in the human ternary thrombin-generating complex.

    PubMed

    Shim, Joong-Youn; Lee, Chang Jun; Wu, Sangwook; Pedersen, Lee G

    2015-04-01

    An all-atom human ternary model for the prothrombinase-prothrombin complex, including metal ions and post-translationally modified residues, was constructed from existing X-ray crystal structures. The factor Xa-prothrombin interface was taken from an existing ternary model, which locates the active site of factor Xa in the vicinity of prothrombin cleavage positions. The three sulfotyrosine residues at the C-terminal sequence of factor Va A2 domain are accommodated by modelling rational interactions with positively charged patches on the surface of prothrombin. The entire model is then solvent-equilibrated with molecular dynamics. This ternary model for the thrombin-generating complex provides an estimate as to the role of the C-terminus of the factor Va A2 domain: to establish an interface between FXa and prothrombin and to stabilize the orientation of this interface. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Hollow-Cathode Source Generates Plasma

    NASA Technical Reports Server (NTRS)

    Deininger, W. D.; Aston, G.; Pless, L. C.

    1989-01-01

    Device generates argon, krypton, or xenon plasma via thermionic emission and electrical discharge within hollow cathode and ejects plasma into surrounding vacuum. Goes from cold start up to full operation in less than 5 s after initial application of power. Exposed to moist air between operations without significant degradation of starting and running characteristics. Plasma generated by electrical discharge in cathode barrel sustained and aided by thermionic emission from emitter tube. Emitter tube does not depend on rare-earth oxides, making it vulnerable to contamination by exposure to atmosphere. Device modified for use as source of plasma in laboratory experiments or industrial processes.

  1. Hydrogen ionic plasma generated using Al plasma grid

    SciTech Connect

    Oohara, W.; Anegawa, N.; Egawa, M.; Kawata, K.; Kamikawa, T.

    2016-08-15

    Negative hydrogen ions are produced in the apertures of a plasma grid made of aluminum under the irradiation of positive ions, generating an ionic plasma consisting of positive and negative ions. The saturation current ratio obtained using a Langmuir probe reflects the existence ratio of electrons and is found to increase in connection with the diffusion of the ionic plasma. The local increment of the current ratio suggests the collapse of negative ions and the replacement of detached electrons.

  2. Hydrogen ionic plasma generated using Al plasma grid

    NASA Astrophysics Data System (ADS)

    Oohara, W.; Anegawa, N.; Egawa, M.; Kawata, K.; Kamikawa, T.

    2016-08-01

    Negative hydrogen ions are produced in the apertures of a plasma grid made of aluminum under the irradiation of positive ions, generating an ionic plasma consisting of positive and negative ions. The saturation current ratio obtained using a Langmuir probe reflects the existence ratio of electrons and is found to increase in connection with the diffusion of the ionic plasma. The local increment of the current ratio suggests the collapse of negative ions and the replacement of detached electrons.

  3. Effect of Chronic Blood Transfusion on Biomarkers of Coagulation Activation and Thrombin Generation in Sickle Cell Patients at Risk for Stroke

    PubMed Central

    Hyacinth, Hyacinth I.; Adams, Robert J.; Greenberg, Charles S.; Voeks, Jenifer H.; Hill, Allyson; Hibbert, Jacqueline M.; Gee, Beatrice E.

    2015-01-01

    Hypercoagulability in sickle cell disease (SCD) is associated with multiple SCD phenotypes, association with stroke risk has not been well described. We hypothesized that serum levels of biomarkers of coagulation activation correlate with high transcranial Doppler ultrasound velocity and decreases with blood transfusion therapy in SCD patients. Stored serum samples from subjects in the Stroke Prevention in Sickle Cell Anemia (STOP) trial were analyzed using ELISA and protein multiplexing techniques. 40 subjects from each treatment arm (Standard Care [SC] and Transfusion [Tx]) at three time points—baseline, study exit and one year post-trial and 10 each of age matched children with SCD but normal TCD (SNTCD) and with normal hemoglobin (HbAA) were analyzed. At baseline, median vWF, TAT and D-dimer levels were significantly higher among STOP subjects than either HbAA or SNTCD. At study exit, median hemoglobin level was significantly higher while median TCD velocity was significantly lower in Tx compared to SC subjects. Median vWF (409.6 vs. 542.9 μg/ml), TAT (24.8 vs. 40.0 ng/ml) and D-dimer (9.2 vs. 19.1 μg/ml) levels were also significantly lower in the Tx compared to the SC group at study exit. Blood levels of biomarkers coagulation activation/thrombin generation correlated positively with TCD velocity and negatively with number of blood transfusions. Biomarkers of coagulation activation/thrombin generation were significantly elevated in children with SCD, at high risk for stroke. Reduction in levels of these biomarkers correlated with reduction in stroke risk (lower TCD velocity), indicating a possible role for hypercoagulation in SCD associated stroke. PMID:26305570

  4. Microwave-generated plasma thruster

    NASA Astrophysics Data System (ADS)

    Hooper, E. B.

    1991-05-01

    A concept for high power density and efficiency plasma thruster based on electron cyclotron resonance heating (ECRH) is described. Initial estimates are made of the parameters, leading to a conceptual design. An effort for detail physics design and proof-of-principal tests is also proposed.

  5. Microwave-generated plasma thruster

    SciTech Connect

    Hooper, E.B.

    1991-05-11

    A concept for high power density and efficiency plasma thruster based on electron cyclotron resonance heating (ECRH) is described. Initial estimates are made of the parameters, leading to a conceptual design. An effort for detail physics design and proof-of-principal tests is also proposed. 20 refs., 2 figs., 1 tab.

  6. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects.

    PubMed

    Theuwissen, Elke; Cranenburg, Ellen C; Knapen, Marjo H; Magdeleyns, Elke J; Teunissen, Kirsten J; Schurgers, Leon J; Smit, Egbert; Vermeer, Cees

    2012-11-14

    Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10-40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose-response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 μg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and high-dose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.

  7. Anti-inflammatory and anti-fibrinolytic effects of thrombomodulin alfa through carboxypeptidase B2 in the presence of thrombin.

    PubMed

    Tawara, Shunsuke; Sakai, Takumi; Matsuzaki, Osamu

    2016-11-01

    Thrombomodulin (TM) alfa, a recombinant human soluble TM, enhances activation of pro-carboxypeptidase B2 (pro-CPB2) by thrombin. Activated pro-CPB2 (CPB2) exerts anti-inflammatory and anti-fibrinolytic activities. Therefore, TM alfa may also have anti-inflammatory and anti-fibrinolytic effects through CPB2. However, these effects of TM alfa have not been elucidated. In the present study, we investigated the effects of TM alfa on inactivation of complement component C5a as an anti-inflammatory effect and prolongation of clot lysis time as an anti-fibrinolytic effect via CPB2 in vitro. CPB2 activity and tissue factor-induced thrombin generation was examined by a chromogenic assay. C5a inactivation was evaluated by C-terminal cleavage of C5a and inhibition of C5a-induced human neutrophil migration. Clot lysis time prolongation was examined by a tissue-type plasminogen activator-induced clot lysis assay. CPB2 activity in human plasma was increased by TM alfa and thrombin in a concentration-dependent manner. TM alfa inhibited tissue factor-induced thrombin generation and enhanced pro-CPB2 activation in human plasma simultaneously. The mass spectrum of C5a treated with TM alfa, thrombin, and pro-CPB2 was decreased at 156m/z, indicating that TM alfa enhanced the processing of C5a to C-terminal-cleaved C5a, an inactive form of C5a. C5a-induced human neutrophil migration was decreased after C5a treatment with TM alfa, thrombin, and pro-CPB2. TM alfa prolonged the clot lysis time in human plasma, and this effect was completely abolished by addition of a CPB2 inhibitor. TM alfa exerts anti-inflammatory and anti-fibrinolytic effects through CPB2 in the presence of thrombin in vitro. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Plasma generating apparatus for large area plasma processing

    DOEpatents

    Tsai, C.C.; Gorbatkin, S.M.; Berry, L.A.

    1991-07-16

    A plasma generating apparatus for plasma processing applications is based on a permanent magnet line-cusp plasma confinement chamber coupled to a compact single-coil microwave waveguide launcher. The device creates an electron cyclotron resonance (ECR) plasma in the launcher and a second ECR plasma is created in the line cusps due to a 0.0875 tesla magnetic field in that region. Additional special magnetic field configuring reduces the magnetic field at the substrate to below 0.001 tesla. The resulting plasma source is capable of producing large-area (20-cm diam), highly uniform (.+-.5%) ion beams with current densities above 5 mA/cm[sup 2]. The source has been used to etch photoresist on 5-inch diam silicon wafers with good uniformity. 3 figures.

  9. Plasma generating apparatus for large area plasma processing

    DOEpatents

    Tsai, Chin-Chi; Gorbatkin, Steven M.; Berry, Lee A.

    1991-01-01

    A plasma generating apparatus for plasma processing applications is based on a permanent magnet line-cusp plasma confinement chamber coupled to a compact single-coil microwave waveguide launcher. The device creates an electron cyclotron resonance (ECR) plasma in the launcher and a second ECR plasma is created in the line cusps due to a 0.0875 tesla magnetic field in that region. Additional special magnetic field configuring reduces the magnetic field at the substrate to below 0.001 tesla. The resulting plasma source is capable of producing large-area (20-cm diam), highly uniform (.+-.5%) ion beams with current densities above 5 mA/cm.sup.2. The source has been used to etch photoresist on 5-inch diam silicon wafers with good uniformity.

  10. High frequency plasma generator for ion thrusters

    NASA Technical Reports Server (NTRS)

    Goede, H.; Divergilio, W. F.; Fosnight, V. V.; Komatsu, G.

    1984-01-01

    The results of a program to experimentally develop two new types of plasma generators for 30 cm electrostatic argon ion thrusters are presented. The two plasma generating methods selected for this study were by radio frequency induction (RFI), operating at an input power frequency of 1 MHz, and by electron cyclotron heating (ECH) at an operating frequency of 5.0 GHz. Both of these generators utilize multiline cusp permanent magnet configurations for plasma confinement and beam profile optimization. The program goals were to develop a plasma generator possessing the characteristics of high electrical efficiency (low eV/ion) and simplicity of operation while maintaining the reliability and durability of the conventional hollow cathode plasma sources. The RFI plasma generator has achieved minimum discharge losses of 120 eV/ion while the ECH generator has obtained 145 eV/ion, assuming a 90% ion optical transparency of the electrostatic acceleration system. Details of experimental tests with a variety of magnet configurations are presented.

  11. Electrodynamic plasma motor/generator experiment

    NASA Technical Reports Server (NTRS)

    Mccoy, James E.

    1987-01-01

    The Plasma Motor/Generator Proof of Function (PMG/POF) experiment, a low-cost payload for flight aboard the Shuttle Orbiter using the Hitchhiker G carrier, is discussed. The primary objective of this experiment is to verify that hollow cathode plasma sources can couple electric currents from either end of a long wire moving through the space plasma in LEO into and through that plasma to produce a PMG circuit. The support structure and the electrical components of the experiment are described. The experimental operation is discussed, including the calibration, experimental measurements, and follow-on missions.

  12. An amplitude modulated radio frequency plasma generator

    NASA Astrophysics Data System (ADS)

    Lei, Fan; Li, Xiaoping; Liu, Yanming; Liu, Donglin; Yang, Min; Xie, Kai; Yao, Bo

    2017-04-01

    A glow discharge plasma generator and diagnostic system has been developed to study the effects of rapidly variable plasmas on electromagnetic wave propagation, mimicking the plasma sheath conditions encountered in space vehicle reentry. The plasma chamber is 400 mm in diameter and 240 mm in length, with a 300-mm-diameter unobstructed clear aperture. Electron densities produced are in the mid 1010 electrons/cm3. An 800 W radio frequency (RF) generator is capacitively coupled through an RF matcher to an internally cooled stainless steel electrode to form the plasma. The RF power is amplitude modulated by a waveform generator that operates at different frequencies. The resulting plasma contains electron density modulations caused by the varying power levels. A 10 GHz microwave horn antenna pair situated on opposite sides of the chamber serves as the source and detector of probe radiation. The microwave power feed to the source horn is split and one portion is sent directly to a high-speed recording oscilloscope. On mixing this with the signal from the pickup horn antenna, the plasma-induced phase shift between the two signals gives the path-integrated electron density with its complete time dependent variation. Care is taken to avoid microwave reflections and extensive shielding is in place to minimize electronic pickup. Data clearly show the low frequency modulation of the electron density as well as higher harmonics and plasma fluctuations.

  13. 30-cm electron cyclotron plasma generator

    NASA Technical Reports Server (NTRS)

    Goede, Hank

    1987-01-01

    Experimental results on the development of a 30-cm-diam electron cyclotron resonance plasma generator are presented. This plasma source utilizes samarium-cobalt magnets and microwave power at a frequency of 4.9 GHz to produce a uniform plasma with densities of up to 3 x 10 to the 11th/cu cm in a continuous fashion. The plasma generator contains no internal structures, and is thus inherently simple in construction and operation and inherently durable. The generator was operated with two different magnetic geometries. One used the rare-earth magnets arranged in an axial line cusp configuration, which directly showed plasma production taking place near the walls of the generator where the electron temperature was highest but with the plasma density peaking in the central low B-field regions. The second configuration had magnets arranged to form azimuthal line cusps with approximately closed electron drift surfaces; this configuration showed an improved electrical efficiency of about 135 eV/ion.

  14. Ion beams from laser-generated plasmas

    NASA Technical Reports Server (NTRS)

    Hughes, R. H.; Anderson, R. J.; Gray, L. G.; Rosenfeld, J. P.; Manka, C. K.; Carruth, M. R.

    1980-01-01

    The paper describes the space-charge-limited beams produced by the plasma blowoffs generated by 20-MW bursts of 1.06-micron radiation from an active Q-switched Nd:YAG laser. Laser power densities near 10 to the 11th/sq cm on solid targets generate thermalized plasma plumes which drift to a 15-kV gridded extraction gap where the ions are extracted, accelerated, and electrostatically focused; the spatially defined ion beams are then magnetically analyzed to determine the charge state content in the beams formed from carbon, aluminum, copper, and lead targets. This technique preserves time-of-flight (TOF) information in the plasma drift region, which permits plasma ion temperatures and mass flow velocities to be determined from the Maxwellian ion curve TOF shapes for the individual charge species.

  15. Combined impact features for laser plasma generation

    NASA Astrophysics Data System (ADS)

    Loktionov, E.; Protasov, Yu; Telekh, V.

    2017-05-01

    Laser-induced plasma has been considered for multiple applications by the moment, and its characteristics strongly depend on laser radiation parameters. Reaching demanded values for the latter might be rather costly, but, in certain cases, similar or even better results could be reached in case of additional impact (optical, electric, magnetic, corpuscular, mechanical etc.). Combined impact effects are mainly based on target properties or interaction mechanism change, and found to decrease plasma generation thresholds by orders of magnitude, improve energy efficiency significantly, and also broaden the range of plasma parameters. Application area, efficiency and optimal regimes for laser plasma generation at such combined impact have been considered. Analysis based on published data and own experiments was performed for both target material and induced plasma flows. Criterial parameters have been suggested to characterize both combined impact and response to it. The data on plasma generation thresholds, controlled parameters, working media supply systems and recovery rate of droplets are very important for technology setups, including those for material modification.

  16. Blood coagulation: hemostasis and thrombin regulation.

    PubMed

    Tanaka, Kenichi A; Key, Nigel S; Levy, Jerrold H

    2009-05-01

    Perioperative bleeding is a major challenge particularly because of increasing clinical use of potent antithrombotic drugs. Understanding current concepts of coagulation is important in determining the preoperative bleeding risk of patients, and in managing hemostatic therapy perioperatively. The serine protease thrombin plays pivotal roles in the activation of additional serine protease zymogens (inactive enzymatic precursors), cofactors, and cell-surface receptors. Thrombin generation is closely regulated to locally achieve rapid hemostasis after injury without causing uncontrolled systemic thrombosis. During surgery, there are major disturbances in coagulation and inflammatory systems because of hemorrhage/hemodilution, blood transfusion, and surgical stresses. Postoperative bleeding often requires allogeneic blood transfusions, which support thrombin generation and hemostasis. However, procoagulant activity and inflammation are increased postoperatively; thus, antithrombotic therapy may be required to prevent perioperative thrombotic complications. There have been significant advances in the management of perioperative hemostasis and thrombosis because of the introduction of novel hemostatic and antithrombotic drugs. However, a limitation of current treatment is that conventional clotting tests do not reflect the entire physiological processes of coagulation making optimal pharmacologic therapy difficult. Understanding the in vivo regulatory mechanisms and pharmacologic modulation of thrombin generation may help control bleeding without potentially increasing prothrombotic risks. In this review, we focus on the regulatory mechanisms of hemostasis and thrombin generation using multiple, simplified models of coagulation.

  17. Surface plasma source with saddle antenna radio frequency plasma generator.

    PubMed

    Dudnikov, V; Johnson, R P; Murray, S; Pennisi, T; Piller, C; Santana, M; Stockli, M; Welton, R

    2012-02-01

    A prototype RF H(-) surface plasma source (SPS) with saddle (SA) RF antenna is developed which will provide better power efficiency for high pulsed and average current, higher brightness with longer lifetime and higher reliability. Several versions of new plasma generators with small AlN discharge chambers and different antennas and magnetic field configurations were tested in the plasma source test stand. A prototype SA SPS was installed in the Spallation Neutron Source (SNS) ion source test stand with a larger, normal-sized SNS AlN chamber that achieved unanalyzed peak currents of up to 67 mA with an apparent efficiency up to 1.6 mA∕kW. Control experiments with H(-) beam produced by SNS SPS with internal and external antennas were conducted. A new version of the RF triggering plasma gun has been designed. A saddle antenna SPS with water cooling is fabricated for high duty factor testing.

  18. Surface plasma source with saddle antenna radio frequency plasma generator

    SciTech Connect

    Dudnikov, V.; Johnson, R. P.; Murray, S.; Pennisi, T.; Piller, C.; Santana, M.; Stockli, M.; Welton, R.

    2012-02-15

    A prototype RF H{sup -} surface plasma source (SPS) with saddle (SA) RF antenna is developed which will provide better power efficiency for high pulsed and average current, higher brightness with longer lifetime and higher reliability. Several versions of new plasma generators with small AlN discharge chambers and different antennas and magnetic field configurations were tested in the plasma source test stand. A prototype SA SPS was installed in the Spallation Neutron Source (SNS) ion source test stand with a larger, normal-sized SNS AlN chamber that achieved unanalyzed peak currents of up to 67 mA with an apparent efficiency up to 1.6 mA/kW. Control experiments with H{sup -} beam produced by SNS SPS with internal and external antennas were conducted. A new version of the RF triggering plasma gun has been designed. A saddle antenna SPS with water cooling is fabricated for high duty factor testing.

  19. Characterization of railgun-generated plasma armatures

    SciTech Connect

    Propp, A.D.

    1991-01-01

    Production and acceleration of plasmas using railguns is of interest because of the high temperatures and velocities which can be achieved. Railgun-generated plasmas can be used to model difficult-to-study phenomena such as the conditions present when a space vehicle re-enters the earth's atmosphere. There is also interest in the use of plasma railguns in material-processing applications such as deposition of heated particles onto a substrate. To understand and control these processes it is necessary to be able to determine parameters of the plasmas such as temperature, density, and composition. The methods by which these plasma characteristics can be systematically determined are the foci of this study. A rectangular-bore railgun and the vacuum chamber in which it was enclosed were constructed and successfully operated. Magnetic probes and phototransistors were used to determine the velocities of the plasma armatures produced by the railgun. Gated plasma-emission spectroscopy was used to determine the composition, electron density, and temperature at various positions within the plasma armatures.

  20. Cold plasma brush generated at atmospheric pressure

    SciTech Connect

    Duan Yixiang; Huang, C.; Yu, Q. S.

    2007-01-15

    A cold plasma brush is generated at atmospheric pressure with low power consumption in the level of several watts (as low as 4 W) up to tens of watts (up to 45 W). The plasma can be ignited and sustained in both continuous and pulsed modes with different plasma gases such as argon or helium, but argon was selected as a primary gas for use in this work. The brush-shaped plasma is formed and extended outside of the discharge chamber with typical dimension of 10-15 mm in width and less than 1.0 mm in thickness, which are adjustable by changing the discharge chamber design and operating conditions. The brush-shaped plasma provides some unique features and distinct nonequilibrium plasma characteristics. Temperature measurements using a thermocouple thermometer showed that the gas phase temperatures of the plasma brush are close to room temperature (as low as 42 deg. C) when running with a relatively high gas flow rate of about 3500 ml/min. For an argon plasma brush, the operating voltage from less than 500 V to about 2500 V was tested, with an argon gas flow rate varied from less than 1000 to 3500 ml/min. The cold plasma brush can most efficiently use the discharge power as well as the plasma gas for material and surface treatment. The very low power consumption of such an atmospheric argon plasma brush provides many unique advantages in practical applications including battery-powered operation and use in large-scale applications. Several polymer film samples were tested for surface treatment with the newly developed device, and successful changes of the wettability property from hydrophobic to hydrophilic were achieved within a few seconds.

  1. Cold plasma brush generated at atmospheric pressure.

    PubMed

    Duan, Yixiang; Huang, C; Yu, Q S

    2007-01-01

    A cold plasma brush is generated at atmospheric pressure with low power consumption in the level of several watts (as low as 4 W) up to tens of watts (up to 45 W). The plasma can be ignited and sustained in both continuous and pulsed modes with different plasma gases such as argon or helium, but argon was selected as a primary gas for use in this work. The brush-shaped plasma is formed and extended outside of the discharge chamber with typical dimension of 10-15 mm in width and less than 1.0 mm in thickness, which are adjustable by changing the discharge chamber design and operating conditions. The brush-shaped plasma provides some unique features and distinct nonequilibrium plasma characteristics. Temperature measurements using a thermocouple thermometer showed that the gas phase temperatures of the plasma brush are close to room temperature (as low as 42 degrees C) when running with a relatively high gas flow rate of about 3500 ml/min. For an argon plasma brush, the operating voltage from less than 500 V to about 2500 V was tested, with an argon gas flow rate varied from less than 1000 to 3500 ml/min. The cold plasma brush can most efficiently use the discharge power as well as the plasma gas for material and surface treatment. The very low power consumption of such an atmospheric argon plasma brush provides many unique advantages in practical applications including battery-powered operation and use in large-scale applications. Several polymer film samples were tested for surface treatment with the newly developed device, and successful changes of the wettability property from hydrophobic to hydrophilic were achieved within a few seconds.

  2. Extreme hydrogen plasma densities achieved in a linear plasma generator

    SciTech Connect

    Rooij, G. J. van; Veremiyenko, V. P.; Goedheer, W. J.; de Groot, B.; Kleyn, A. W.; Smeets, P. H. M.; Versloot, T. W.; Whyte, D. G.; Engeln, R.; Schram, D. C.; Cardozo, N. J. Lopes

    2007-03-19

    A magnetized hydrogen plasma beam was generated with a cascaded arc, expanding in a vacuum vessel at an axial magnetic field of up to 1.6 T. Its characteristics were measured at a distance of 4 cm from the nozzle: up to a 2 cm beam diameter, 7.5x10{sup 20} m{sup -3} electron density, {approx}2 eV electron and ion temperatures, and 3.5 km/s axial plasma velocity. This gives a 2.6x10{sup 24} H{sup +} m{sup -2} s{sup -1} peak ion flux density, which is unprecedented in linear plasma generators. The high efficiency of the source is obtained by the combined action of the magnetic field and an optimized nozzle geometry. This is interpreted as a cross-field return current that leads to power dissipation in the beam just outside the source.

  3. Nonlinear subharmonic generation in nonuniform plasmas

    NASA Astrophysics Data System (ADS)

    Gradov, O. M.; Stenflo, L.

    1980-07-01

    Direct subharmonic wave generation in a nonuniform plasma is considered. That mechanism exists only when leaking surface waves can be parametrically excited. An expression for the instability growth rate, which includes collisions, resonance absorption and leaking losses, is derived. A possibility of generating subharmonics at omega(0)/4, 3-omega(0)/4, and 5-omega(0)/4, where omega(0) is the pump wave frequency, is pointed out, and the corresponding field intensities are estimated. The conditions for total energy absorption are discussed, and the pump wave intensity, which produces complete absorption, is obtained for a plasma with a steep density gradient.

  4. High Frequency Plasma Generators for Ion Thrusters

    NASA Technical Reports Server (NTRS)

    Divergilio, W. F.; Goede, H.; Fosnight, V. V.

    1981-01-01

    The results of a one year program to experimentally adapt two new types of high frequency plasma generators to Argon ion thrusters and to analytically study a third high frequency source concept are presented. Conventional 30 cm two grid ion extraction was utilized or proposed for all three sources. The two plasma generating methods selected for experimental study were a radio frequency induction (RFI) source, operating at about 1 MHz, and an electron cyclotron heated (ECH) plasma source operating at about 5 GHz. Both sources utilize multi-linecusp permanent magnet configurations for plasma confinement. The plasma characteristics, plasma loading of the rf antenna, and the rf frequency dependence of source efficiency and antenna circuit efficiency are described for the RFI Multi-cusp source. In a series of tests of this source at Lewis Research Center, minimum discharge losses of 220+/-10 eV/ion were obtained with propellant utilization of .45 at a beam current of 3 amperes. Possible improvement modifications are discussed.

  5. Highly enhanced electrochemiluminescence based on pseudo triple-enzyme cascade catalysis and in situ generation of co-reactant for thrombin detection.

    PubMed

    Xiao, Lijuan; Chai, Yaqin; Yuan, Ruo; Wang, Haijun; Bai, Lijuan

    2014-03-07

    In this work, a novel pseudo triple-enzyme cascade catalysis amplification strategy was employed to fabricate a highly sensitive electrochemiluminescence (ECL) aptasensor for thrombin (TB) detection. The signal amplification of the proposed aptasensor was based on the synergistic catalysis of glucose dehydrogenase (GDH) and hemin/G-quadruplex to generate a co-reactant in situ for the ECL of peroxydisulfate. Gold nanorods (AuNRs) conjugated with GDH and hemin/G-quadruplex were used as the secondary aptamer bioconjugate (TBA II) in this aptasensor. TB was sandwiched between TBA II and a thiol-terminated TB aptamer which self-assembled on the AuNRs-modified electrode. The pseudo triple-enzyme cascade catalysis was completed as follows: firstly, GDH could effectively catalyze the oxidation of glucose to gluconolactone, coupling with the reduction of β-nicotinamide adenine dinucleotide hydrate (NAD(+)) into β-nicotinamide adenine dinucleotide hydrogen (NADH). Then, the hemin/G-quadruplex acted as NADH oxidase, could rapidly oxidize NADH into NAD(+) accompanied with the generation of H2O2. Simultaneously, the hemin/G-quadruplex served as the horseradish peroxidase (HRP)-mimicking DNAzyme that further catalyzed the reduction of H2O2 to generate O2in situ. Then the O2 produced acted as the co-reactant of peroxydisulfate, resulting in significant ECL signal amplification and highly sensitive ECL detection. The proposed aptasensor showed a wide linear range of 0.0001-50 nM with a low detection limit of 33 fM (S/N = 3) for TB determination. The present work demonstrated that the novel strategy has great advantages of sensitivity, selectivity and reproducibility, which hold new promise for highly sensitive bioassays applied in clinical detection.

  6. Plasma focus experiments powered by explosive generators

    NASA Astrophysics Data System (ADS)

    Freeman, B. L.; Caird, R. S.; Erickson, D. J.; Fowler, C. M.; Garn, W. B.; Kruse, H. W.; King, J. C.; Bartram, D. E.; Kruse, P. J.

    1983-03-01

    The plasma focus project began as an effort to develop an intense, pulsed, expendable neutron radiographic source. Since previous efforts to power a plasma focus with explosive generators were successful, we proposed to couple plate generators to a coaxial-geometry plasma focus to achieve this goal. Utilizing a small capacitor bank and a selected set of diagnostics, the explosive experiments were successfully conducted with maximum currents of 1.5 MA to 2.4 MA. A maximum neutron yield of approx. 3 x 10 (11) (DD) neutrons was achieved at the 2.4 MA level. Since the neutron yield did scale as a power of the maximum delivered current, and the neutron-producing source region was small, this approach is an attractive option to achieve a neutron radiographic source. The need for a reliable open-circuiting switch at several megamperes has resulted in postponement of the project.

  7. Plasma generators, reactor systems and related methods

    SciTech Connect

    Kong, Peter C.; Pink, Robert J.; Lee, James E.

    2007-06-19

    A plasma generator, reactor and associated systems and methods are provided in accordance with the present invention. A plasma reactor may include multiple sections or modules which are removably coupled together to form a chamber. Associated with each section is an electrode set including three electrodes with each electrode being coupled to a single phase of a three-phase alternating current (AC) power supply. The electrodes are disposed about a longitudinal centerline of the chamber and are arranged to provide and extended arc and generate an extended body of plasma. The electrodes are displaceable relative to the longitudinal centerline of the chamber. A control system may be utilized so as to automatically displace the electrodes and define an electrode gap responsive to measure voltage or current levels of the associated power supply.

  8. Plasma driven neutron/gamma generator

    DOEpatents

    Leung, Ka-Ngo; Antolak, Arlyn

    2015-03-03

    An apparatus for the generation of neutron/gamma rays is described including a chamber which defines an ion source, said apparatus including an RF antenna positioned outside of or within the chamber. Positioned within the chamber is a target material. One or more sets of confining magnets are also provided to create a cross B magnetic field directly above the target. To generate neutrons/gamma rays, the appropriate source gas is first introduced into the chamber, the RF antenna energized and a plasma formed. A series of high voltage pulses are then applied to the target. A plasma sheath, which serves as an accelerating gap, is formed upon application of the high voltage pulse to the target. Depending upon the selected combination of source gas and target material, either neutrons or gamma rays are generated, which may be used for cargo inspection, and the like.

  9. Changes in the pattern of distribution of von Willebrand factor in rat aortic endothelial cells following thrombin generation in vivo.

    PubMed

    Senis, Y A; Richardson, M; Tinlin, S; Maurice, D H; Giles, A R

    1996-04-01

    The pattern of distribution of von Willebrand factor (VWF) in relatively large sheets of rat aortic endothelial cells (EC) obtained by the Häutchen technique were analysed by immunocytochemistry and light microscopy. EC were examined pre and post administration of a procoagulant mixture of factor Xa (F.Xa) and phosphotidylcholine/phosphotidylserine (PCPS) vesicles which was demonstrated to result in the selective loss of high molecular weight multimers (HMWM) of plasma VWF in the rat. In placebo animals the pattern was heterogenous both in overall distribution and in individual cells which showed both a diffuse and granular pattern. Groups of intensely stained EC were oriented parallel to the longitudinal axis of the aorta and staining was particularly prominent around the orifices of the intercostal arteries, implicating shear-stress as a possible factor in VWF expression by EC. Changes in the pattern of distribution of staining were observed at various time points post-infusion of F.Xa/PCPS, suggesting the immediate release of VWF from EC stores followed by the recruitment of EC to synthesize and store VWF. These changes are consistent with the decrease in EC Weibel-Palade Body (WPB) content observed by EM in previously reported studies using this model.

  10. Contributions of procoagulants and anticoagulants to the international normalized ratio and thrombin generation assay in patients treated with warfarin: potential role of protein Z as a powerful determinant of coagulation assays.

    PubMed

    Choi, Qute; Kim, Ji-Eun; Hyun, Jungwon; Han, Kyou-Sup; Kim, Hyun Kyung

    2013-07-01

    The effects of warfarin are measured with the international normalized ratio (INR). However, the thrombin generation assay (TGA) may offer more information about global coagulation. We analyzed the monitoring performance of the TGA and INR and investigated the impact of procoagulants (fibrinogen, factor (F)II, FVII, FIX, and FX) and anticoagulants (proteins C, S, and Z) on them. The TGA was performed on a calibrated automated thrombogram, producing lag time, endogenous thrombin potential (ETP), and peak thrombin in 239 patients treated with warfarin. Pro- and anticoagulant levels were also measured. The INR was significantly and inversely correlated with ETP. The therapeutic range of ETP comparable to an INR range of 2.0-3.0 was 290.1-494.6. ETP showed comparable performance to the INR as a warfarin-monitoring parameter with respect to clinical complication rate. The median levels of FII, FVII, FIX, and FX and proteins C and Z tended to decrease gradually with increasing anticoagulation intensity according to the INR or ETP. Of note, protein Z levels decreased dramatically with increasing anticoagulation status. INRs were significantly determined by FII, FVII, and protein Z. ETP was significantly dependent on FVII, and proteins C and Z concentration. Protein Z significantly reduced the total amount of thrombin generation and prolonged PT value in vitro. The INR and ETP exhibit similar efficacy for warfarin monitoring according to the clinical complication rate. Protein Z is considered to be a significant determinant of INR and ETP in patients on warfarin therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Terahertz twisted beams generation in plasma

    NASA Astrophysics Data System (ADS)

    Sobhani, Hassan; Vaziri (Khamedi), Mohammad; Rooholamininejad, Hossien; Bahrampour, Alireza

    2016-08-01

    The resonant vortex terahertz beam generation by the cross-focusing of two twisted coaxial laser beams is investigated. For the resonant excitation of terahertz radiation, the rippled density in plasma and the ripple wave number is suitably chosen to satisfy the phase matching condition. The nonlinear current density at terahertz frequency arises due to the spatial variation of two Laguerre-Gaussian coupled field. The terahertz intensity scales as the ponderomotive force of laser beams which imparts an oscillatory velocity to the electrons and, in fact, input Laguerre-Gaussian laser beams properties such as vortex charge number and beam waist. Various laser and plasma parameters are employed to yield vortex terahertz radiation with higher efficiency. Also, it is shown that when the beating frequency approaches plasma frequency, the amplitude of THz radiation increases.

  12. Endogenous thrombin potential in Behçet's disease: relationship with thrombosis and anticoagulant therapy.

    PubMed

    Mejía, Juan-Carlos; Espinosa, Gerard; Tàssies, Dolors; Reverter, Joan-Carles; Cervera, Ricard

    2014-01-01

    To analyse the relationship between an automated thrombin generation test, the endogenous thrombin potential (ETP), and other hypercoagulability markers, with vascular involvement in patients with Behçet's disease (BD). Patients and methods. We analysed 56 BD patients (30 men; mean age, 34.4 ± 14.3 years) without any known thrombophilic factor, of which 17 had previously suffered from thrombosis (deep venous thrombosis in 14 and ischaemic stroke in 3), and 56 controls matched for age and sex. Additionally, we also evaluated 20 plasma samples with an international normalised ratio (INR) between 1.5 and 5.0 obtained from patients with atrial fibrillation but without a history of embolic events that were under treatment with acenocumarol. Thrombin generation was measured as ETP with a chromogenic assay in an automated analyser. Factor VIII, von Willebrand factor antigen, prothrombin fragment 1.2, D-dimer and plasmin-antiplasmin complexes were also measured. BD patients showed higher ETP values than controls (471.3± 49.3 vs. 427.5± 31.3 mA; p<0.001). Additionally, BD patients with a history of thrombosis had higher ETP values than patients without thrombosis (496.6± 36.5 vs. 460.7± 50.5 mA; p<0.01). Factor VIII and von Willebrand factor antigen were also elevated in BD patients, but only von Willebrand factor antigen showed statistically significant differences between BD patients with and without thrombosis. Acenocumarol treatment reduced thrombin generation in BD patients in parallel to INR levels, reaching values similar to those of patients with atrial fibrillation and similar INR. BD is associated with thrombosis, and increased thrombin generation (measured as ETP) is a promising marker of hypercoagulability.

  13. Impact Generated Plasmas on the Lunar Surface

    NASA Astrophysics Data System (ADS)

    Horanyi, M.; Munsat, T.; Robertson, S. H.; Sternovsky, Z.; Wang, X.

    2009-12-01

    Lunar dust mobilization and transport remains a debated issue. There are several historical data sets from in situ and remote sensing observations that indicate the presence of lofted dust populations, possibly reaching high altitudes over the lunar surface. The expected charge density of the surface, combined with the relatively weak electric fields in a UV produced plasma sheath on the dayside, seem insufficient to explain these observations. While the surface potentials are much higher on the nightside, the very low plasma density results in a large screening distance and, hence, an even weaker electric field. In addition to solar wind plasma and UV radiation, the lunar surface is also exposed to the continual bombardment by interplanetary dust particles. Based on measurements at Earth, the Moon is expected to collect about 5×103 kg/day of dust which hits the surface at high speeds (>> km/s). These impacts generate secondary particles with a typical mass yield of 103 - 104 that form a permanently present dust exosphere about the Moon. In addition, these impacts also generate neutral and plasma clouds. Impact-generated neutrals are suspected to be one of the major sources of the tenuous lunar atmosphere, in addition to out-gassing and sputtering by solar wind ions. The impact plasma cloud is expected to expand, cool, and recombine, but for a short period of time it will significantly increase the plasma density near the surface, as well as the surface charge density. The combination of these is expected to result in a highly increased efficiency to mobilize and loft small charged grains from the surface. We report on the status of the modeling of the impact generated plasma clouds, as well as on the planned series of experiments to observe its properties at the dust accelerator facility of the recently established NASA Lunar Science Institute: Colorado Center for Lunar Dust and Atmospheric Studies. We will also discuss the possible observational opportunities to

  14. Joint health scores in a haemophilia A cohort from Pakistan with minimal or no access to factor VIII concentrate: correlation with thrombin generation and underlying mutation.

    PubMed

    Khanum, F; Bowen, D J; Kerr, B C; Collins, P W

    2014-05-01

    Haemophilia A is associated with recurrent joint bleeding which leads to synovitis and debilitating arthropathy. Coagulation factor VIII level is an important determinant of bleed number and development of arthropathy . The aim of this study was to compare the haemophilia joint health score (HJHS) and Gilbert score with severity, age, thrombin generation (TG) and underlying mutation in a haemophilia A cohort which had minimal access to haemostatic replacement therapy. Ninety-two haemophilia A individuals were recruited from Pakistan. Age, age at first bleed, target joints, haemophilic arthropathy joints, HJHS and Gilbert score were recorded. A strong correlation was found between HJHS and Gilbert score (r = 0.98), both were significantly higher in severe (n = 59) compared with non-severe (n = 29) individuals before the age of 12 years (P ≤ 0.01) but not thereafter. When individuals were divided according to developmental age (<12 years, 12-16 years and >16 years), both HJHS and Gilbert score were significantly lower in the youngest group (P ≤ 0.001), there was no difference between 12-16 years and >16 years. In severe individuals there was no correlation between in vitro TG and joint score, whereas in non-severe individuals there was a weak negative correlation. In the severe group, no significant difference was observed for either joint score according to the underlying mutation type (inversion, missense, nonsense, frameshift). In this cohort of haemophilia A individuals with minimal access to haemostatic treatment, haemophilic arthropathy correlated with severity and age; among severe individuals, joint health scores did not relate to either the underlying mutation or in vitro TG.

  15. Runaway electron generation in a cooling plasma

    SciTech Connect

    Smith, H.; Helander, P.; Eriksson, L.-G.; Fueloep, T.

    2005-12-15

    The usual calculation of Dreicer [Phys. Rev. 115, 238 (1959); 117, 329 (1960)] generation of runaway electrons assumes that the plasma is in a steady state. In a tokamak disruption this is not necessarily true since the plasma cools down quickly and the collision time for electrons at the runaway threshold energy can be comparable to the cooling time. The electron distribution function then acquires a high-energy tail which can easily be converted to a burst of runaways by the rising electric field. This process is investigated and simple criteria for its importance are derived. If no rapid losses of fast electrons occur, this can be a more important source of runaway electrons than ordinary Dreicer generation in tokamak disruptions.

  16. Pulsed Energy Systems for Generating Plasmas

    NASA Technical Reports Server (NTRS)

    Rose, M. Franklin; Shotts, Z.

    2005-01-01

    This paper will describe the techniques needed to electrically generate highly ionized dense plasmas for a variety of applications. The components needed in pulsed circuits are described in terms of general performance parameters currently available from commercial vendors. Examples of pulsed systems using these components are described and technical data from laboratory experiments presented. Experimental data are given for point designs, capable of multi-megawatt power levels.

  17. Harmonic generation in magnetized quantum plasma

    SciTech Connect

    Kumar, Punit; Singh, Abhisek Kumar; Singh, Shiv

    2016-05-06

    A study of second harmonic generation by propagation of a linearly polarized electromagnetic wave through homogeneous high density quantum plasma in the presence of transverse magnetic field. The nonlinear current density and dispersion relations for the fundamental and second harmonic frequencies have been obtained using the recently developed quantum hydrodynamic (QHD) model. The effect of quantum Bohm potential, Fermi pressure and the electron spin have been taken into account. The second harmonic is found to be less dispersed than the first.

  18. Effect of Thrombin Inhibitors on Positive Feedback in the Coagulation Cascade.

    PubMed

    Ustinov, N B; Zav'yalova, E G; Kopylov, A M

    2016-03-01

    The coagulation cascade is a series of sequential reactions of limited proteolysis of protein factors resulting in generation of thrombin. Thrombin mediates both positive and negative feedback in regulating this cascade by taking part in activation of several factors. Some thrombin inhibitors, by affecting positive feedback, inhibit generation of thrombin itself. In the current study, we used two thrombin inhibitors: argatroban, a low molecular weight reversible competitive inhibitor that binds to the active site, and bivalirudin, a bivalent oligopeptide that blocks the active site and binding center of protein substrates (exosite I). Appearance rate and total amount of thrombin were measured in a thrombin generation assay (TGA) using a fluorescent substrate. We found that argatroban slows the appearance of thrombin and lowers its amount. Bivalirudin also slows appearance of thrombin, but it does not decrease its amount, perhaps because the region being bound to the active site undergoes hydrolysis so that the inhibitor stops binding to thrombin. Many reactions of the coagulation cascade proceed on the surface of phospholipid micelles (PLMs). In the case of argatroban, PLMs do not affect the results of the TGA, whereas for bivalirudin they lower its inhibitory activity. It seems that PLMs stabilize protein complexes (wherein thrombin exosite I is hindered) mediating positive feedback in the coagulation cascade, e.g. complexes of thrombin with factor V and VIII.

  19. Beat-wave generation of plasmons in semiconductor plasmas

    SciTech Connect

    Berezhiani, V.I.; Mahajan, S.M. |

    1995-08-01

    It is shown that in semiconductor plasmas, it is possible to generate large amplitude plasma waves by the beating of two laser beams with frequency difference close to the plasma frequency. For narrow gap seimconductors (for example n-type InSb), the system can simulate the physics underlying beat wave generation in relativistic gaseous plasmas.

  20. Disparate temporal expression of the prothrombin and thrombin receptor genes during mouse development.

    PubMed Central

    Soifer, S. J.; Peters, K. G.; O'Keefe, J.; Coughlin, S. R.

    1994-01-01

    The protease thrombin is a potent agonist for platelet aggregation, mesenchymal cell proliferation, and endothelial production of growth factors and adhesion molecules. Thrombin also modulates neurite outgrowth in neuronal cultures. These apparently disparate responses to thrombin appear to be largely mediated by the recently cloned thrombin receptor. In the adult, thrombin is generated from its zymogen prothrombin at sites of vascular injury when circulating coagulation factors meet extravascular tissue factor. In this context thrombin's varied actions may mediate responses to wounding. Whether thrombin's actions on cells may also play a role in development is unknown. We examined the expression of thrombin receptor, prothrombin, and tissue factor by in situ hybridization in mouse development. Thrombin receptor mRNA was expressed widely in mesenchymal cell populations during early organogenesis (E9.5) and was particularly abundant in developing heart and blood vessels. Robust receptor expression was also noted in the germinal epithelium of the hindbrain. Thrombin receptor expression became more restricted with time and by the fetal growth stage (E16.5) was most readily detected in certain neurons, endocardial and endothelial cells, and within lung and liver. In contrast to the thrombin receptor, prothrombin mRNA was limited to the embryonic liver and was not detected until E12.5, well after the onset of receptor expression. mRNA for tissue factor, one important trigger for thrombin generation in the adult, was detected in embryonic epithelia from E9.5-12.5. In several instances, tissue factor-expressing epithelia were surrounded by thrombin receptor-expressing mesenchyme. These data suggest a possible role for the thrombin receptor in development. The finding of robust thrombin receptor expression before prothrombin mRNA was detected raises the question of whether other proteases or peptide ligands can activate the thrombin receptor. Images Figure 1 Figure 2

  1. Microwave generated plasma light source apparatus

    SciTech Connect

    Yoshizawa, K.; Ito, H.; Kodama, H.; Komura, H.; Minowa, Y.

    1985-02-05

    A microwave generated plasma light source including a microwave generator, a microwave cavity having a light reflecting member forming at least a portion of the cavity, and a member transparent to light and opaque to microwaves disposed across an opening of the cavity opposite the feeding opening through which the microwave generator is coupled. An electrodeless discharge bulb is disposed at a position in the cavity such that the cavity operates as a resonant cavity at least when the bulb is emitting light. In the bulb is encapsulated at least one discharge light emissive substance. The bulb has a shape and is sufficiently small that the bulb acts substantially as a point light source.

  2. Thyristor stack for pulsed inductive plasma generation

    SciTech Connect

    Teske, C.; Jacoby, J.; Schweizer, W.; Wiechula, J.

    2009-03-15

    A thyristor stack for pulsed inductive plasma generation has been developed and tested. The stack design includes a free wheeling diode assembly for current reversal. Triggering of the device is achieved by a high side biased, self supplied gate driver unit using gating energy derived from a local snubber network. The structure guarantees a hard firing gate pulse for the required high dI/dt application. A single fiber optic command is needed to achieve a simultaneous turn on of the thyristors. The stack assembly is used for switching a series resonant circuit with a ringing frequency of 30 kHz. In the prototype pulsed power system described here an inductive discharge has been generated with a pulse duration of 120 {mu}s and a pulse energy of 50 J. A maximum power transfer efficiency of 84% and a peak power of 480 kW inside the discharge were achieved. System tests were performed with a purely inductive load and an inductively generated plasma acting as a load through transformer action at a voltage level of 4.1 kV, a peak current of 5 kA, and a current switching rate of 1 kA/{mu}s.

  3. Thyristor stack for pulsed inductive plasma generation.

    PubMed

    Teske, C; Jacoby, J; Schweizer, W; Wiechula, J

    2009-03-01

    A thyristor stack for pulsed inductive plasma generation has been developed and tested. The stack design includes a free wheeling diode assembly for current reversal. Triggering of the device is achieved by a high side biased, self supplied gate driver unit using gating energy derived from a local snubber network. The structure guarantees a hard firing gate pulse for the required high dI/dt application. A single fiber optic command is needed to achieve a simultaneous turn on of the thyristors. The stack assembly is used for switching a series resonant circuit with a ringing frequency of 30 kHz. In the prototype pulsed power system described here an inductive discharge has been generated with a pulse duration of 120 micros and a pulse energy of 50 J. A maximum power transfer efficiency of 84% and a peak power of 480 kW inside the discharge were achieved. System tests were performed with a purely inductive load and an inductively generated plasma acting as a load through transformer action at a voltage level of 4.1 kV, a peak current of 5 kA, and a current switching rate of 1 kA/micros.

  4. Plasma membrane associated phospholipase C from human platelets: Synergistic stimulation of phosphatidylinositol 4,5-bisphosphate hydrolysis by thrombin and guanosine 5 prime -O-(3-thiotriphosphate)

    SciTech Connect

    Baldassare, J.J.; Henderson, P.A.; Fisher, G.J. )

    1989-01-10

    The effects of thrombin and GTP{gamma}S on the hydrolysis of phosphoinositides by membrane-associated phospholipase C (PLC) from human platelets were examined with endogenous ({sup 3}H)inositol-labeled membranes or with lipid vesicles containing either ({sup 3}H)phosphatidylinositol or ({sup 3}H)phosphatidylinositol 4,5-bisphosphate. GTP{gamma}S (1 {mu}M) or thrombin (1 unit/mL) did not stimulate release of inositol trisphosphate (IP{sub 3}), inositol bisphosphate (IP{sub 2}), or inositol phosphate (IP) from ({sup 3}H)inositol-labeled membranes. IP{sub 2} and IP{sub 3}, but not IP, from ({sup 3}H)inositol-labeled membranes were, however, stimulated 3-fold by GTP{gamma}S (1 {mu}M) plus thrombin (1 unit/mL). A higher concentration of GTP{gamma}S (100 {mu}M) alone also stimulated IP{sub 2} and IP{sub 3}, but not IP, release. In the presence of 1 mM calcium, release of IP{sub 2} and IP{sub 3} was increased 6-fold over basal levels; however, formation of IP was not observed. At submicromolar calcium concentration, hydrolysis of exogenous phosphatidylinositol 4,5-bisphosphate (PIP{sub 2}) by platelet membrane associated PLC was also markedly enhanced by GTP{gamma}S (100 {mu}M) or GTP{gamma}S (1 {mu}M) plus thrombin (1 unit/mL). Under identical conditions, exogenous phosphatidylinositol (PI) was not hydrolyzed. The same substrate specificity was observed when the membrane-associated PLC was activated with 1 mM calcium. Thrombin-induced hydrolysis of PIP{sub 2} was inhibited by treatment of the membranes with pertussis toxin or pretreatment of intact platelets with 12-O-tetradecanoyl-13-acetate (TPA) prior to preparation of membranes. Pertussis toxin did not inhibit GTP{gamma}S (100 {mu}M) or calcium (1 mM) dependent PIP{sub 2} breakdown, while TPA inhibited GTP{gamma}S-dependent but not calcium-dependent phospholipase C activity.

  5. Volumetric Near-Field Microwave Plasma Generation

    NASA Technical Reports Server (NTRS)

    Exton, R. J.; Balla, R. Jeffrey; Herring, G. C.; Popovic, S.; Vuskovic, L.

    2003-01-01

    A periodic series of microwave-induced plasmoids is generated using the outgoing wave from a microwave horn and the reflected wave from a nearby on-axis concave reflector. The plasmoids are spaced at half-wavelength separations according to a standing-wave pattern. The plasmoids are enhanced by an effective focusing in the near field of the horn (Fresnel region) as a result of a diffractive narrowing. Optical imaging, electron density, and rotational temperature measurements characterize the near field plasma region. Volumetric microwave discharges may have application to combustion ignition in scramjet engines.

  6. Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin

    PubMed Central

    Sidhu, Preetpal Singh; Liang, Aiye; Mehta, Akul Y.; Abdel Aziz, May H.; Zhou, Qibing; Desai, Umesh R.

    2011-01-01

    Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, eleven exhibited reasonable inhibition of human α-thrombin at pH 7.4. Structure activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A t-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC50 of 7.3 μM under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin. PMID:21714536

  7. Autoactivation of Thrombin Precursors*

    PubMed Central

    Pozzi, Nicola; Chen, Zhiwei; Zapata, Fatima; Niu, Weiling; Barranco-Medina, Sergio; Pelc, Leslie A.; Di Cera, Enrico

    2013-01-01

    Trypsin-like proteases are synthesized as inactive zymogens and convert to the mature form upon activation by specific enzymes, often assisted by cofactors. Central to this paradigm is that the zymogen does not convert spontaneously to the mature enzyme, which in turn does not feed back to activate its zymogen form. In the blood, the zymogens prothrombin and prethrombin-2 require the prothrombinase complex to be converted to the mature protease thrombin, which is unable to activate prothrombin or prethrombin-2. Here, we show that replacement of key residues within the activation domain causes these zymogens to spontaneously convert to thrombin. The conversion is started by the zymogen itself, which is capable of binding ligands at the active site, and is abrogated by inactivation of the catalytic residue Ser-195. The product of autoactivation is functionally and structurally equivalent to wild-type thrombin. Zymogen autoactivation is explained by conformational selection, a basic property of the trypsin fold uncovered by structural and rapid kinetics studies. Both the zymogen and protease undergo a pre-existing equilibrium between active and inactive forms. The equilibrium regulates catalytic activity in the protease and has the potential to unleash activity in the zymogen to produce autoactivation. A new strategy emerges for the facile production of enzymes through zymogen autoactivation that is broadly applicable to trypsin-like proteases of biotechnological and clinical interest. PMID:23467412

  8. Power consumption analysis DBD plasma ozone generator

    NASA Astrophysics Data System (ADS)

    Nur, M.; Restiwijaya, M.; Muchlisin, Z.; Susan, I. A.; Arianto, F.; Widyanto, S. A.

    2016-11-01

    Studies on the consumption of energy by an ozone generator with various constructions electrodes of dielectric barrier discharge plasma (DBDP) reactor has been carried out. This research was done to get the configuration of the reactor, that is capable to produce high ozone concentrations with low energy consumption. BDBP reactors were constructed by spiral- cylindrical configuration, plasma ozone was generated by high voltage AC voltage up to 25 kV and maximum frequency of 23 kHz. The reactor consists of an active electrode in the form of a spiral-shaped with variation diameter Dc, and it was made by using copper wire with diameter Dw. In this research, we variated number of loops coil windings N as well as Dc and Dw. Ozone concentrations greater when the wire's diameter Dw and the diameter of the coil windings applied was greater. We found that impedance greater will minimize the concentration of ozone, in contrary to the greater capacitance will increase the concentration of ozone. The ozone concentrations increase with augmenting of power. Maximum power is effective at DBD reactor spiral-cylinder is on the Dc = 20 mm, Dw = 1.2 mm, and the number of coil windings N = 10 loops with the resulting concentration is greater than 20 ppm and it consumes energy of 177.60 watts

  9. Effect of thrombin on maturing human megakaryocytes.

    PubMed Central

    Cramer, E. M.; Massé, J. M.; Caen, J. P.; Garcia, I.; Breton-Gorius, J.; Debili, N.; Vainchenker, W.

    1993-01-01

    Thrombin causes platelet activation and secretion. In some nucleated cells, it is mitogenic. In this study, we have investigated how human megakaryocytes (MKs) respond to this agonist and whether the response depends on the maturation stage. MKs were cultured from bone marrow precursors in liquid culture in the presence of normal plasma. To determine whether thrombin can activate MKs, 14-day MK cultures were incubated with thrombin for 5 minutes, and cells were studied by electron microscopy, either by standard techniques or after embedding in glycol-methacrylate for immunoelectron microscopy. Ultrastructural examination of thrombin-treated MKs revealed dramatic morphological changes reminiscent of those found in platelets, including shape change and organelle centralization that involved immature as well as mature cells. MKs were also able to secrete alpha-granule proteins in the dilated cisternae of the demarcation membrane system, as shown by immunogold staining for thrombospondin and glycoprotein Ib. These changes were rapid (less than 5 minutes) but despite them, MKs remained viable for more than 24 hours. To determine whether thrombin has a mitogenic activity, it was added to the culture of MKs from day 3 to day 10 of culture at concentrations varying from 0.1 to 10 U/ml. Cells were subsequently studied by a double staining technique using flow cytometry to determine MK number and ploidy. No changes were observed in these two parameters, showing that thrombin is not mitogenic for MKs at the concentrations used. In conclusion, this study confirms for human MKs previous observations made about guinea pig MKs (Fedorko et al, Lab Invest 1977, 36:32). In addition, it demonstrates that immature MKs are able to respond to thrombin and that more mature cells can secrete alpha-granule proteins into the demarcation membrane system, which is in continuity with the extracellular space. This phenomenon may have implications for pathological states such as myelofibrosis

  10. Prominent protein Z-induced thrombin inhibition in cirrhosis: a new functional assay for hypercoagulability assessment.

    PubMed

    Kim, Seon Young; Kim, Ji-Eun; Kim, Yoon Jun; Han, Kyou-Sup; Kim, Hyun Kyung

    2015-04-01

    Protein Z (PZ) is an anticoagulant that accelerates the inhibitory effect of PZ-dependent protease inhibitor (ZPI) on coagulation factor Xa. We assessed functional status of PZ system in 158 patients with liver cirrhosis and 59 healthy controls. Plasma PZ and ZPI levels were measured by enzyme immunoassay. Thrombin generation assays (TGA) were performed with and without thrombomodulin (TM) or PZ, and the ratios were calculated by dividing TGA values with TM or PZ by values without TM or PZ. PZ and ZPI levels were reduced and elevated in advanced cirrhosis, respectively. The lag time ratio-PZ was significantly higher in cirrhosis patients than controls and correlated with the model for end-stage liver disease score. The peak thrombin ratio-PZ and endogenous thrombin potential (ETP) ratio-PZ were significantly lower in cirrhosis patients than controls and correlated with the severity of liver cirrhosis. The peak thrombin ratio-PZ was dramatically reduced in advanced cirrhosis. Cirrhosis patients had a significantly higher ETP ratio-TM than the controls, although the ratio was not correlated with cirrhosis severity. The lag time ratio-PZ and peak time ratio-PZ were significantly correlated with the levels of all coagulation and anticoagulation factors. Interestingly, the lag time ratio-PZ and peak thrombin ratio-PZ were significantly associated with thrombotic events. The anticoagulant role of PZ is insufficient in advanced stages of cirrhosis. Our newly developed functional assay for measuring the PZ system is expected to reflect the ongoing hypercoagulability of cirrhosis. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  11. RF generated atmospheric pressure plasmas and applications

    NASA Astrophysics Data System (ADS)

    Park, Jaeyoung; Herrmann, Hans W.; Henins, Ivars; Gautier, Donald C.

    2001-10-01

    RF generated atmospheric pressure plasma sources have been developed for various materials applications. They operate with rf power and produce a α-mode capacitive discharge that is stable, steady-state, non-thermal, and volumetric. The plasma parameters of this source have been measured: electron densities of 10^11 cm-3 and electron temperatures of 2 eV by using neutral bremsstrahlung emission. Localized electron heating near the sheath boundary has been observed and is related to the discharge stability and α to γ mode (or arcing) transition using 1D fluid model. The discharge stability improves with increase in rf frequency. The electrode surface property such as the secondary electron emission coefficient also plays a significant role in determining α to γ mode transition. For example, a stable α-mode air discharge is produced using 100 MHz rf power with the use of a boron nitride cover on one of the electrodes. In comparison, an air discharge becomes unstable at a lower rf frequency (e.g. 13.56 MHz) or with an alumina cover. Similar results were obtained with various feedgas such as steam, CO_2, and hydrocarbon containing gases. Further characterization of this high frequency source is under progress. For its applications, we have successfully demonstrated the effective neutralization of actual chemical warfare agents such as VX, GD and HD. In addition, significant progresses have been made in the area of etching of organic and metal film etching, and production of novel materials.

  12. Plasma Motor Generator (PMG) electrodynamic tether experiment

    NASA Technical Reports Server (NTRS)

    Grossi, Mario D.

    1995-01-01

    The Plasma Motor Generator (PMG) flight of June 26, 1993 has been the most sophisticated and most successful mission that has been carried out thus far with an electrodynamic tether. Three papers from the Smithsonian Astrophysical Observatory, Washington, DC concerned with the PMG, submitted at the Fourth International Space Conference on Tethers in Space, in Washington, DC, in April 1995, are contained in this document. The three papers are (1) Electromagnetic interactions between the PMG tether and the magneto-ionic medium of the Ionosphere; (2) Tether-current-voltage characteristics, as determined by the Hollow Cathode Operation Modes; and (3) Hawaii-Hilo ground observations on the occasion for the PMG flight of June 23, 1993.

  13. Thrombin adhesive properties: induction by plasmin and heparan sulfate

    PubMed Central

    1993-01-01

    We have previously demonstrated that chemically modified thrombin preparations induce endothelial cell (EC) adhesion, spreading and cytoskeletal reorganization via an Arg-Gly-Asp (RGD) sequence and the alpha v beta 3 integrin. Native thrombin, however, did not exhibit adhesive properties, consistent with crystal structure analysis, showing that Gly-Asp residues of the RGD epitope are buried within the molecule. We have now identified a possible physiological mean of converting thrombin to an adhesive protein. Plasmin, the major end product of the fibrinolytic system, converted thrombin to an adhesive protein for EC in a time and dose-dependent manner. EC adhesion and spreading was also induced by a low molecular weight (approximately 3,000 D) cleavage fragment generated upon incubation of thrombin with plasmin. Cell adhesion mediated by this fragment was completely inhibited by the synthetic peptide GRGDSP. Conversion of thrombin to an adhesive molecule was significantly enhanced in the presence of heparin or heparan sulfate, while other glycosaminoglycans (GAGs) (e.g., dermatan sulfate, keratan sulfate, chondroitin sulfate) had no effect. The role of cell surface heparan sulfate in thrombin conversion to EC adhesive protein was investigated using CHO cell mutants defective in various aspects of GAG synthesis. Incubation of both thrombin and a suboptimal amount of plasmin on the surface of formaldehyde fixed wild- type CHO-KI cells resulted in an efficient conversion of thrombin to an adhesive molecule, as indicated by subsequent induction of EC attachment. In contrast, there was no effect to incubation of thrombin and plasmin with fixed CHO mutant cells lacking both heparan sulfate and chondroitin sulfate, or with cells expressing no heparan sulfate and a three-fold increase in chondroitin sulfate. A similar gain of adhesive properties was obtained upon incubation of thrombin and plasmin in contact with native, but not heparinase-treated extracellular matrix (ECM

  14. EMF generation in low-temperature plasma

    NASA Astrophysics Data System (ADS)

    Pal, Alexander; Babichev, Valery; Dyatko, Nikolay; Filippov, Anatoly; Starostin, Andrey

    2016-09-01

    EMF generation in plasma created by an e-beam in electropositive gases at atmospheric pressure was investigated experimentally and numerically. It was found that propagation of 120 keV e-beam with cross-section 1 . 2 × 2 cm2 and current of 240 μA through argon at 105 Pa gas pressure between an aluminum exit window and an iron collector was followed by 360 μA current of opposite direction. A numerical modeling of the current flux was performed in an one-dimensional approximation along the axis z in the direction of e-beam propagation. It is seen, that the current density grows with increasing the ionization rate and the largest effect takes place in argon. The discovered effect of the current flux is determined by nonuniform gas ionization resulting in different diffusion electron fluxes near different electrodes and, therefore, in different near-electrodes potential falls. This difference creates a steady current flux in the inter-electrode gap. The mechanism of EMF generation is analogous to the Dember effect at the nonuniform photoexcitation of semiconductors. The work was supported by the Russian Science Foundation, Project No. 16-12-10511.

  15. Plasmas generated in bubbles immersed in liquids: direct current streamers versus microwave plasma

    NASA Astrophysics Data System (ADS)

    Levko, Dmitry; Sharma, Ashish; Raja, Laxminarayan L.

    2016-07-01

    Two approaches to generate non-equilibrium atmospheric-pressure plasma in bubbles immersed in liquids are compared using high-fidelity 2D fluid simulations. In the first approach, corona/streamer like plasma is generated using high-voltage negative and positive pulses applied between two electrodes (pin-to-plane geometry) immersed in liquid. In the second, the plasma is generated using a remote microwave source (frequency 2.45 GHz). We find that the microwave approach requires less energy, while generating a denser, more chemically reactive and more uniform plasma within the bubble volume, as compared to the plasma generated using high-voltage pulsing.

  16. Thrombin inhibitor design.

    PubMed

    Sanderson, P E; Naylor-Olsen, A M

    1998-08-01

    Recently, iv formulated direct thrombin inhibitors have been shown to be safe and efficacious alternatives to heparin. These results have fueled the hopes for an orally active compound. Such a compound could be a significant advance over warfarin if it had predictable pharmacokinetics and a duration of action sufficient for once or twice a day dosing. In order to develop an orally active compound which meets these criteria, the deficiencies of the prototype inhibitor efegatran have had to be addressed. First, using a combination of structure based design and empirical structure optimization, more selective compounds have been identified by modifying the P1 group or by incorporating different peptidomimetic P2/P3 scaffolds. Secondly, this optimization has resulted in the development of potent and selective non-covalent inhibitors, thus bypassing the liabilities of the serine trap. Thirdly, oral bioavailability has been achieved while maintaining selectivity and efficacy through the incorporation of progressively less basic P1 groups. The duration of action of these compounds remains to be optimized. Other advances in thrombin inhibitor design have included the development of uncharged P1 groups and the discovery of two non-peptide templates.

  17. Plasma cell treatment device Plasma-on-Chip: Monitoring plasma-generated reactive species in microwells.

    PubMed

    Oh, Jun-Seok; Kojima, Shinya; Sasaki, Minoru; Hatta, Akimitsu; Kumagai, Shinya

    2017-02-08

    We have developed a plasma cell treatment device called Plasma-on-Chip that enables the real-time monitoring of a single cell culture during plasma treatment. The device consists of three parts: 1) microwells for cell culture, 2) a microplasma device for generating reactive oxygen and nitrogen species (RONS) for use in cell treatment, and 3) through-holes (microchannels) that connect each microwell with the microplasma region for RONS delivery. Here, we analysed the delivery of the RONS to the liquid culture medium stored in the microwells. We developed a simple experimental set-up using a microdevice and applied in situ ultraviolet absorption spectroscopy with high sensitivity for detecting RONS in liquid. The plasma-generated RONS were delivered into the liquid culture medium via the through-holes fabricated into the microdevice. The RONS concentrations were on the order of 10-100 μM depending on the size of the through-holes. In contrast, we found that the amount of dissolved oxygen was almost constant. To investigate the process of RONS generation, we numerically analysed the gas flow in the through-holes. We suggest that the circulating gas flow in the through-holes promotes the interaction between the plasma (ionised gas) and the liquid, resulting in enhanced RONS concentrations.

  18. Plasma cell treatment device Plasma-on-Chip: Monitoring plasma-generated reactive species in microwells

    NASA Astrophysics Data System (ADS)

    Oh, Jun-Seok; Kojima, Shinya; Sasaki, Minoru; Hatta, Akimitsu; Kumagai, Shinya

    2017-02-01

    We have developed a plasma cell treatment device called Plasma-on-Chip that enables the real-time monitoring of a single cell culture during plasma treatment. The device consists of three parts: 1) microwells for cell culture, 2) a microplasma device for generating reactive oxygen and nitrogen species (RONS) for use in cell treatment, and 3) through-holes (microchannels) that connect each microwell with the microplasma region for RONS delivery. Here, we analysed the delivery of the RONS to the liquid culture medium stored in the microwells. We developed a simple experimental set-up using a microdevice and applied in situ ultraviolet absorption spectroscopy with high sensitivity for detecting RONS in liquid. The plasma-generated RONS were delivered into the liquid culture medium via the through-holes fabricated into the microdevice. The RONS concentrations were on the order of 10-100 μM depending on the size of the through-holes. In contrast, we found that the amount of dissolved oxygen was almost constant. To investigate the process of RONS generation, we numerically analysed the gas flow in the through-holes. We suggest that the circulating gas flow in the through-holes promotes the interaction between the plasma (ionised gas) and the liquid, resulting in enhanced RONS concentrations.

  19. Plasma cell treatment device Plasma-on-Chip: Monitoring plasma-generated reactive species in microwells

    PubMed Central

    Oh, Jun-Seok; Kojima, Shinya; Sasaki, Minoru; Hatta, Akimitsu; Kumagai, Shinya

    2017-01-01

    We have developed a plasma cell treatment device called Plasma-on-Chip that enables the real-time monitoring of a single cell culture during plasma treatment. The device consists of three parts: 1) microwells for cell culture, 2) a microplasma device for generating reactive oxygen and nitrogen species (RONS) for use in cell treatment, and 3) through-holes (microchannels) that connect each microwell with the microplasma region for RONS delivery. Here, we analysed the delivery of the RONS to the liquid culture medium stored in the microwells. We developed a simple experimental set-up using a microdevice and applied in situ ultraviolet absorption spectroscopy with high sensitivity for detecting RONS in liquid. The plasma-generated RONS were delivered into the liquid culture medium via the through-holes fabricated into the microdevice. The RONS concentrations were on the order of 10–100 μM depending on the size of the through-holes. In contrast, we found that the amount of dissolved oxygen was almost constant. To investigate the process of RONS generation, we numerically analysed the gas flow in the through-holes. We suggest that the circulating gas flow in the through-holes promotes the interaction between the plasma (ionised gas) and the liquid, resulting in enhanced RONS concentrations. PMID:28176800

  20. Evidence for a hyperglycaemia-dependent decrease of antithrombin III-thrombin complex formation in humans.

    PubMed

    Ceriello, A; Giugliano, D; Quatraro, A; Marchi, E; Barbanti, M; Lefèbvre, P

    1990-03-01

    In the presence of increased levels of fibrinopeptide A, decreased antithrombin III biological activity, and thrombin-antithrombin III complex levels are seen in diabetic patients. Induced-hyperglycaemia in diabetic and normal subjects decreased antithrombin III activity and thrombin-antithrombin III levels, and increased fibrinopeptide A plasma levels, while antithrombin III concentration did not change; heparin was shown to reduced these phenomena. In diabetic patients, euglycaemia induced by insulin infusion restored antithrombin III activity, thrombin-antithrombin III complex and fibrinopeptide A concentrations; heparin administration had the same effects. These data stress the role of a hyperglycaemia-dependent decrease of antithrombin III activity in precipitating thrombin hyperactivity in diabetes mellitus.

  1. Plasma structures for quasiphase matched high harmonic generation

    SciTech Connect

    Sheinfux, A. H.; Henis, Z.; Levin, M.; Zigler, A.

    2011-04-04

    A scheme for creation of periodic plasma structures by ablating a lithographic pattern is demonstrated. A proof of principle experiment was conducted, and plasma parameters were measured as a function of time with spatial resolution <10 and 100 {mu}m periodicity. Several possible applications, in particular, quasiphase matching for high harmonic generation in plasma are considered.

  2. Three-dimensional model of electron beam generated plasma

    NASA Astrophysics Data System (ADS)

    Rauf, Shahid; Balakrishna, Ajit; Agarwal, Ankur; Dorf, Leonid; Collins, Kenneth; Boris, David R.; Walton, Scott G.

    2017-06-01

    A three-dimensional model for magnetized electron beam generated plasma is described, which includes a coupled fluid simulation of the bulk plasma and a Monte Carlo model for beam electrons. A modified form of the classical expressions for magnetized-plasma electron transport coefficients is used in the fluid plasma model. The plasma model is calibrated and validated using Langmuir probe measurements in a cylindrical electron beam generated plasma, where the beam is launched parallel to the magnetic field. The electron density (n e ) and temperature (T e ) are measured along and across the beam for several gas pressures and magnetic fields in Ar. The validated plasma model is then used to examine a three-dimensional electron beam generated plasma system. Generally, plasma densities are on the order of 1016 m-3 and, since there is no externally applied electric field in the plasma region, T e is below 1.25 eV in Ar. The chamber in the simulation is slightly asymmetric perpendicular to the axis of the electron beam and the magnetic field. This asymmetry combined with the E × B drift produce non-uniformities in the plasma even if the magnetic field is spatially uniform in the chamber. However, the cross-field plasma uniformity can be controlled by tailoring the magnetic field profile to enhance or reduce plasma production near the periphery of the chamber.

  3. Plasma generated during underwater pulsed laser processing

    NASA Astrophysics Data System (ADS)

    Hoffman, Jacek; Chrzanowska, Justyna; Moscicki, Tomasz; Radziejewska, Joanna; Stobinski, Leszek; Szymanski, Zygmunt

    2017-09-01

    The plasma induced during underwater pulsed laser ablation of graphite is studied both experimentally and theoretically. The results of the experiment show that the maximum plasma temperature of 25000 K is reached 20 ns from the beginning of the laser pulse and decreases to 6500 K after 1000 ns. The observed OH absorption band shows that the plasma plume is surrounded by the thin layer of dissociated water vapour at a temperature around 5500 K. The hydrodynamic model applied shows similar maximum plasma temperature at delay times between 14 ns and 30 ns. The calculations show also that already at 14th ns, the plasma electron density reaches 0.97·1027 m-3, which is the critical density for 1064 nm radiation. At the same time the plasma pressure is 2 GPa, which is consisted with earlier measurements of the peak pressure exerted on a target in similar conditions.

  4. Enhancement of terahertz wave generation from laser induced plasma

    SciTech Connect

    Xie Xu; Xu Jingzhou; Dai Jianming; Zhang, X.-C.

    2007-04-02

    It is well known that air plasma induced by ultrashort laser pulses emits broadband terahertz waves. The authors report the study of terahertz wave generation from the laser induced plasma where there is a preexisting plasma background. When a laser beam from a Ti:sapphire amplifier is used to generate a terahertz wave, enhancement of the generation is observed if there is another laser beam creating a plasma background. The enhancement of the terahertz wave amplitude lasts hundreds of picoseconds after the preionized background is created, with a maximum enhancement up to 250% observed.

  5. Generation of quasistationary magnetic fields in a turbulent laser plasma

    NASA Astrophysics Data System (ADS)

    Bychenkov, V. Iu.; Gradov, O. M.; Chokparova, G. A.

    1984-07-01

    A theory is derived for the generation of quasi-stationary magnetic fields in a laser plasma with well developed ion-acoustic turbulence. Qualitative changes are caused in the nature of the magnetic-field generation by an anomalous anisotropic transport in the turbulent plasma. The role played by turbulent diffusion and thermodiffusive transport in the magnetic-field saturation is discussed.

  6. Highly selective and rapidly activatable fluorogenic Thrombin sensors and application in human lung tissue.

    PubMed

    Megia-Fernandez, Alicia; Mills, Bethany; Michels, Chesney; Chankeshwara, Sunay V; Dhaliwal, Kevin; Bradley, Mark

    2017-05-23

    A library of FRET-based peptides were prepared and studied as Thrombin substrates. This identified probes that showed selective activation by Thrombin, low fluorescent background signals, stability to Factor Xa, matrix metalloproteases, and primary human inflammatory cell lysates and supernatant. These were selected for further optimization, creating a second generation of fluorogenic probes with improved solubility and Plasmin resistance. The optimised probe allowed the detection of Thrombin activity in ex vivo fibrotic human tissue.

  7. [Dose-effect relationship of traditional Chinese medicine formula for promoting blood circulation to remove stasis on ADP-induced platelet aggregation and rabbit plasma thrombin time].

    PubMed

    Zhang, Yanhua; Tang, Yuping; Guo, Jianming; Ding, Anwei; Duan, Jinao

    2009-11-01

    To investigate the effect of five traditional Chinese medicine formula for promoting blood circulation to remove stasis (Xuefuzhuyu Tang, Shaofuzhuyu Tang, Gexiazhuyu Tang, ShentongZhuyu Tang, Tongqiaohuoxue Tang) on platelet aggregation and clotting time in a dose-response relationship. The platelet aggregation was tested with Born's method and thrombin time (TT) method was established to determine the clotting time. The formula for promoting blood circulation to remove stasis showed significant inhibitory effects on the platelet aggregation and prolonged clotting time, the supernate of 80% alcohol solution showed the most potent inhibitory activity among the three kinds of samples from one formula (P < 0.01), especially the supernate of Shaofuzhuyu Tang and Gexiazhuyu Tang were better than other formula on platelet aggregation. About the anticoagulant, the whole formula showed the evidently prolonging the clotting time than other two fractions (P < 0.01) and the precipitation were the worst. The formula for promoting blood circulation to remove stasis showed significant effect on platelet aggregation and clotting time, and different samples of the formula had different efficacy. The study established a foundation for further bio-activity evaluation of these formulae and provided evidence for the treatment of cardiovascular and cerebrovascular diseases.

  8. Addition of in-vitro generated endothelial microparticles to von-Willebrand plasma improves primary and secondary hemostasis.

    PubMed

    Trummer, Arne; Werwitzke, Sonja; Wermes, Cornelia; Ganser, Arnold; Birschmann, Ingvild; Budde, Ulrich; Tiede, Andreas

    2014-03-01

    Increased endothelial microparticles (EMP) as markers for endothelial activation have been associated with worse outcomes in clinical prothrombotic situations. The procoagulant properties of EMP can be attributed to the expression of phospholipids, tissue factor and von-Willebrand factor on their surface. We therefore investigated whether addition of in-vitro generated EMP modifies hemostasis in plasma from patients with severe von-Willebrand disease (VWD). A large EMP pool was obtained from stimulated endothelial cell lines and EMP concentration was quantified by flow cytometry. The influence of EMP on primary and secondary hemostasis in VWD plasma was assessed using ristocetin-induced platelet aggregation (RIPA) and thrombin generation in a calibrated automated thrombogram (CAT), respectively. After addition of EMP, there was a significant increase in the maximal aggregation level in RIPA as well as a significant shortening of lag time and time-to-peak in CAT in comparison to control buffer. In summary, in vitro-generated EMP have the potential to improve hemostasis in severe VWD plasma and these results warrant further clinical reseach regarding their contribution to the clinical bleeding phenotype as well as their potential to improve replacement therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Self-generated magnetic fields in q-distributed plasmas

    SciTech Connect

    Li Dingguo; Liu Sanqiu; Li Xiaoqing

    2013-02-15

    A quasi-steady magnetic field can be generated with high-frequency electromagnetic radiation through wave-wave and wave-particle interactions in astrophysical plasmas and laser-produced plasmas. Nonlinear coupling equations of self-generated magnetic fields are obtained in nonextensive distribution frame, as a generalization for the standard Maxwellian distribution frame. The numerical results show that self-generated magnetic fields may collapse and lead to various turbulent patterns with different index q.

  10. Generator of chemically active low-temperature plasma

    NASA Astrophysics Data System (ADS)

    Tyuftyaev, A. S.; Gadzhiev, M. Kh; Sargsyan, M. A.; Demirov, N. A.; Spector, N. O.

    2016-11-01

    A new generator of high enthalpy (H 0 > 40 kJ/g), chemically active nitrogen and air plasmas was designed and constructed. Main feature of the generator is an expanding channel of an output electrode; the generator belongs to the class of DC plasma torches with thermionic cathode with an efficiency of 80%. The generator ensures the formation of a slightly divergent plasma jet (2α = 12°) with a diameter of D = 10-12 mm, an electric arc maximum power of 20-50 kW, plasma forming gas flow rate 1.0-2.0 g/s, and the average plasma temperature at an outlet of 8000-11000 K.

  11. Plasma-based studies on 4th generation light sources

    NASA Astrophysics Data System (ADS)

    Lee, R. W.; Baldis, H. A.; Cauble, R. C.; Landen, O. L.; Wark, J. S.; Ng, A.; Rose, S. J.; Lewis, C.; Riley, D.; Gauthier, J.-C.; Audebert, P.

    2001-08-01

    The construction of a short pulse tunable x-ray laser source will be a watershed for plasma-based and warm dense matter research. The areas we will discuss below can be separated broadly into warm dense matter (WDM) research, laser probing of near solid density plasmas, and laser-plasma spectroscopy of ions in plasmas. The area of WDM refers to that part of the density-temperature phase space where the standard theories of condensed matter physics and/or plasma statistical physics are invalid. Warm dense matter, therefore, defines a region between solids and plasmas, a regime that is found in planetary interiors, cool dense stars, and in every plasma device where one starts from a solid, e.g., laser-solid matter produced plasma as well as all inertial fusion schemes. The study of dense plasmas has been severely hampered by the fact that laser-based methods have been unavailable. The single most useful diagnostic of local plasma conditions, e.g., the temperature (Te), the density (ne), and the ionization (Z), has been Thomson scattering. However, due to the fact that visible light will not propagate at electron densities, ne⩾1022cm-3 implies dense plasmas can not be probed. The 4th generation sources, LCLS and Tesla will remove these restrictions. Laser-based plasma spectroscopic techniques have been used with great success to determine the line shapes of atomic transitions in plasmas, study the population kinetics of atomic systems embedded in plasmas, and look at redistribution of radiation. However, the possibilities end for plasmas with ne⩾1022 since light propagation through the medium is severely altered by the plasma. The entire field of high Z plasma kinetics from laser produced plasma will then be available to study with the tunable source.

  12. Plasma-Based Studies on 4th Generation Light Sources

    SciTech Connect

    Lee, R W; Baldis, H A; Cauble, R C; Landen, O L; Wark, J S; Ng, A; Rose, S J; Lewis, C; Riley, D; Gauthier, J-C; Audebert, P

    2000-11-28

    The construction of a short pulse tunable x-ray laser source will be a watershed for plasma-based and warm dense matter research. The areas we will discuss below can be separated broadly into warn dense matter (WDM) research, laser probing of near solid density plasmas, and laser-plasma spectroscopy of ions in plasmas. The area of WDM refers to that part of the density-temperature phase space where the standard theories of condensed matter physics and/or plasma statistical physics are invalid. Warm dense matter, therefore, defines a region between solids and plasmas, a regime that is found in planetary interiors, cool dense stars, and in every plasma device where one starts from a solid, e.g., laser-solid matter produced plasma as well as all inertial fusion schemes. The study of dense plasmas has been severely hampered by the fact that laser-based methods have been unavailable. The single most useful diagnostic of local plasma conditions, e.g., the temperature (T{sub e}), the density (n{sub e}), and the ionization (Z), has been Thomson scattering. However, due to the fact that visible light will not propagate at electron densities, n{sub e}, {ge} 10{sup 22} cm{sup -3} implies dense plasmas can not be probed. The 4th generation sources, LCLS and Tesla will remove these restrictions. Laser-based plasma spectroscopic techniques have been used with great success to determine the line shapes of atomic transitions in plasmas, study the population kinetics of atomic systems embedded in plasmas, and look at redistribution of radiation. However. the possibilities end for plasmas with n{sub e} {ge} 10{sup 22} since light propagation through the medium is severely altered by the plasma. The entire field of high Z plasma kinetics from laser produced plasma will then be available to study with the tunable source.

  13. Effects of the glycoprotein IIb/IIIa receptor antagonist c7E3 Fab and anticoagulants on platelet aggregation and thrombin potential under high coagulant challenge in vitro.

    PubMed

    Koestenberger, M; Gallistl, S; Cvirn, G; Roschitz, B; Muntean, W

    2000-07-01

    The present study was performed to investigate the combined effects of the platelet glycoprotein IIb/IIIa receptor antagonist c7E3 Fab (abciximab) and the anticoagulants unfractionated heparin (UH), low molecular weight heparin (LMWH), and recombinant hirudin (rH) on platelet aggregation and thrombin generation under high coagulant challenge by extrinsic activation of platelet-rich plasma. Platelet aggregation and thrombin generation were assessed simultaneously in the presence of different concentrations of abciximab and anticoagulants. Increasing concentrations of abciximab resulted in a dose-dependent anti-aggregating effect with a maximum at 20 microg/ml. Doses of 5, 10, and 20 microg/ml abciximab prolonged the lag phase until the onset of platelet aggregation, but this effect was independent of the dosage used. Abciximab had no influence on the thrombin potential under our high coagulant challenge. UH, LMWH, and rH showed a dose-dependent prolongation of the lag phase until the onset of platelet aggregation and decreased the thrombin potential. Addition of anticoagulants did not contribute to further inhibition of platelet aggregation in the presence of abciximab, but the combination of abciximab and anticoagulants exhibited an additive effect on prolongation of the lag phase until the onset of platelet aggregation. Addition of abciximab to anticoagulants did not result in further decrease of the thrombin potential. Our study demonstrates the respective specific effects of abciximab and anticoagulants on platelet aggregation and thrombin potential under high coagulant challenge, and also an additive effect of abciximab and the anticoagulants UH, LMWH, and rH on the lag phase until the onset of platelet aggregation.

  14. The influence of plasma motion on disruption generated runaway electrons

    SciTech Connect

    Russo, A.J.

    1991-01-01

    One of the possible consequences of disruptions is the generation of runaway electrons which can impact plasma facing components and cause damage due to high local energy deposition. This problem becomes more serious as the machine size and plasma current increases. Since large size and high currents are characteristics of proposed future machines, control of runaway generation is an important design consideration. A lumped circuit model for disruption runaway electron generation indicates that control circuitry on strongly influence runaway behavior. A comparison of disruption data from several shots on JET and D3-D with model results, demonstrate the effects of plasma motion on runaway number density and energy. 6 refs., 12 figs.

  15. Kerf generation during the plasma cutting process

    NASA Astrophysics Data System (ADS)

    Dodun, Oana; Bangu, Sanda Ilii; Slǎtineanu, LaurenÅ£iu; Vasile, Merticaru; Beşliu, Irina; CoteaÅ£ǎ, Margareta

    2016-10-01

    The plasma beam cutting is a machining method applied in order to detach parts or workpieces from plate type workpiece. Essentially, a plasma jet is sent to workpiece, determining melting, vaporizing and removing of the material from the workpiece. If there is a relative movement between the plasma jet and the workpiece, a kerf gradually appears. Many factors exert influence on the kerf characteristics. A full factorial experiment with three independent variables at two levels was designed, in order to highlight the influence exerted by the cutting speed, workpiece thickness and arc current on the kerf width in the superior and inferior zones and on the kerf taper angle, respectively. Power type empirical mathematical models were determined by mathematical processing of the experimental results.

  16. Evaluation of Potential Thrombin Inhibitors from the White Mangrove (Laguncularia racemosa (L.) C.F. Gaertn.)

    PubMed Central

    Rodrigues, Caroline Fabri Bittencourt; Gaeta, Henrique Hessel; Belchor, Mariana Novo; Ferreira, Marcelo José Pena; Pinho, Marcus Vinícius Terashima; de Oliveira Toyama, Daniela; Toyama, Marcos Hikari

    2015-01-01

    The aim of this work was to verify the effects of methanol (MeOH) and hydroalcoholic (HA) extracts and their respective partition phases obtained from white mangrove (Laguncularia racemosa (L.) C.F. Gaertn.) leaves on human thrombin activity. Among the extracts and phases tested, only the ethyl acetate and butanolic partitions significantly inhibited human thrombin activity and the coagulation of plasma in the presence of this enzyme. Chromatographic analyses of the thrombin samples incubated with these phases revealed that different compounds were able to interact with thrombin. The butanolic phase of the MeOH extract had the most potent inhibitory effects, reducing enzymatic activity and thrombin-induced plasma coagulation. Two glycosylated flavonoids in this partition were identified as the most potent inhibitors of human thrombin activity, namely quercetin-3-O-arabinoside (QAra) and quercetin-3-O-rhamnoside (Qn). Chromatographic analyses of thrombin samples incubated with these flavonoids demonstrated the chemical modification of this enzyme, suggesting that the MeOH extract contained other compounds that both induced structural changes in thrombin and diminished its activity. In this article, we show that despite the near absence of the medical use of mangrove compounds, this plant contains natural compounds with potential therapeutic applications. PMID:26197325

  17. Slot-Antenna/Permanent-Magnet Device for Generating Plasma

    NASA Technical Reports Server (NTRS)

    Foster, John E.

    2007-01-01

    A device that includes a rectangular-waveguide/slot-antenna structure and permanent magnets has been devised as a means of generating a substantially uniform plasma over a relatively large area, using relatively low input power and a low gas flow rate. The device utilizes electron cyclotron resonance (ECR) excited by microwave power to efficiently generate plasma in a manner that is completely electrodeless in the sense that, in principle, there is no electrical contact between the plasma and the antenna. Plasmas generated by devices like this one are suitable for use as sources of ions and/or electrons for diverse material-processing applications (e.g., etching or deposition) and for ion thrusters. The absence of plasma/electrode contact essentially prevents plasma-induced erosion of the antenna, thereby also helping to minimize contamination of the plasma and of objects exposed to the plasma. Consequently, the operational lifetime of the rectangular-waveguide/ slot-antenna structure is long and the lifetime of the plasma source is limited by the lifetime of the associated charged-particle-extraction grid (if used) or the lifetime of the microwave power source. The device includes a series of matched radiating slot pairs that are distributed along the length of a plasma-source discharge chamber (see figure). This arrangement enables the production of plasma in a distributed fashion, thereby giving rise to a uniform plasma profile. A uniform plasma profile is necessary for uniformity in any electron- or ion-extraction electrostatic optics. The slotted configuration of the waveguide/ antenna structure makes the device scalable to larger areas and higher powers. All that is needed for scaling up is the attachment of additional matched radiating slots along the length of the discharge chamber. If it is desired to make the power per slot remain constant in scaling up, then the input microwave power must be increased accordingly. Unlike in prior ECR microwave plasma-generating

  18. Inductively generated streaming plasma ion source

    DOEpatents

    Glidden, Steven C.; Sanders, Howard D.; Greenly, John B.

    2006-07-25

    A novel pulsed, neutralized ion beam source is provided. The source uses pulsed inductive breakdown of neutral gas, and magnetic acceleration and control of the resulting plasma, to form a beam. The beam supplies ions for applications requiring excellent control of ion species, low remittance, high current density, and spatial uniformity.

  19. Plasma treatment for next-generation nanobiointerfaces.

    PubMed

    Levchenko, Igor; Keidar, Michael; Mai-Prochnow, Anne; Modic, Martina; Cvelbar, Uros; Fang, Jinghua; Ostrikov, Kostya Ken

    2015-06-23

    Energy deficiency, global poverty, chronic hunger, chronic diseases, and environment conservation are among the major problems threatening the whole mankind. Nanostructure-based technologies could be a possible solution. Such techniques are now used for the production of many vitally important products including cultured and fermented food, antibiotics, various medicines, and biofuels. On the other hand, the nanostructure-based technologies still demonstrate low efficiency and controllability, and thus still are not capable to decisively address the global problems. Furthermore, future technologies should ensure lowest possible environmental impact by implementing green production principles. One of the most promising approaches to address these challenges are the sophisticatedly engineered biointerfaces. Here, the authors briefly evaluate the potential of the plasma-based techniques for the fabrication of complex biointerfaces. The authors consider mainly the atmospheric and inductively coupled plasma environments and show several examples of the artificial plasma-created biointerfaces, which can be used for the biotechnological and medical processes, as well as for the drug delivery devices, fluidised bed bioreactors, catalytic reactors, and others. A special attention is paid to the plasma-based treatment and processing of the biointerfaces formed by arrays of carbon nanotubes and graphene flakes.

  20. Thrombin Increases Expression of Fibronectin Antigen on the Platelet Surface

    NASA Astrophysics Data System (ADS)

    Ginsberg, Mark H.; Painter, Richard G.; Forsyth, Jane; Birdwell, Charles; Plow, Edward F.

    1980-02-01

    Fibronectins (fn) are adhesive glycoproteins which bind to collagen and to fibrin and appear to be important in cellular adhesion to other cells or surfaces. Fn-related antigen is present in human platelets, suggesting a possible role for fn in the adhesive properties of platelets. We have studied the localization of fn in resting and thrombin-stimulated platelets by immunofluorescence and quantitative binding of radiolabeled antibody. In resting fixed platelets, variable light surface staining for fn was observed. When these cells were made permeable to antibody with detergent, staining for fn was markedly enhanced and was present in a punctate distribution, suggesting intracellular localization. Stimulation with thrombin, which is associated with increased platelet adhesiveness, resulted in increased staining for fn antigen on intact platelets. These stimulated cells did not leak 51Cr nor did they stain for F-actin, thus documenting that the increased fn staining was not due to loss of plasma membrane integrity. The thrombin-induced increase in accessible platelet fn antigen was confirmed by quantitative antibody binding studies in which thrombin-stimulated platelets specifically bound 15 times as much radiolabeled F(ab')2 anti-fn as did resting cells. Thus, thrombin stimulation results in increased expression of fn antigen on the platelet surface. Here it may participate in interactions with fibrin, connective tissue, or other cells.

  1. Coupling of the thrombin receptor to G12 may account for selective effects of thrombin on gene expression and DNA synthesis in 1321N1 astrocytoma cells.

    PubMed Central

    Post, G R; Collins, L R; Kennedy, E D; Moskowitz, S A; Aragay, A M; Goldstein, D; Brown, J H

    1996-01-01

    In 1321N1 astrocytoma cells, thrombin, but not carbachol, induces AP-1-mediated gene expression and DNA synthesis. To understand the divergent effects of these G protein-coupled receptor agonists on cellular responses, we examined Gq-dependent signaling events induced by thrombin receptor and muscarinic acetylcholine receptor stimulation. Thrombin and carbachol induce comparable changes in phosphoinositide and phosphatidylcholine hydrolysis, mobilization of intracellular Ca2+, diglyceride generation, and redistribution of protein kinase C; thus, activation of these Gq-signaling pathways appears to be insufficient for gene expression and mitogenesis. Thrombin increases Ras and mitogen-activated protein kinase activation to a greater extent than carbachol in 1321N1 cells. The effects of thrombin are not mediated through Gi, since ribosylation of Gi/Go proteins by pertussis toxin does not prevent thrombin-induced gene expression or thrombin-stimulated DNA synthesis. We recently reported that the pertussis toxin-insensitive G12 protein is required for thrombin-induced DNA synthesis. We demonstrate here, using transfection of receptors and G proteins in COS-7 cells, that G alpha 12 selectively couples the thrombin receptor to AP-1-mediated gene expression. This does not appear to result from increased mitogen-activated protein kinase activity but may reflect activation of a tyrosine kinase pathway. We suggest that preferential coupling of the thrombin receptor to G12 accounts for the selective ability of thrombin to stimulate Ras, mitogen-activated protein kinase, gene expression, and mitogenesis in 1321N1 cells. Images PMID:8930892

  2. Ultra-High Intensity Magnetic Field Generation in Dense Plasma

    SciTech Connect

    Fisch, Nathaniel J.

    2014-01-08

    The main objective of this grant proposal was to explore the efficient generation of intense currents. Whereas the efficient generation of electric current in low-­energy-­density plasma has occupied the attention of the magnetic fusion community for several decades, scant attention has been paid to carrying over to high-­energy-­density plasma the ideas for steady-­state current drive developed for low-­energy-­density plasma, or, for that matter, to inventing new methodologies for generating electric current in high-­energy-­density plasma. What we proposed to do was to identify new mechanisms to accomplish current generation, and to assess the operation, physics, and engineering basis of new forms of current drive in regimes appropriate for new fusion concepts.

  3. A research program in magnetogasdynamics utilizing hypervelocity coaxial plasma generators

    NASA Technical Reports Server (NTRS)

    Spight, C.

    1976-01-01

    A broadly-gauged research program in magnetogasdynamics utilizing hypervelocity coaxial plasma generators is presented. A complete hypervelocity coaxial plasma generator facility was assembled and tested. Significant progress was made in the direction of understanding the important processes in the interaction of hypervelocity MGD flow with transverse applied fields. It is now proposed to utilize the accumulated experimental capability and theoretical analysis in application to the analysis and design parameterization of pulsed magnetogasdynamic direct energy convertor configurations.

  4. Plasma x-ray sources powered by megajoule magnetocumulative generators.

    PubMed

    Popkov, N F; Ya Averchenkov, V; Pikar', A S; Ryaslov, E A; Kargin, V I; Lazarev, S A; Borovkov, V V

    1995-01-01

    We have performed experiments using magnetocumulative generators (MCGs) to power three different types of high-energy-density plasma discharges suitable for intense x-ray generation. They include the H-pressed discharge, the capillary z-pinch, and the θ-pinch. The MCGs were operated with, and without, plasma opening switches. The characteristic currents were approximately 10 MA and characteristic time scales approximately 1 μs. In this paper we describe the characteristics of these experiments.

  5. Electron beam manipulation, injection and acceleration in plasma wakefield accelerators by optically generated plasma density spikes

    NASA Astrophysics Data System (ADS)

    Wittig, Georg; Karger, Oliver S.; Knetsch, Alexander; Xi, Yunfeng; Deng, Aihua; Rosenzweig, James B.; Bruhwiler, David L.; Smith, Jonathan; Sheng, Zheng-Ming; Jaroszynski, Dino A.; Manahan, Grace G.; Hidding, Bernhard

    2016-09-01

    We discuss considerations regarding a novel and robust scheme for optically triggered electron bunch generation in plasma wakefield accelerators [1]. In this technique, a transversely propagating focused laser pulse ignites a quasi-stationary plasma column before the arrival of the plasma wake. This localized plasma density enhancement or optical "plasma torch" distorts the blowout during the arrival of the electron drive bunch and modifies the electron trajectories, resulting in controlled injection. By changing the gas density, and the laser pulse parameters such as beam waist and intensity, and by moving the focal point of the laser pulse, the shape of the plasma torch, and therefore the generated trailing beam, can be tuned easily. The proposed method is much more flexible and faster in generating gas density transitions when compared to hydrodynamics-based methods, and it accommodates experimentalists needs as it is a purely optical process and straightforward to implement.

  6. Hydrogen Generation from the Dissociation of Water Using Microwave Plasmas

    NASA Astrophysics Data System (ADS)

    Yong, Ho Jung; Soo Ouk, Jang; Hyun Jong, You

    2013-06-01

    Hydrogen is produced by direct dissociation of water vapor, i.e., splitting water molecules by the electrons in water plasma at low pressure (<10-50 Torr) using microwave plasma discharge. This condition generates a high electron temperature, which facilitates the direct dissociation of water molecules. A microwave plasma source is developed, utilizing the magnetron of a microwave oven and a TE10 rectangular waveguide. The quantity of the generated hydrogen is measured using a residual gas analyzer. The electron density and temperature are measured by a Langmuir probe, and the neutral temperature is calculated from the OH line intensity.

  7. Intracellular Ascorbate Prevents Endothelial Barrier Permeabilization by Thrombin*

    PubMed Central

    Parker, William H.; Qu, Zhi-chao; May, James M.

    2015-01-01

    Intracellular ascorbate (vitamin C) has previously been shown to tighten the endothelial barrier and maintain barrier integrity during acute inflammation in vitro. However, the downstream effectors of ascorbate in the regulation of endothelial permeability remain unclear. In this study, we evaluated ascorbate as a mediator of thrombin-induced barrier permeabilization in human umbilical vein endothelial cells and their immortalized hybridoma line, EA.hy926. We found that the vitamin fully prevented increased permeability to the polysaccharide inulin by thrombin in a dose-dependent manner, and it took effect both before and after subjection to thrombin. Thrombin exposure consumed intracellular ascorbate but not the endogenous antioxidant GSH. Likewise, the antioxidants dithiothreitol and tempol did not reverse permeabilization. We identified a novel role for ascorbate in preserving cAMP during thrombin stimulation, resulting in two downstream effects. First, ascorbate maintained the cortical actin cytoskeleton in a Rap1- and Rac1-dependent manner, thus preserving stable adherens junctions between adjacent cells. Second, ascorbate prevented actin polymerization and formation of stress fibers by reducing the activation of RhoA and phosphorylation of myosin light chain. Although ascorbate and thrombin both required calcium for their respective effects, ascorbate did not prevent thrombin permeabilization by obstructing calcium influx. However, preservation of cAMP by ascorbate was found to depend on both the production of nitric oxide by endothelial nitric-oxide synthase, which ascorbate is known to activate, and the subsequent generation cGMP by guanylate cyclase. Together, these data implicate ascorbate in the prevention of inflammatory endothelial barrier permeabilization and explain the underlying signaling mechanism. PMID:26152729

  8. Intracellular Ascorbate Prevents Endothelial Barrier Permeabilization by Thrombin.

    PubMed

    Parker, William H; Qu, Zhi-chao; May, James M

    2015-08-28

    Intracellular ascorbate (vitamin C) has previously been shown to tighten the endothelial barrier and maintain barrier integrity during acute inflammation in vitro. However, the downstream effectors of ascorbate in the regulation of endothelial permeability remain unclear. In this study, we evaluated ascorbate as a mediator of thrombin-induced barrier permeabilization in human umbilical vein endothelial cells and their immortalized hybridoma line, EA.hy926. We found that the vitamin fully prevented increased permeability to the polysaccharide inulin by thrombin in a dose-dependent manner, and it took effect both before and after subjection to thrombin. Thrombin exposure consumed intracellular ascorbate but not the endogenous antioxidant GSH. Likewise, the antioxidants dithiothreitol and tempol did not reverse permeabilization. We identified a novel role for ascorbate in preserving cAMP during thrombin stimulation, resulting in two downstream effects. First, ascorbate maintained the cortical actin cytoskeleton in a Rap1- and Rac1-dependent manner, thus preserving stable adherens junctions between adjacent cells. Second, ascorbate prevented actin polymerization and formation of stress fibers by reducing the activation of RhoA and phosphorylation of myosin light chain. Although ascorbate and thrombin both required calcium for their respective effects, ascorbate did not prevent thrombin permeabilization by obstructing calcium influx. However, preservation of cAMP by ascorbate was found to depend on both the production of nitric oxide by endothelial nitric-oxide synthase, which ascorbate is known to activate, and the subsequent generation cGMP by guanylate cyclase. Together, these data implicate ascorbate in the prevention of inflammatory endothelial barrier permeabilization and explain the underlying signaling mechanism.

  9. Dense Plasma Heating and Radiation Generation.

    DTIC Science & Technology

    1980-05-30

    INSTRUCTIONS ~~~~~~ B OUET ~iNPGEFORE COMPLETING FORM I. RPORTmumsZ. GVT AC INNo.i S. ACCIPIENT’S CATALOG MUM694 ~~ 80-0981 F,6-~IS~ � 4. r r~ejandsw... p M. Kristiansen and M.O. Hagler AFOSR 74-2639 ~ 9. 9%RFOR4fpN ORGAMIZAT1om NAME ANO ADDRESS 10. PROGRAM ELEMEN T. DRO.IECT, TASK Plasma Laboratory...8217AA P ’t1JIMIS Dept. of Electrical Engineering 2301/A Texas Tech University, Lubbock, Texas 79409, 61102F 20Il It. CONTROLLING OFFICE MAMIE AND AOhESS

  10. Plasma erosion switches with imploding plasma loads on a multiterawatt pulsed power generator

    NASA Astrophysics Data System (ADS)

    Stringfield, R.; Schneider, R.; Genuario, R. D.; Roth, I.; Childers, K.; Stallings, C.; Dakin, D.

    1981-03-01

    Plasma erosion switches have been fielded on the PITHON generator during imploding plasma experiments. Theta pinch plasma guns were used to inject carbon plasmas of densities in the range of 10 to the 12th to 10 to the 14th/cu cm between the electrodes of the vacuum power feed region, upstream from an imploding plasma load. Current monitors indicated that the erosion switches carried substantial current early in time, diverting it from the load. Late in the pulse the erosion switches opened, transferring the current to an imploding plasma with the effect of sharpening the current rise time at the load. Associated with the sharper rise time was an improvement in the quality of the plasma implosions. The results of varying the density and total number of particles in the plasma of the switches are presented with regard to the effect on the current along the vacuum feed and on the behavior of vacuum flowing electrons.

  11. Plasma erosion switches with imploding plasma loads on the pithon generator

    NASA Astrophysics Data System (ADS)

    Stringfield, R.; Schneider, R.; Genuario, R. D.; Roth, I.; Childers, K.; Stallings, C.; Dakin, D.

    1981-03-01

    Plasma erosion switches have been fielded on the PITHON generator during imploding plasma experiments. Theta pinch plasma guns were used to inject carbon plasmas of densities in the range 10 12-10 14/cm 3 between the electrodes of the vacuum power feed region, upstream from an imploding plasma load. Current monitors indicated that the erosion switches carried substantial current early in time, diverting it from the load. Late in the pulse the erosion switches opened, transferring the current to an imploding plasma with the effect of sharpening the current risetime at the load. Associated with the sharper risetime was an improvement in the quality of the plasma implosions. The results of varying the density and total number of particles in the plasma of the switches are presented with regard to the effect on the current along the vacuum feed and on the behavior of vacuum flowing electrons.

  12. Optimum plasma conditions for the efficient high-order harmonic generation in platinum plasma

    SciTech Connect

    Ganeev, Rashid A.; Elouga Bom, Luc B.; Kieffer, Jean-Claude; Ozaki, Tsuneyuki

    2007-06-15

    We studied the optimum plasma conditions that are required for efficient high-order harmonic generation in platinum plume. Harmonics up to the 49th order ({lambda}=16.32 nm) are analyzed under various conditions of laser-plasma interaction. Time-resolved ultraviolet spectra of platinum plasma at both optimum and nonoptimum conditions of harmonic generation are presented. We calculated the ionization states of the plasma, free electron density, and singly charged ion density at different prepulse intensities and compared them with experimental results.

  13. Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate.

    PubMed

    Dinkelaar, Jasper; Patiwael, Sanne; Harenberg, Job; Leyte, Anja; Brinkman, Herm Jan M

    2014-11-01

    Specific mass spectrometry and direct activated factor X (Xa)- and thrombin inhibition assays do not allow determination of the reversal of anticoagulant effects of non-vitamin K direct oral anticoagulants (NOACs) by prothrombin complex concentrate (PCC). The objective of this study was the evaluation of the applicability of a variety of commercially available global coagulation assays in analyzing the reversal of NOAC anticoagulation by PCC. Plasma and whole blood were spiked with apixaban or dabigatran and PCC was added to these samples. Prothrombin time (PT), modified PT (mPT), activated partial prothrombin time (APTT), thrombography (CAT method) and thromboelastography (ROTEM, TEG) were performed. Assays triggered by contact activation (APTT, INTEM) did not show inhibitor reversal by PCC. Assays triggered by tissue factor (TF) showed NOAC type and NOAC concentration dependent anticoagulation reversal effects of PCC ranging from partial normalization to overcorrection of the following parameters: clotting or reaction time (PT, mPT TEG-TF, EXTEM, FIBTEM); angle in thromboelastography (TEG-TF); thrombin generation (CAT) lag time, endogenous thrombin potential (ETP) and peak thrombin. Extent of reversal was assay reagent dependent. ETP (5 pM TF) was the only parameter showing complete reversal of anticoagulation by PCC for all NOACs ranging from 200 to 800 μg/L. ETP fits with the concept that reversal assessment of NOAC anticoagulation by PCC should be based on measurements on the clotting potential or thrombin generating potential of the plasma or whole blood patient sample. Low sensitivity of ETP for NOACs and its correlation with bleeding are issues that remain to be resolved.

  14. Induction therapy alters plasma fibrin clot properties in multiple myeloma patients: association with thromboembolic complications.

    PubMed

    Undas, Anetta; Zubkiewicz-Usnarska, Lidia; Helbig, Grzegorz; Woszczyk, Dariusz; Kozińska, Justyna; Dmoszyńska, Anna; Dębski, Jakub; Podolak-Dawidziak, Maria; Kuliczkowski, Kazimierz

    2015-09-01

    Induction therapy in patients with multiple myeloma increases the risk of thromboembolism. We have recently shown that multiple myeloma patients tend to form denser fibrin clots displaying poor lysability. We investigated the effect of induction therapy on fibrin clot properties in multiple myeloma patients. Ex-vivo plasma fibrin clot permeability, turbidity, susceptibility to lysis, thrombin generation, factor VIII and fibrinolytic proteins were compared in 48 multiple myeloma patients prior to and following 3 months of induction therapy, mainly with cyclophosphamide-thalidomide-dexamethasone regimen. Patients on thromboprophylaxis with aspirin or heparins were eligible. A 3-month induction therapy resulted in improved clot properties, that is higher clot permeability, compaction, shorter lag phase and higher final turbidity, along with shorter clot lysis time and higher rate of D-dimer release from fibrin clots than the baseline values. The therapy also resulted in lower thrombin generation, antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI), but elevated factor VIII. Progressive disease was associated with lower posttreatment clot permeability and lysability. Despite thromboprophylaxis, two patients developed ischemic stroke and 10 had venous thromboembolism. They were characterized by pretreatment lower clot permeability, prolonged clot lysis time, longer lag phase, higher peak thrombin generation, TAFI and plasminogen activator inhibitor -1. Formation of denser plasma fibrin clots with reduced lysability and increased thrombin generation at baseline could predispose to thrombotic complications during induction treatment in multiple myeloma patients. We observed improved fibrin clot properties and thrombin generation in multiple myeloma patients except those with progressive disease.

  15. Global plasma simulations using dynamically generated chemical models

    SciTech Connect

    Munro, James J.; Tennyson, Jonathan

    2008-07-15

    Extensive molecular data are a key requirement in understanding modern technical plasmas. A method for coupling molecular data with chemical models in a global plasma simulation to enable rapid testing and evaluation of new plasmas is presented. A global plasma model (GLOBALKIN) is extended using an expert system (Quantemol-P) to enable ad hoc simulations using new plasma recipes. A set of atomic and molecular species to be considered in the plasma simulation is specified by the user. The expert system generates a complete set of reaction pathways for both the gas and surface reactions in a plasma. This set is pruned by discarding unphysical reactions and reaction data not appropriate to technical plasmas (such as autodetachment). The species, gas phase reactions, surface reactions, and plasma properties can be adjusted to control the simulation. The reaction list is populated through a database of molecular parameters and cross sections; missing data can be calculated through molecular cross sections using a further expert system (Quantemol-N) which applies the R-matrix method to electron-molecule collisions. For cases where the R-matrix method is not appropriate, other methods are used to maximize the range of cross-section data available. The Quantemol-P expert system allows rapid creation of new plasma recipes and investigation of their effects allowing a greater level of flexibility than previously achievable.

  16. A large volume uniform plasma generator for the experiments of electromagnetic wave propagation in plasma

    SciTech Connect

    Yang Min; Li Xiaoping; Xie Kai; Liu Donglin; Liu Yanming

    2013-01-15

    A large volume uniform plasma generator is proposed for the experiments of electromagnetic (EM) wave propagation in plasma, to reproduce a 'black out' phenomenon with long duration in an environment of the ordinary laboratory. The plasma generator achieves a controllable approximate uniform plasma in volume of 260 mm Multiplication-Sign 260 mm Multiplication-Sign 180 mm without the magnetic confinement. The plasma is produced by the glow discharge, and the special discharge structure is built to bring a steady approximate uniform plasma environment in the electromagnetic wave propagation path without any other barriers. In addition, the electron density and luminosity distributions of plasma under different discharge conditions were diagnosed and experimentally investigated. Both the electron density and the plasma uniformity are directly proportional to the input power and in roughly reverse proportion to the gas pressure in the chamber. Furthermore, the experiments of electromagnetic wave propagation in plasma are conducted in this plasma generator. Blackout phenomena at GPS signal are observed under this system and the measured attenuation curve is of reasonable agreement with the theoretical one, which suggests the effectiveness of the proposed method.

  17. Plasma Physics Simulations on Next Generation Platforms

    NASA Astrophysics Data System (ADS)

    Koniges, Alice

    2013-10-01

    The current high-performance computing revolution provides opportunity for major increases in computational power over the next several years, if it can be harnessed. This transition from simply increasing the single-processor and network performance to a different architectural paradigms forces application programmers to rethink the basic models of parallel programming from both the language and problem division standpoints. One of the major computing facilities available to researchers in fusion energy is the National Energy Research Scientific Computing Center. As the mission computing center for DOE, Office of Science, NERSC is tasked with helping users to overcome the challenges of this revolution both through the use of new parallel constructs and languages and also by enabling a broader user community to take advantage of multi-core performance. We discuss the programming model challenges facing researchers in fusion and plasma physics in for a variety of simulations ranging from particle-in-cell to fluid-gyrokinetic and MHD models.

  18. Carbon Multicharged Ion Generation from Laser Plasma

    NASA Astrophysics Data System (ADS)

    Balki, Oguzhan; Elsayed-Ali, Hani E.

    2014-10-01

    Multicharged ions (MCI) have potential uses in different areas such as microelectronics and medical physics. Carbon MCI therapy for cancer treatment is considered due to its localized energy delivery to hard-to-reach tumors at a minimal damage to surrounding tissues. We use a Q-switched Nd:YAG laser with 40 ns pulse width operated at 1064 nm to ablate a graphite target in ultrahigh vacuum. A time-of-flight energy analyzer followed by a Faraday cup is used to characterize the carbon MCI extracted from the laser plasma. The MCI charge state and energy distribution are obtained. With increase in the laser fluence, the ion charge states and ion energy are increased. Carbon MCI up to C+6 are observed along with carbon clusters. When an acceleration voltage is applied between the carbon target and a grounded mesh, ion extraction is observed to increase with the applied voltage. National Science Foundation.

  19. On the generation of magnetic field enhanced microwave plasma line

    NASA Astrophysics Data System (ADS)

    Chen, Longwei; Zhao, Ying; Wu, Kenan; Wang, Qi; Meng, Yuedong; Ren, Zhaoxing

    2016-12-01

    Microwave linear plasmas sustained by surface waves have attracted much attention due to the potential abilities to generate large-scale and uniform non-equilibrium plasmas. An external magnetic field was generally applied to enhance and stabilize plasma sources because the magnetic field decreased the electron losses on the wall. The effects of magnetic field on the generation and propagation mechanisms of the microwave plasma were tentatively investigated based on a 2-D numerical model combining a coupled system of Maxwell's equations and continuity equations. The mobility of electrons and effective electric conductivity of the plasma were considered as a full tensor in the presence of magnetic field. Numerical results indicate that both cases of magnetic field in the axial-direction and radial-direction benefit the generation of a high-density plasma; the former one allows the microwave to propagate longer in the axis direction compared to the latter one. The time-averaged power flow density and the amplitude of the electric field on the inner rod of coaxial waveguide attenuate with the propagation of the microwave for both cases of with and without external magnetic field. The attenuation becomes smaller in the presence of appropriately higher axial-direction magnetic field, which allows more microwave energies to transmit along the axial direction. Meanwhile, the anisotropic properties of the plasma, like electron mobility, in the presence of the magnetic field confine more charged particles in the direction of the magnetic field line.

  20. Characterization of inductively coupled plasma generated by a quadruple antenna

    NASA Astrophysics Data System (ADS)

    Shafir, G.; Zolotukhin, D.; Godyak, V.; Shlapakovski, A.; Gleizer, S.; Slutsker, Ya; Gad, R.; Bernshtam, V.; Ralchenko, Yu; Krasik, Ya E.

    2017-02-01

    The results of the characterization of large-scale RF plasma for studying nonlinear interaction with a high-power (˜400 MW) short duration (˜0.8 ns) microwave (˜10 GHz) beam are presented. The plasma was generated inside a Pyrex tube 80 cm in length and 25 cm in diameter filled by either Ar or He gas at a pressure in the range 1.3-13 Pa using a 2 MHz RF generator with a matching system and a quadruple antenna. Good matching was obtained between the plasma parameters, which were determined using different methods including a movable Langmuir probe, microwave cut-off, interferometry, and optical emission spectroscopy. It was shown that, depending on the gas pressure and RF power delivered to the antenna, the plasma density and electron temperature can be controlled in the range 1 × 1010-5 × 1012 cm-3 and 1-3.5 eV, respectively. The plasma density was found to be uniform in terms of axial (˜60 cm) and radial (˜10 cm) dimensions. Further, it was also shown that the application of the quadruple antenna, with resonating capacitors inserted in its arms, decreases the capacitive coupling of the antenna and the plasma as well as the RF power loss along the antenna. These features make this plasma source suitable for microwave plasma wake field experiments.

  1. Spontaneous generation of rotation in tokamak plasmas

    SciTech Connect

    Parra Diaz, Felix

    2013-12-24

    Three different aspects of intrinsic rotation have been treated. i) A new, first principles model for intrinsic rotation [F.I. Parra, M. Barnes and P.J. Catto, Nucl. Fusion 51, 113001 (2011)] has been implemented in the gyrokinetic code GS2. The results obtained with the code are consistent with several experimental observations, namely the rotation peaking observed after an L-H transition, the rotation reversal observed in Ohmic plasmas, and the change in rotation that follows Lower Hybrid wave injection. ii) The model in [F.I. Parra, M. Barnes and P.J. Catto, Nucl. Fusion 51, 113001 (2011)] has several simplifying assumptions that seem to be satisfied in most tokamaks. To check the importance of these hypotheses, first principles equations that do not rely on these simplifying assumptions have been derived, and a version of these new equations has been implemented in GS2 as well. iii) A tokamak cross-section that drives large intrinsic rotation has been proposed for future large tokamaks. In large tokamaks, intrinsic rotation is expected to be very small unless some up-down asymmetry is introduced. The research conducted under this contract indicates that tilted ellipticity is the most efficient way to drive intrinsic rotation.

  2. Magnetic Field Generation During the Collision of Narrow Plasma Clouds

    NASA Astrophysics Data System (ADS)

    Sakai, Jun-ichi; Kazimura, Yoshihiro; Haruki, Takayuki

    1999-06-01

    We investigate the dynamics of the collision of narrow plasma clouds,whose transverse dimension is on the order of the electron skin depth.A 2D3V (two dimensions in space and three dimensions in velocity space)particle-in-cell (PIC) collisionless relativistic code is used toshow the generation of a quasi-staticmagnetic field during the collision of narrow plasma clouds both inelectron-ion and electron-positron (pair) plasmas. The localizedstrong magnetic fluxes result in the generation of the charge separationwith complicated structures, which may be sources of electromagneticas well as Langmuir waves. We also present one applicationof this process, which occurs during coalescence of magnetic islandsin a current sheet of pair plasmas.

  3. Study of parameters of a facility generating compressive plasma flows

    NASA Astrophysics Data System (ADS)

    Leyvi, A. Ya

    2017-05-01

    The prosperity of plasma technologies stimulates making of a facility generating compressive plasma flows at the South Ural State University. The facility is a compact-geometry magnetoplasma compressor with the following parameters: stored energy up to 15 kJ, voltage of a bank from 3 to 5 kV; nitrogen, air, and other gases can serve as its operating gas. The investigation of parameters of the facility showed the following parameters of compressive plasma flows: impulse duration of up to 120 μs, discharge current of 50-120 kA, speed of plasma flow of 15-30 km/s. By contrast to the available facilities, the parameters of the developed facility can be adjusted in a wide range of voltage from 2 kV to 10 kV, its design permits generating CPF in horizontal and vertical positions.

  4. Electrode assemblies, plasma apparatuses and systems including electrode assemblies, and methods for generating plasma

    DOEpatents

    Kong, Peter C; Grandy, Jon D; Detering, Brent A; Zuck, Larry D

    2013-09-17

    Electrode assemblies for plasma reactors include a structure or device for constraining an arc endpoint to a selected area or region on an electrode. In some embodiments, the structure or device may comprise one or more insulating members covering a portion of an electrode. In additional embodiments, the structure or device may provide a magnetic field configured to control a location of an arc endpoint on the electrode. Plasma generating modules, apparatus, and systems include such electrode assemblies. Methods for generating a plasma include covering at least a portion of a surface of an electrode with an electrically insulating member to constrain a location of an arc endpoint on the electrode. Additional methods for generating a plasma include generating a magnetic field to constrain a location of an arc endpoint on an electrode.

  5. Charge-exchange plasma generated by an ion thruster

    NASA Technical Reports Server (NTRS)

    Kaufman, H. R.

    1977-01-01

    The charge exchange plasma generated by an ion thruster was investigated experimentally using both 5 cm and 15 cm thrusters. Results are shown for wide ranges of radial distance from the thruster and angle from the beam direction. Considerations of test environment, as well as distance from the thruster, indicate that a valid simulation of a thruster on a spacecraft was obtained. A calculation procedure and a sample calculation of charge exchange plasma density and saturation electron current density are included.

  6. Thrombin stimulates insulin secretion via protease-activated receptor-3.

    PubMed

    Hänzelmann, Sonja; Wang, Jinling; Güney, Emre; Tang, Yunzhao; Zhang, Enming; Axelsson, Annika S; Nenonen, Hannah; Salehi, Albert S; Wollheim, Claes B; Zetterberg, Eva; Berntorp, Erik; Costa, Ivan G; Castelo, Robert; Rosengren, Anders H

    2015-01-01

    The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co-expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes ('module') including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a 'tethered ligand' to regulate cellular signaling. We have characterized the effect of PAR3 activation on insulin secretion by static insulin secretion measurements, capacitance measurements, studies of diabetic animal models and patient samples. We demonstrate that thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3. Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single β-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca(2+) release from intracellular stores. Moreover, we observed that the expression of tissue factor, which regulates thrombin generation, was increased in human islets from T2D donors and associated with enhanced β-cell exocytosis. Finally, we demonstrate that thrombin generation potential in patients with T2D was associated with increased fasting insulin and insulinogenic index. The findings provide a previously unrecognized link between hypercoagulability and hyperinsulinemia and suggest that reducing thrombin activity or blocking PAR3 cleavage could potentially counteract the exaggerated insulin secretion that drives insulin resistance and β-cell exhaustion in T2D.

  7. Edge Plasma Boundary Layer Generated By Kink Modes in Tokamaks

    SciTech Connect

    L.E. Zakharov

    2010-11-22

    This paper describes the structure of the electric current generated by external kink modes at the plasma edge using the ideally conducting plasma model. It is found that the edge current layer is created by both wall touching and free boundary kink modes. Near marginal stability, the total edge current has a universal expression as a result of partial compensation of the δ-functional surface current by the bulk current at the edge. The resolution of an apparent paradox with the pressure balance across the plasma boundary in the presence of the surface currents is provided.

  8. Generation of auroral kilometric radiation in inhomogeneous magnetospheric plasma

    NASA Astrophysics Data System (ADS)

    Burinskaya, T. M.; Shevelev, M. M.

    2017-01-01

    The generation of auroral kilometric radiation in a narrow 3D plasma cavity, in which a weakly relativistic electron flow is propagated along the magnetic field against a low-density cold background plasma, is studied. The time dynamics of the propagation and intensification of waves are analyzed using geometric optics equations. The waves have different wave vector components and start from the cavity center at an altitude of about the Earth's radius at plasma parameters typical for the auroral zone at this altitude. It is shown that the global inhomogeneity of the Earth's magnetic field is of key importance in shaping the auroral kilometric radiation spectra.

  9. Magnetic Cusp Configuration of the SPL Plasma Generator

    SciTech Connect

    Kronberger, Matthias; Chaudet, Elodie; Favre, Gilles; Lettry, Jacques; Kuechler, Detlef; Moyret, Pierre; Paoluzzi, Mauro; Prever-Loiri, Laurent; Schmitzer, Claus; Scrivens, Richard; Steyaert, Didier

    2011-09-26

    The Superconducting Proton Linac (SPL) is a novel linear accelerator concept currently studied at CERN. As part of this study, a new Cs-free, RF-driven external antenna H{sup -} plasma generator has been developed to withstand an average thermal load of 6 kW. The magnetic configuration of the new plasma generator includes a dodecapole cusp field and a filter field separating the plasma heating and H{sup -} production regions. Ferrites surrounding the RF antenna serve in enhancing the coupling of the RF to the plasma. Due to the space requirements of the plasma chamber cooling circuit, the cusp magnets are pushed outwards compared to Linac4 and the cusp field strength in the plasma region is reduced by 40% when N-S magnetized magnets are used. The cusp field strength and plasma confinement can be improved by replacing the N-S magnets with offset Halbach elements of which each consists of three magnetic sub-elements with different magnetization direction. A design challenge is the dissipation of RF power induced by eddy currents in the cusp and filter magnets which may lead to overheating and demagnetization. In view of this, a copper magnet cage has been developed that shields the cusp magnets from the radiation of the RF antenna.

  10. Generation of low-temperature air plasma for food processing

    NASA Astrophysics Data System (ADS)

    Stepanova, Olga; Demidova, Maria; Astafiev, Alexander; Pinchuk, Mikhail; Balkir, Pinar; Turantas, Fulya

    2015-11-01

    The project is aimed at developing a physical and technical foundation of generating plasma with low gas temperature at atmospheric pressure for food industry needs. As known, plasma has an antimicrobial effect on the numerous types of microorganisms, including those that cause food spoilage. In this work an original experimental setup has been developed for the treatment of different foods. It is based on initiating corona or dielectric-barrier discharge in a chamber filled with ambient air in combination with a certain helium admixture. The experimental setup provides various conditions of discharge generation (including discharge gap geometry, supply voltage, velocity of gas flow, content of helium admixture in air and working pressure) and allows for the measurement of the electrical discharge parameters. Some recommendations on choosing optimal conditions of discharge generation for experiments on plasma food processing are developed.

  11. A portable microchip for ultrasensitive and high-throughput assay of thrombin by rolling circle amplification and hemin/G-quadruplex system.

    PubMed

    Lin, Xuexia; Chen, Qiushui; Liu, Wu; Li, Haifang; Lin, Jin-Ming

    2014-06-15

    In this work, a convenient and high-throughput colorimetric assay was developed on an aptamer-modified microchip for ultrasensitive detection of thrombin using rolling circle amplification and G-quadruplex DNAzyme. This system consisted of an aptamer-modified microchip and a secondary aptamer. The secondary aptamer contained a thrombin aptamer and a primer with a G-quadruplex circular template. RCA technology was used to improve the sensitivity by producing the multiple G-quadruplex units. To generate colorimetric signal, G-quadruplex DNAzyme was used to catalyze the H2O2-mediated oxidation of 2,2'-azinobis (3-ethylbenzothiozoline)-6-sulfonic acid. At the optimal conditions, the linear range for thrombin was 0.100-50.000 pg/mL, and the limit of detection was down to 0.083 pg/mL. Moreover, the developed method was successfully applied to detect thrombin from human plasma and serum, indicating that this approach has great potential in clinical diagnosis and medical investigation.

  12. A study of single and binary ion plasma expansion into laboratory-generated plasma wakes

    NASA Technical Reports Server (NTRS)

    Wright, Kenneth Herbert, Jr.

    1988-01-01

    Plasma expansion into the wake of a large rectangular plate immersed in a collisionless, supersonic plasma was investigated in laboratory experiments. The experimental conditions address both single ion and binary ion plasma flows for the case of a body whose size is large in comparison with the Debye length, when the potential difference between the body and the plasma is relatively small. A new plasma source was developed to generate equi-velocity, binary ion plasma flows, which allows access to new parameter space that have previously been unavailable for laboratory studies. Specifically, the new parameters are the ionic mass ratio and the ionic component density ratio. In a series of experiments, a krypton-neon plasma is employed where the ambient density ratio of neon to krypton is varied more than an order of magnitude. The expansion in both the single ion and binary ion plasma cases is limited to early times, i.e., a few ion plasma periods, by the combination of plasma density, plasma drift speed, and vacuum chamber size, which prevented detailed comparison with self-similar theory.

  13. Harmonic generation by circularly polarized laser beams propagating in plasma

    SciTech Connect

    Agrawal, Ekta; Hemlata,; Jha, Pallavi

    2015-04-15

    An analytical theory is developed for studying the phenomenon of generation of harmonics by the propagation of an obliquely incident, circularly polarized laser beam in homogeneous, underdense plasma. The amplitudes of second and third harmonic radiation as well as detuning distance have been obtained and their variation with the angle of incidence is analyzed. The amplitude of harmonic radiation increases with the angle of incidence while the detuning distance decreases, for a given plasma electron density. It is observed that the generated second and third harmonic radiation is linearly and elliptically polarized, respectively. The harmonic radiation vanishes at normal incidence of the circularly polarized laser beam.

  14. Overdense plasma generation in a compact ion source

    NASA Astrophysics Data System (ADS)

    Castro, G.; Mascali, D.; Gammino, S.; Torrisi, G.; Romano, F. P.; Celona, L.; Altana, C.; Caliri, C.; Gambino, N.; Lanaia, D.; Miracoli, R.; Neri, L.; Sorbello, G.

    2017-05-01

    Electron cyclotron resonance ion sources (ECRIS) are widely used plasma based machines for the production of intense ion beams in science and industry. The performance of modern devices is limited by the presence of the density cut-off, above which electromagnetic (EM) waves sustaining the plasma are reflected. We hereby discuss the systematic data analysis of electrostatic wave generation in an ECR prototype operating at 3.75 GHz-0.1 THz. In particular, electron Bernstein waves (EBW) have been excited. EBW have already been generated in large-scale plasma devices for thermonuclear fusion purposes. In ion sources where L c ˜ λ RF (L c being the plasma chamber size and λ RF the pumping wave wavelength) the EM field assumes a modal behaviour; thus both plasma and EM field self-organize so that no optical-like wave launching is possible (i.e. the cavity effect dominates on the optical path). The collected data, however, supported by 3D full-wave simulations, actually demonstrate that a Budden-type X-B conversion scenario can be established above some critical RF power thresholds, operating in an off-ECR regime. The generation and absorption of the EBW has been demonstrated by the presence of three peculiar signatures: along with the establishment of an overdense plasma, generation of supra-thermal electrons and modification (non-linear broadening) of the EM spectrum measured within the plasma have been observed. At the threshold establishing such a heating regime, the collected data provide evidence for a fast rotation of the electron fluid.

  15. Foil-less plasma-filled diode for HPM generator

    NASA Astrophysics Data System (ADS)

    Eltchaninov, A. A.; Kovalchuk, B. M.; Kurkan, I. K.; Zherlitsyn, A. A.

    2014-11-01

    Plasma-filled diode regarded as perspective source of electron beam feeding HPM generator of GW power level, comparing to conventional explosive emission vacuum diode. Electron beam generation occurs in plasma double layer, where plasma boundary plays as an anode. It allows cancelling the usage of anode foils or grids in HPM generators with the virtual cathode, which could limit its life time to few shots. The presence of ions in the e-beam drift space could raise the limiting current for a drift space, but it could affect to microwave generation also. Sectioned plasma-filled diode with beam current of about 100 kA, electron beam energy of about 0.5 MV and beam current density of 1-10 kA/cm2 was realized. Cylindrical transport channel with the diameter of 200 mm and the length of about 30 cm was attached to the diode. Beam current measurements in a drift space were performed. Computer simulations of electron beam transport with the presence of ions were carried out with the 2.5D axisymmetric version of PiC-code KARAT. Obtained results would help optimizing electrodynamic system of HPM generator subjected to the presence of ions.

  16. Clustered gases as a medium for efficient plasma waveguide generation.

    PubMed

    Milchberg, H M; Kim, K Y; Kumarappan, V; Layer, B D; Sheng, H

    2006-03-15

    Clustered gas jets are shown to be an efficient means for plasma waveguide generation, for both femtosecond and picosecond generation pulses. These waveguides enable significantly lower on-axis plasma density (less than 10(18) cm(-3)) than in conventional hydrodynamic plasma waveguides generated in unclustered gases. Using femtosecond pump pulses, self-guided propagation and strong absorption (more than 70%) are used to produce long centimetre scale channels in an argon cluster jet, and a subsequent intense pulse is coupled into the guide with 50% efficiency and guided at above 10(17)W cm(-2) intensity over 40 Rayleigh lengths. We also demonstrate efficient generation of waveguides using 100 ps axicon-generated Bessel-beam pump pulses. Despite the expected sub-picosecond cluster disassembly time, we observe long pulse absorption efficiencies up to a maximum of 35%. Simulations show that in the far leading edge of the long laser pulse, the volume of heated clusters evolves to a locally uniform and cool plasma already near ionization saturation, which is then efficiently heated by the remainder of the pulse.

  17. Analysis of plasmas generated by fission fragments. [nuclear pumped lasers and helium plasma

    NASA Technical Reports Server (NTRS)

    Deese, J. E.; Hassan, H. A.

    1977-01-01

    A kinetic model is developed for a plasma generated by fission fragments and the results are employed to study helium plasma generated in a tube coated with fissionable material. Because both the heavy particles and electrons play important roles in creating the plasma, their effects are considered simultaneously. The calculations are carried out for a range of neutron fluxes and pressures. In general, the predictions of the theory are in good agreement with available intensity measurements. Moreover, the theory predicts the experimentally measured inversions. However, the calculated gain coefficients are such that lasing is not expected to take place in a helium plasma generated by fission fragments. The effects of an externally applied electric field are also considered.

  18. How Na+ Activates Thrombin – A Review of the Functional and Structural Data

    PubMed Central

    Huntington, James A.

    2009-01-01

    Thrombin is often referred to as the ultimate blood coagulation protease. This is true in both senses: it is the final protease generated in the series of proteolytic events known as the blood coagulation cascade, and it is the effector of clot formation, cleaving over twelve different substrates and interacting with at least six cofactors. Regulation of thrombin activity is thus of great relevance to determining the correct haemostatic balance, with dysregulation leading to bleeding or thrombosis. One of the most enigmatic and controversial regulators of thrombin activity is the monovalent cation Na+. When bound to Na+, thrombin adopts a ‘fast’ conformation which cleaves all procoagulant substrates more rapidly, and when free of Na+, thrombin reverts to a ‘slow’ state which preferentially activates the protein C anticoagulant pathway. Thus, Na+ binding allosterically modulates the activity of thrombin and helps determine the haemostatic balance. Over the last 30 years there has been a great deal of research into the structural basis of thrombin allostery. Biochemical and mutagenesis studies established which regions and residues are involved in the slow→fast conformational change, and recently several crystal structures of the putative slow form have been solved. In this article I review the biochemical and crystallographic data to see if we are any closer to understanding the conformational basis of the Na+ activation of thrombin. PMID:18979627

  19. Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets

    PubMed Central

    Corona de la Peña, Norma; Gutiérrez-Aguilar, Manuel; Hernández-Reséndiz, Ileana; Marín-Hernández, Álvaro

    2017-01-01

    Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway i.e., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3–38 times vs. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation. PMID:28817667

  20. Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets.

    PubMed

    Corona de la Peña, Norma; Gutiérrez-Aguilar, Manuel; Hernández-Reséndiz, Ileana; Marín-Hernández, Álvaro; Rodríguez-Enríquez, Sara

    2017-01-01

    Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway i.e., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3-38 times vs. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation.

  1. Thrombin Induces Inositol Trisphosphate-Mediated Spatially Extensive Responses in Lung Microvessels.

    PubMed

    Escue, Rachel; Kandasamy, Kathirvel; Parthasarathi, Kaushik

    2017-04-01

    Activation of plasma membrane receptors initiates compartmentalized second messenger signaling. Whether this compartmentalization facilitates the preferential intercellular diffusion of specific second messengers is unclear. Toward this, the receptor-mediated agonist, thrombin, was instilled into microvessels in a restricted region of isolated blood-perfused mouse lungs. Subsequently, the thrombin-induced increase in endothelial F-actin was determined using confocal fluorescence microscopy. Increased F-actin was evident in microvessels directly treated with thrombin and in those located in adjoining thrombin-free regions. This increase was abrogated by inhibiting inositol trisphosphate-mediated calcium release with Xestospongin C (XeC). XeC also inhibited the thrombin-induced increase in the amplitude of endothelial cytosolic Ca(2+) oscillations. Instillation of thrombin and XeC into adjacent restricted regions increased F-actin in microvessels in the thrombin-treated and adjacent regions but not in those in the XeC-treated region. Thus, inositol trisphosphate, and not calcium, diffused interendothelially to the spatially remote thrombin-free microvessels. Thus, activation of plasma membrane receptors increased the ambit of inflammatory responses via a second messenger different from that used by stimuli that induce cell-wide increases in second messengers. Thrombin however failed to induce the spatially extensive response in microvessels of mice lacking endothelial connexin43, suggesting a role for connexin43 gap junctions. Compartmental second messenger signaling and interendothelial communication define the specific second messenger involved in exacerbating proinflammatory responses to receptor-mediated agonists.

  2. Thrombin stimulates mitogenesis in pig cerebrovascular smooth muscle cells involving activation of pro-matrix metalloproteinase-2.

    PubMed

    Wang, Zhongbiao; Kong, Lingwei; Kang, Jing; Morgan, Joe H; Shillcutt, Samuel D; Robinson, Joe S; Nakayama, Don K

    2009-02-27

    Generation of thrombin is associated with vascular remodeling that involves proliferation of vascular smooth muscle cells (SMCs) and activation of pro-matrix metalloproteinases (pro-MMPs). The present study was to investigate whether thrombin would induce mitogenesis and activation of pro-MMPs in cerebrovascular SMCs (CSMCs), and if so, whether MMP activity would contribute to the CSMC mitogenesis. CSMCs were cultured from pig middle cerebral arteries and stimulated with thrombin. Thrombin (0.1-5U/ml), in a dose-dependent fashion, stimulated mitogenesis in CSMCs as detected by bromo-2'-deoxy-uridine (BrdU) incorporation. Additionally, zymographic analyses showed that thrombin stimulated the appearance of the active form of MMP-2 (MMP-2) in a concentration-dependent manner, but not the release of pro-MMP-2. Thrombin did not affect expression of cell-associated pro-MMP-2 protein as evaluated by Western blot analysis. Treatment with the synthetic MMP inhibitor GM6001 or antibodies to MMP-2 significantly reduced thrombin-induced BrdU incorporation in CSMCs. In conclusion, thrombin activates pro-MMP-2 in the absence of elevated pro-MMP-2 expression and secretion in CSMCs, and thrombin induces CSMC mitogenesis involving its action on MMP-2. These findings suggest that thrombin may have relevance in cerebrovascular remodeling associated with brain atherosclerosis and atherothrombotic ischemic stroke through a mechanism involving MMP-dependent CSMC mitogenesis.

  3. Targeting thrombin: an inflammatory neurotoxin in Alzheimer's disease.

    PubMed

    Grammas, Paula; Martinez, Joseph M

    2014-01-01

    The Alzheimer's disease (AD) epidemic proceeds unabated. Estimates suggest 5.4 million Americans and 36 million people worldwide have AD. No single mechanism or pathologic mediator can account for AD progression. Currently no disease modifying therapies are available. There is a large literature documenting an association among cardiovascular risk factors (CVRFs), especially diabetes and hypoxia, with increased AD incidence. CVRFs directly impair vascular function and could mediate cerebrovascular dysfunction in AD. This is important as cerebrovascular dysfunction precedes cognitive decline and onset of neurodegenerative changes in AD and AD animal models. In this review we present evidence that thrombin may be a heretofore unexplored target for AD therapy. This idea is based on the following observations. Thrombin is elevated in the brain and cerebral microvasculature in AD, is directly neurotoxic, and causes pro-inflammatory effects in endothelial cells, microglia, and astrocytes. Diabetes- and hypoxia-induced cerebrovascular effects are mediated by thrombin. Thrombin inhibitors block the effects of hypoxia on brain endothelial cells and reduce vascular inflammation in transgenic AD mice. Based on reports that reducing cerebrovascular expression of inflammatory proteins in AD mice is associated with improved cognition, we propose thrombin inhibitors could prove useful for improving cognition in AD patients. The next generation of AD therapeutics should not focus on single target drugs but rather employ a multi-component cocktail approach. We propose thrombin inhibitors be considered as potential contributors to the dementia therapy pharmacopeia. The urgent need for disease-modifying drugs in AD demands new thinking about disease pathogenesis and exploration of novel drug targets.

  4. Generation of radiation by intense plasma and electromagnetic undulators

    SciTech Connect

    Joshi, C.

    1991-10-01

    We examine the characteristics of the classical radiation emission resulting from the interaction of a relativistic electron beam that propagates perpendicularly through a large amplitude relativistic plasma wave. Such a study is useful for evaluating the feasibility of using relativistic plasma waves as extremely short wavelength undulators for generating short wavelength radiation. The electron trajectories in a plasma wave undulator and in an ac FEL undulator are obtained using perturbation techniques. The spontaneous radiation frequency spectrum and angular distribution emitted by a single electron oscillating in these two undulators are then calculated. The radiation gain of a copropagating electromagnetic wave is calculated. The approximate analytic results for the trajectories, spontaneous radiation and gain are compared with 3-D simulation results. The characteristics of the plasma wave undulator are compared with the ac FEL undulator and linearly polarized magnetic undulator. 50 refs., 26 figs., 3 tabs.

  5. Opacity measurements in shock-generated argon plasmas

    SciTech Connect

    Erskine, D.

    1993-07-01

    Dense plasmas having uniform and constant density and temperature are generated by passage of a planar shock wave through gas. The opacity of the plasma is accurately measured versus wavelength by recording the risetime of emitted light. This technique is applicable to a wide variety of species and plasma conditions. Initial experiments in argon have produced plasmas with 2 eV temperatures, 0.004--0.04 g/cm{sup 3} densities, and coupling parameters {Gamma} {approximately}0.3--0.7. Measurements in visible light are compared with calculations using the HOPE code. An interesting peak in the capacity at 400 nm is observed for the first time and is identified with the 4s-5p transition in excited neutral argon atoms.

  6. Development of rf plasma generators for neutral beams

    SciTech Connect

    Vella, M.C.; Ehlers, K.W.; Kippenhan, D.; Pincosy, P.A.; Pyle, R.V.; DiVergilio, W.F.; Fosnight, V.V.

    1984-10-01

    The development of low frequency (1-2 MHz) rf plasma generators for high power neutral beam applications is summarized. Immersed couplers from one to three turns were used. Acceptable plasma profiles, less than or equal to 15% max/min, were obtained in a variety of field-free magnetic bucket and magnetic filter-bucket sources, with 10 x 10 cm or 10 x 40 cm extraction areas. Hydrogen beam properties were measured with a 7 x 10 cm accelerator operated at 80 kV. Atomic fraction and power efficiency were at least as high as with arc plasmas in similar chambers. The potential advantages of an rf plasma source are: ease of operation; reliability; and extended service lifetime.

  7. Secondary electron emission from plasma-generated nanostructured tungsten fuzz

    DOE PAGES

    Patino, M.; Raitses, Y.; Wirz, R.

    2016-11-14

    Recently, several researchers (e.g., Q. Yang, Y.-W. You, L. Liu, H. Fan, W. Ni, D. Liu, C. S. Liu, G. Benstetter, and Y. Wang, Scientific Reports 5, 10959 (2015)) have shown that tungsten fuzz can grow on a hot tungsten surface under bombardment by energetic helium ions in different plasma discharges and applications, including magnetic fusion devices with plasma facing tungsten components. This work reports direct measurements of the total effective secondary electron emission (SEE) from tungsten fuzz. Using dedicated material surface diagnostics and in-situ characterization, we find two important results: (1) SEE values for tungsten fuzz are 40-63% lowermore » than for smooth tungsten and (2) the SEE values for tungsten fuzz are independent of the angle of the incident electron. The reduction in SEE from tungsten fuzz is most pronounced at high incident angles, which has important implications for many plasma devices since in a negative-going sheath the potential structure leads to relatively high incident angles for the electrons at the plasma confining walls. Overall, low SEE will create a relatively higher sheath potential difference that reduces plasma electron energy loss to the confining wall. Thus the presence or self-generation in a plasma of a low SEE surface such as tungsten fuzz can be desirable for improved performance of many plasma devices.:7px« less

  8. Preliminary characterization of a laser-generated plasma sheet

    DOE PAGES

    Keiter, P. A.; Malamud, G.; Trantham, M.; ...

    2014-12-10

    We present the results from recent experiments to create a flowing plasma sheet. Two groups of three laser beams with nominally 1.5 kJ of energy per group were focused to separate pointing locations, driving a shock into a wedge target. As the shock breaks out of the wedge, the plasma is focused on center, creating a sheet of plasma. Measurements at 60 ns indicate the plasma sheet has propagated 2825 microns with an average velocity of 49 microns/ns. These experiments follow previous experiments, which are aimed at studying similar physics as that found in the hot spot region of cataclysmicmore » variables. Krauland et al created a flowing plasma, which represents the flowing plasma from the secondary star. This flow interacted with a stationary object, which represented the disk around the white dwarf. A reverse shock is a shock formed when a freely expanding plasma encounters an obstacle. Reverse shocks can be generated by a blast wave propagating through a medium. As a result, they can also be found in binary star systems where the flowing gas from a companion star interacts with the accretion disk of the primary star.« less

  9. Secondary electron emission from plasma-generated nanostructured tungsten fuzz

    NASA Astrophysics Data System (ADS)

    Patino, M.; Raitses, Y.; Wirz, R.

    2016-11-01

    Recently, several researchers [e.g., Yang et al., Sci. Rep. 5, 10959 (2015)] have shown that tungsten fuzz can grow on a hot tungsten surface under bombardment by energetic helium ions in different plasma discharges and applications, including magnetic fusion devices with plasma facing tungsten components. This work reports the direct measurements of the total effective secondary electron emission (SEE) from tungsten fuzz. Using dedicated material surface diagnostics and in-situ characterization, we find two important results: (1) SEE values for tungsten fuzz are 40%-63% lower than for smooth tungsten and (2) the SEE values for tungsten fuzz are independent of the angle of the incident electron. The reduction in SEE from tungsten fuzz is most pronounced at high incident angles, which has important implications for many plasma devices since in a negative-going sheath the potential structure leads to relatively high incident angles for the electrons at the plasma confining walls. Overall, low SEE will create a relatively higher sheath potential difference that reduces plasma electron energy loss to the confining wall. Thus, the presence or self-generation in a plasma of a low SEE surface such as tungsten fuzz can be desirable for improved performance of many plasma devices.

  10. Secondary electron emission from plasma-generated nanostructured tungsten fuzz

    SciTech Connect

    Patino, M.; Raitses, Y.; Wirz, R.

    2016-11-14

    Recently, several researchers (e.g., Q. Yang, Y.-W. You, L. Liu, H. Fan, W. Ni, D. Liu, C. S. Liu, G. Benstetter, and Y. Wang, Scientific Reports 5, 10959 (2015)) have shown that tungsten fuzz can grow on a hot tungsten surface under bombardment by energetic helium ions in different plasma discharges and applications, including magnetic fusion devices with plasma facing tungsten components. This work reports direct measurements of the total effective secondary electron emission (SEE) from tungsten fuzz. Using dedicated material surface diagnostics and in-situ characterization, we find two important results: (1) SEE values for tungsten fuzz are 40-63% lower than for smooth tungsten and (2) the SEE values for tungsten fuzz are independent of the angle of the incident electron. The reduction in SEE from tungsten fuzz is most pronounced at high incident angles, which has important implications for many plasma devices since in a negative-going sheath the potential structure leads to relatively high incident angles for the electrons at the plasma confining walls. Overall, low SEE will create a relatively higher sheath potential difference that reduces plasma electron energy loss to the confining wall. Thus the presence or self-generation in a plasma of a low SEE surface such as tungsten fuzz can be desirable for improved performance of many plasma devices.:7px

  11. Preliminary characterization of a laser-generated plasma sheet

    SciTech Connect

    Keiter, P. A.; Malamud, G.; Trantham, M.; Fein, J.; Davis, J.; Klein, S. R.; Drake, R. P.

    2014-12-10

    We present the results from recent experiments to create a flowing plasma sheet. Two groups of three laser beams with nominally 1.5 kJ of energy per group were focused to separate pointing locations, driving a shock into a wedge target. As the shock breaks out of the wedge, the plasma is focused on center, creating a sheet of plasma. Measurements at 60 ns indicate the plasma sheet has propagated 2825 microns with an average velocity of 49 microns/ns. These experiments follow previous experiments, which are aimed at studying similar physics as that found in the hot spot region of cataclysmic variables. Krauland et al created a flowing plasma, which represents the flowing plasma from the secondary star. This flow interacted with a stationary object, which represented the disk around the white dwarf. A reverse shock is a shock formed when a freely expanding plasma encounters an obstacle. Reverse shocks can be generated by a blast wave propagating through a medium. As a result, they can also be found in binary star systems where the flowing gas from a companion star interacts with the accretion disk of the primary star.

  12. Generation of nano roughness on fibrous materials by atmospheric plasma

    NASA Astrophysics Data System (ADS)

    Kulyk, I.; Scapinello, M.; Stefan, M.

    2012-12-01

    Atmospheric plasma technology finds novel applications in textile industry. It eliminates the usage of water and of hazard liquid chemicals, making production much more eco-friendly and economically convenient. Due to chemical effects of atmospheric plasma, it permits to optimize dyeing and laminating affinity of fabrics, as well as anti-microbial treatments. Other important applications such as increase of mechanical resistance of fiber sleeves and of yarns, anti-pilling properties of fabrics and anti-shrinking property of wool fabrics were studied in this work. These results could be attributed to the generation of nano roughness on fibers surface by atmospheric plasma. Nano roughness generation is extensively studied at different conditions. Alternative explanations for the important practical results on textile materials and discussed.

  13. Design and fabrication of a 30 second pulsed plasma generator

    SciTech Connect

    Biagi, L.A.; Ehlers, K.W.; Lietzke, A.F.; Matuk, C.A.; Maruyama, Y.; Paterson, J.A.; Tanabe, J.T.

    1983-10-01

    The design and fabrication techniques for a large hybrid magnetic cusp plasma generator developed for 30 sec pulse length are described. Included are the magnetic cusp geometry features, water cooling characteristics, filament structures, and the high energy density actively cooled anode and electron dump employed.

  14. Use of Plasma Actuators as a Moving-Wake Generator

    NASA Technical Reports Server (NTRS)

    Corke, Thomas C.; Thomas, Flint O.; Klapetzky Michael J.

    2007-01-01

    The work documented in this report tests the concept of using plasma actuators as a simple and easy way to generate a simulated moving-wake and the disturbances associated with it in turbines. This wake is caused by the blades of the upstream stages of the turbine. Two types of devices, one constructed of arrays of NACA 0018 airfoils, and the one constructed of flat plates were studied. The airfoils or plates were equipped with surface mounted dielectric barrier discharge (DBD) plasma actuators, which were used to generate flow disturbances resembling moving-wakes. CTA hot-wire anemometry and flow visualization using a smoke-wire were used to investigate the wake independence at various spacings and downstream locations. The flat plates were found to produce better results than the airfoils in creating large velocity fluctuations in the free-stream flow. Different dielectric materials, plasma actuator locations, leading edge contours, angles of attack and plate spacings were investigated, some with positive results. The magnitudes of the velocity fluctuations were found to be comparable to existing mechanical moving-wake generators, thus proving the feasibility of using plasma actuators as a moving-wake generator.

  15. Air spark-like plasma source for antimicrobial NOx generation

    NASA Astrophysics Data System (ADS)

    Pavlovich, M. J.; Ono, T.; Galleher, C.; Curtis, B.; Clark, D. S.; Machala, Z.; Graves, D. B.

    2014-12-01

    We demonstrate and analyse the generation of nitrogen oxides and their antimicrobial efficacy using atmospheric air spark-like plasmas. Spark-like discharges in air in a 1 L confined volume are shown to generate NOx at an initial rate of about 1.5  ×  1016 NOx molecules/J dissipated in the plasma. Such a discharge operating in this confined volume generates on the order of 6000 ppm NOx in 10 min. Around 90% of the NOx is in the form of NO2 after several minutes of operation in the confined volume, suggesting that NO2 is the dominant antimicrobial component. The strong antimicrobial action of the NOx mixture after several minutes of plasma operation is demonstrated by measuring rates of E. coli disinfection on surfaces and in water exposed to the NOx mixture. Some possible applications of plasma generation of NOx (perhaps followed by dissolution in water) include disinfection of surfaces, skin or wound antisepsis, and sterilization of medical instruments at or near room temperature.

  16. Intense ion beam generation, plasma radiation source and plasma opening switch research

    NASA Astrophysics Data System (ADS)

    Hammer, D. A.; Coleman, M. D.; Qi, N.; Similon, P. L.; Sudan, R. N.

    1989-04-01

    This report describes research on intense ion beam diodes, plasma opening switches and dense z-pinch plasma radiators. Laser induced fluorescence spectroscopy has been used to map the electrostatic potential profile in a plasma-prefilled magnetically insulated ion diode. In a simple planar diode, the measured profile is inconsistent with the electrons being confined in a sheath near the cathode by the magnetic field. Rather, the profile implies the presence of electrons throughout the accelerating gap. A theoretical model of the penetration of current and magnetic field into a plasma, and of the current-driven effective collision frequency has been developed. The snowplow action of the rising magnetic field causes a steep rise in the plasma density at the leading edge. The subsequent multistreaming of the ions caused by ion reflection at the current layer could lead to ion heating through collective effects. The two-dimensional electron flow in the plasma cathode vacuum gap is also treated. Dense z-pinch plasma radiation source experiments have been initiated on the LION accelerator using gas puff and fine wire loads. The x-pinch was found to be a more effective way to generate soft x-rays than a single wire pinch or a gas puff implosion. Plasma opening switch experiments being initiated, and plasma anode ion diode development work being terminated are also briefly described.

  17. Generation of filamentary structures by beam-plasma interaction

    SciTech Connect

    Wang, X.Y.; Lin, Y.

    2006-05-15

    The previous simulations by Wang and Lin [Phys. Plasmas. 10, 3528 (2003)] showed that filaments, frequently observed in space plasmas, can form via the interaction between an ion beam and a background plasma. In this study, the physical mechanism for the generation of the filaments is investigated by a two-dimensional hybrid simulation, in which a field-aligned ion beam with relative beam density n{sub b}=0.1 and beam velocity V{sub b}=10V{sub A} is initiated in a uniform plasma. Right-hand nonresonant ion beam modes, consistent with the linear theory, are found to be dominant in the linear stage of the beam-plasma interaction. In the later nonlinear stage, the nonresonant modes decay and the resonant modes grow through a nonlinear wave coupling. The interaction among the resonant modes leads to the formation of filamentary structures, which are the field-aligned structures (k perpendicular B) of magnetic field B, density, and temperature in the final stage. The filaments are nonlinearly generated in a prey-predator fashion by the parallel and oblique resonant ion beam modes, which meanwhile evolve into two types of shear Alfven modes, with one mainly propagating along the background field B{sub 0} and the other obliquely propagating. The filamentary structures are found to be phase standing in the plasma frame, but their amplitude oscillates with time. In the dominant filament mode, fluctuations in the background ion density, background ion temperature, and beam density are in phase with the fluctuations in B, whereas the significantly enhanced beam temperature is antiphase with B. It is found that the filaments are produced by the interaction of at least two ion beam modes with comparable amplitudes, not by only one single mode, thus their generation mechanism is different from other mechanisms such as the stimulated excitation by the decay of an Alfven wave.

  18. Template-assisted generation of nanocavities within plasma polymer films.

    PubMed

    Vasilev, Krasimir; Casanal, Ana; Challougui, Hela; Griesser, Hans J

    2009-05-21

    The generation of nanosized cavities within thin film layers is of interest for a number of fundamental and applied reasons. One challenge is to make such systems sufficiently robust mechanically. Plasma polymer (pp) films possess excellent mechanical stability if deposition conditions are selected such as to achieve a sufficient density of cross-linking and resistance to extraction of polymeric material by solvents. In this study, gold nanoparticles of 15 and 70 nm diameter were used as sacrificial templates to generate nanocavities in pp films of various thickness values in the tens of nanometers range. A first pp layer was deposited onto substrates using n-heptylamine (HA) to a thickness of 20 nm. Carboxy-thiolated gold nanoparticles were electrostatically bound onto the surface amine groups of the n-heptylamine plasma polymer (HApp) layer. A second HApp layer was then coated to various thicknesses onto the nanoparticle/HApp surface. The template particles embedded thus in-between the two HApp layers were then dissolved using aqueous KCN solution; monitoring of the plasmon resonance band of the gold nanoparticles enabled verification of template stripping and measurement of the kinetics of stripping. AFM topography images showed little change on extraction of the template nanoparticles, indicating that the plasma polymer layer maintained structural integrity upon template extraction and subsequent drying, and thereby prevented collapse of the empty nanocavities. The concept of template stripping to generate controlled size free volume in thin plasma polymer layers is thus shown to produce robust structures.

  19. Syngas Generation from Organic Waste with Plasma Steam Reforming

    NASA Astrophysics Data System (ADS)

    Diaz, G.; Leal-Quiros, E.; Smith, R. A.; Elliott, J.; Unruh, D.

    2014-05-01

    A plasma steam reforming system to process waste is in the process of being set up at the University of California, Merced. The proposed concept will use two different plasma regimes, i.e. glow discharge and arc torches to process a percentage of the total liquid waste stream generated at the campus together with shredded local organic solid waste. One of the main advantages of the plasma technology to be utilized is that it uses graphite electrodes that can be fed to the reactor to achieve continuous operation, thus, electrode or nozzle life is not a concern. The waste to energy conversion process consists of two stages, one where a mixture of steam and hydrogen is generated from the liquid in a glow-discharge cell, and a second stage where the mixture of exhaust gases coming out of the first device are mixed with solid waste in a reactor operating in steam reforming mode interacting with a plasma torch to generate high-quality syngas. In this paper, the results of a thermodynamic model developed for the two stages are shown. The syngas composition obtained indicates that the fraction of CO2 present decreases with increasing temperature and the molar fractions of hydrogen and carbon monoxide become dominant. The fraction of water vapour present in the product gases coming out of the second stage needs to be condensed before the syngas can be utilized in a prime mover.

  20. Dynamics and interactions of pulsed laser generated plasma bubbles in dusty plasma liquids

    SciTech Connect

    Chu Hongyu; Liao Chenting; I Lin

    2005-10-31

    The plasma bubble with dust particle depletion can be generated by a nano-second laser pulse focused on one of the dust particles suspended in a strongly coupled dusty plasma liquid. The bubble dynamics at different time scales, including the initial forming and later traveling stages are investigated. In the first stage, dust particles are pushed outward by the outward ion flow associated with the plume generated by the more intensed plasma. The bubble then travels downward at a speed about 60 mm/s associated with a surrounding dipole-like dust flow field. Two bubbles can also be simultaneously generated at different locations by separated laser pulses to study their interactions. Strong coupling is observed between two vertical bubbles. However, two horizontal bubbles are weakly coupled. The possible mechanism is discussed.

  1. A novel, all-dielectric, microwave plasma generator towards development of plasma metamaterials

    NASA Astrophysics Data System (ADS)

    Cohick, Zane; Luo, Wei; Perini, Steven; Baker, Amanda; Wolfe, Douglas; Lanagan, Michael

    2016-11-01

    A proof of concept for a microwave microplasma generator that consists of a halved dielectric resonator is presented. The generator functions via leaking electric fields of the resonant modes — TE01δ and HEM12δ modes are explored. Computational results illustrate the electric fields, whereas the stability of resonance and coupling are studied experimentally. Finally, a working device is presented. This generator promises potentially wireless and low-loss operation. This device may find relevance in plasma metamaterials; each resonator may generate the plasma structures necessary to manipulate electromagnetic radiation. In particular, the all-dielectric nature of the generator will allow low-loss interaction with high-frequency (GHz-THz) waves.

  2. Voltage distribution over capacitively coupled plasma electrode for atmospheric-pressure plasma generation

    PubMed Central

    2013-01-01

    When capacitively coupled plasma (CCP) is used to generate large-area plasma, the standing wave effect becomes significant, which results in the hindering of the uniform plasma process such as in a plasma etcher or plasma chemical vapor deposition. In this study, the transmission line modeling method is applied to calculate the voltage distribution over atmospheric-pressure CCP electrodes with the size of 1 m × 0.2 m. The measured plasma impedance in our previous study was used in the present calculation. The results of the calculations clearly showed the effects of excitation frequency and the impedance of the plasma on the form of the voltage distribution caused by the standing wave effect. In the case of 150 MHz frequency, the standing wave effect causes a drastic change in the voltage distribution via plasma ignition; however, the change is small for 13.56 MHz. It was also clarified that the power application position is important for obtaining a uniform voltage distribution. PMID:23634893

  3. Voltage distribution over capacitively coupled plasma electrode for atmospheric-pressure plasma generation.

    PubMed

    Shuto, Mitsutoshi; Tomino, Fukumi; Ohmi, Hiromasa; Kakiuchi, Hiroaki; Yasutake, Kiyoshi

    2013-05-01

    When capacitively coupled plasma (CCP) is used to generate large-area plasma, the standing wave effect becomes significant, which results in the hindering of the uniform plasma process such as in a plasma etcher or plasma chemical vapor deposition. In this study, the transmission line modeling method is applied to calculate the voltage distribution over atmospheric-pressure CCP electrodes with the size of 1 m × 0.2 m. The measured plasma impedance in our previous study was used in the present calculation. The results of the calculations clearly showed the effects of excitation frequency and the impedance of the plasma on the form of the voltage distribution caused by the standing wave effect. In the case of 150 MHz frequency, the standing wave effect causes a drastic change in the voltage distribution via plasma ignition; however, the change is small for 13.56 MHz. It was also clarified that the power application position is important for obtaining a uniform voltage distribution.

  4. Thrombin and exercise similarly influence expression of cell cycle genes in cultured putative endothelial progenitor cells.

    PubMed

    Lockard, Michael M; Witkowski, Sarah; Jenkins, Nathan T; Spangenburg, Espen E; Obisesan, Thomas O; Hagberg, James M

    2010-06-01

    Acute exercise and exercise training may influence putative endothelial progenitor cell (EPC) number and colony forming units (CFU-ECs), although the mechanisms remain unclear. This study examined the effects of in vitro thrombin supplementation and acute exercise on CFU-EC gene expression, associated with cellular proliferation and differentiation. The effect of habitual physical activity was evaluated through analysis of EPCs from chronically high- and low-active men. Participants were healthy high- and low-active men (n=23), aged 55-80 yr. Circulating CD34+/VEGFR2+ number, CFU-ECs, plasma prothrombin fragment (F1+2), and thrombin-antithrombin III were measured at rest and after 30 min of exercise. Gene expression of cyclin A2, cyclin D1, p27, VE-cadherin, and VEGFR2 was assessed in postexercise CFU-ECs and resting CFU-ECs treated with 0, 1, 5, or 10 U/ml of thrombin. Outcomes were compared between high- and low-active participants. F1+2 and thrombin-antithrombin III, but not CD34+/VEGFR2+ number and CFU-ECs, increased with exercise. Exercise-induced changes in F1+2 correlated with changes in CD34+/VEGFR2+ number in both groups. Thrombin treatments and acute exercise increased cyclin A2 and cyclin D1 expression and decreased p27 expression. One unit per milliliter thrombin increased VEGFR2 and VE-cadherin expression, whereas 5 U/ml, 10 U/ml, and acute exercise did not elicit any changes. An exercise training effect was observed with greater decreases in p27 expression with 5 and 10 U/ml thrombin and greater increases in VEGFR2 and VE-cadherin expression with 1 U/ml thrombin in high-active men. Exercise-induced changes in putative EPC gene expression are associated with thrombin production and may be modulated by long-term exercise training.

  5. Thrombin and exercise similarly influence expression of cell cycle genes in cultured putative endothelial progenitor cells

    PubMed Central

    Lockard, Michael M.; Witkowski, Sarah; Jenkins, Nathan T.; Spangenburg, Espen E.; Obisesan, Thomas O.

    2010-01-01

    Acute exercise and exercise training may influence putative endothelial progenitor cell (EPC) number and colony forming units (CFU-ECs), although the mechanisms remain unclear. This study examined the effects of in vitro thrombin supplementation and acute exercise on CFU-EC gene expression, associated with cellular proliferation and differentiation. The effect of habitual physical activity was evaluated through analysis of EPCs from chronically high- and low-active men. Participants were healthy high- and low-active men (n = 23), aged 55–80 yr. Circulating CD34+/VEGFR2+ number, CFU-ECs, plasma prothrombin fragment (F1+2), and thrombin-antithrombin III were measured at rest and after 30 min of exercise. Gene expression of cyclin A2, cyclin D1, p27, VE-cadherin, and VEGFR2 was assessed in postexercise CFU-ECs and resting CFU-ECs treated with 0, 1, 5, or 10 U/ml of thrombin. Outcomes were compared between high- and low-active participants. F1+2 and thrombin-antithrombin III, but not CD34+/VEGFR2+ number and CFU-ECs, increased with exercise. Exercise-induced changes in F1+2 correlated with changes in CD34+/VEGFR2+ number in both groups. Thrombin treatments and acute exercise increased cyclin A2 and cyclin D1 expression and decreased p27 expression. One unit per milliliter thrombin increased VEGFR2 and VE-cadherin expression, whereas 5 U/ml, 10 U/ml, and acute exercise did not elicit any changes. An exercise training effect was observed with greater decreases in p27 expression with 5 and 10 U/ml thrombin and greater increases in VEGFR2 and VE-cadherin expression with 1 U/ml thrombin in high-active men. Exercise-induced changes in putative EPC gene expression are associated with thrombin production and may be modulated by long-term exercise training. PMID:20378705

  6. Thrombostatin FM compounds: direct thrombin inhibitors - mechanism of action in vitro and in vivo

    SciTech Connect

    Nieman, M T; Burke, F; Warnock, M; Zhou, Y; Sweigart, J; Chen, A; Ricketts, D; Lucchesi, B R; Chen, Z; Cera, E Di; Hilfinger, J; Kim, J S; Mosberg, H I; Schmaier, A H

    2008-04-29

    Novel pentapeptides called Thrombostatin FM compounds consisting mostly of D-isomers and unusual amino acids were prepared based upon the stable angiotensin converting enzyme breakdown product of bradykinin - RPPGF. These peptides are direct thrombin inhibitors prolonging the thrombin clotting time, activated partial thromboplastin time, and prothrombin time at ≥0.78, 1.6, and 1.6 μm, respectively. They competitively inhibit α-thrombin-induced cleavage of a chromogenic substrate at 4.4--8.2 μm. They do not significantly inhibit plasma kallikrein, factor (F) XIIa, FXIa, FIXa, FVIIa-TF, FXa, plasmin or cathepsin G. One form, FM19 [rOicPaF(p-Me)], blocks α-thrombin-induced calcium flux in fibroblasts with an IC50 of 6.9 ± 1.2 μm. FM19 achieved 100% inhibition of threshold α- or γ-thrombin-induced platelet aggregation at 8.4 ± 4.7 μm and 16 ± 4 μm, respectively. The crystal structure of thrombin in complex with FM19 shows that the N-terminal D-Arg retrobinds into the S1 pocket, its second residue Oic interacts with His-57, Tyr-60a and Trp-60d, and its C-terminal p-methyl Phe engages thrombin's aryl binding site composed of Ile-174, Trp-215, and Leu-99. When administered intraperitoneal, intraduodenal, or orally to mice, FM19 prolongs thrombin clotting times and delays carotid artery thrombosis. FM19, a low affinity reversible direct thrombin inhibitor, might be useful as an add-on agent to address an unmet need in platelet inhibition in acute coronary syndromes in diabetics and others who with all current antiplatelet therapy still have reactive platelets.

  7. Generation of pulsed discharge plasma in water with fine bubbles

    NASA Astrophysics Data System (ADS)

    Hayashi, Yui; Takada, Noriharu; Kanda, Hideki; Goto, Motonobu; Goto laboratory Team

    2015-09-01

    Recently, some researchers have proposed electric discharge methods with bubbles in water because the discharge plasma inside bubble was easy to be generated compared to that in water. Almost all of these methods introduced bubbles in the order of millimeter size from a nozzle placed in water. In these methods, bubbles rose one after another owing to high rising speed of millibubble, leading to inefficient gas consumption. We proposed fine bubbles introduction at the discharge area in water. A fine bubble is determined a bubble with less than 100 μm in a diameter. Fine bubbles exhibit extremely slow rising speed. Fine bubbles decrease in size during bubble rising and subsequently collapse in water with OH radical generation. Therefore, combining the discharge plasma with fine bubbles is expected to generate more active species with small amount of gas consumption. In this work, fine bubbles were introduced in water and pulsed discharge plasma was generated between two cylindrical electrodes which placed in water. We examined effects of fine bubbles on electric discharge in water when argon or oxygen gas was utilized as feed gas. Fine bubbles enhanced optical emission of hydrogen and oxygen atoms from H2O molecules, but that of feed gas was not observed. The formation mechanism of H2O2 by electric discharge was supposed to be different from that with no bubbling. Dissolved oxygen in water played a role in H2O2 formation by the discharge with fine bubbles.

  8. Zinc modulates thrombin adsorption to fibrin

    SciTech Connect

    Hopmeier, P.; Halbmayer, M.; Fischer, M.; Marx, G. )

    1990-05-01

    Human thrombin with high affinity to Sepharose insolubilized fibrin monomers (high-affinity thrombin) was used to investigate the effect of Zn(II) on the thrombin adsorption to fibrin. Results showed that at Zn(II) concentrations exceeding 100 mumols/l, thrombin binding to fibrin was decreased concomitant with the Zn(II) concentration and time; at lower Zn(II) concentrations, thrombin adsorption was enhanced. Experimental results were identical by using 125I-labelled high-affinity alpha-thrombin or by measuring the thrombin activity either by chromogenic substrate or by a clotting time method. In contrast, Ca(II) alone (final conc. 3 mmol/l) or in combination with Zn(II) was not effective. However, at higher Ca(II) concentrations (7.5-15 mmol/l), thrombin adsorption was apparently decreased. Control experiments revealed that Zn(II) had no impact on the clottability of fibrinogen, and that the results of the experiments with Ca(II) were not altered by possible cross-linking of fibrin. We conclude that unlike Ca(II), Zn(II) is highly effective in modulating thrombin adsorption to fibrin.

  9. Electric probe investigations of microwave generated, atmospheric pressure, plasma jets

    SciTech Connect

    Porteanu, H. E.; Kuehn, S.; Gesche, R.

    2010-07-15

    We examine the applicability of the Langmuir-type of characterization for atmospheric pressure plasma jets generated in a millimeter-size cavity microwave resonator at 2.45 GHz. Wide range I-V characteristics of helium, argon, nitrogen, air and oxygen are presented for different gas fluxes, distances probe-resonator, and microwave powers. A detailed analysis is performed for the fine variation in the current around the floating potential. A simplified theory specially developed for this case is presented, considering the ionic and electronic saturation currents and the floating potential. Based on this theory, we conclude that, while the charge carrier density depends on gas flow, distance to plasma source, and microwave absorbed power, the electron temperature is quite independent of these parameters. The resulting plasma parameters for helium, argon, and nitrogen are presented.

  10. Advanced targets, diagnostics and applications of laser-generated plasmas

    NASA Astrophysics Data System (ADS)

    Torrisi, L.

    2015-04-01

    High-intensity sub-nanosecond-pulsed lasers irradiating thin targets in vacuum permit generation of electrons and ion acceleration and high photon yield emission in non-equilibrium plasmas. At intensities higher than 1015 W/cm2 thin foils can be irradiated in the target-normal sheath acceleration regime driving ion acceleration in the forward direction above 1 MeV per charge state. The distributions of emitted ions in terms of energy, charge state and angular emission are controlled by laser parameters, irradiation conditions, target geometry and composition. Advanced targets can be employed to increase the laser absorption in thin foils and to enhance the energy and the yield of the ion acceleration process. Semiconductor detectors, Thomson parabola spectrometer and streak camera can be employed as online plasma diagnostics to monitor the plasma parameters, shot by shot. Some applications in the field of the multiple ion implantation, hadrontherapy and nuclear physics are reported.

  11. Beam-generated waves in a large plasma chamber

    NASA Technical Reports Server (NTRS)

    Kellogg, Paul J.; Monson, Steven J.; Holzworth, Robert H.; Jost, R. Jerry

    1986-01-01

    The beam plasma discharge (BPD) and pre-BPD states of plasma waves generated in a large vacuum chamber by an electron beam of energy 0.5-2 keV are measured, and three wave categories are found. The low-frequency waves are suggested to be surface waves on a nonneutral plasma column, with measured properties consistent with the lower hybrid drift instability. The whistler mode spectrum is thought to be a Cerenkov resonance with the lower Trivelpiece-Gould mode, and it may not play an important role in modifying the particle distributions. The high frequency spectrum is seen to be a Cerenkov resonance with the upper Trivelpiece-Gould mode, and it is responsible for the major perturbation of the BPD beam energy.

  12. Electromagnetic radiation generated by arcing in low density plasma

    NASA Technical Reports Server (NTRS)

    Vayner, Boris V.; Ferguson, Dale C.; Snyder, David B.; Doreswamy, C. V.

    1996-01-01

    An unavoidable step in the process of space exploration is to use high-power, very large spacecraft launched into Earth orbit. Obviously, the spacecraft will need powerful energy sources. Previous experience has shown that electrical discharges occur on the surfaces of a high-voltage array, and these discharges (arcs) are undesirable in many respects. Moreover, any high voltage conductor will interact with the surrounding plasma, and that interaction may result in electrical discharges between the conductor and plasma (or between two conductors with different potentials, for example, during docking and extravehicular activity). One very important aspect is the generation of electromagnetic radiation by arcing. To prevent the negative influence of electromagnetic noise on the operation of spacecraft systems, it seems necessary to determine the spectra and absolute levels of the radiation, and to determine limitations on the solar array bias voltage that depend on the parameters of LEO plasma and the technical requirements of the spacecraft equipment. This report describes the results of an experimental study and computer simulation of the electromagnetic radiation generated by arcing on spacecraft surfaces. A large set of high quality data was obtained during the Solar Array Module Plasma Interaction Experiment (SAMPIE, flight STS-62) and ground test. These data include the amplitudes of current, pulse forms, duration of each arc, and spectra of plasma waves. A theoretical explanation of the observed features is presented in this report too. The elaborated model allows us to determine the parameters of the electromagnetic noise for different frequency ranges, distances from the arcing site, and distinct kinds of plasma waves.

  13. Plasma-generated reactive oxygen species for biomedical applications

    NASA Astrophysics Data System (ADS)

    Sousa, J. S.; Hammer, M. U.; Winter, J.; Tresp, H.; Duennbier, M.; Iseni, S.; Martin, V.; Puech, V.; Weltmann, K. D.; Reuter, S.

    2012-10-01

    To get a better insight into the effects of reactive oxygen species (ROS) on cellular components, fundamental studies are essential to determine the nature and concentration of plasma-generated ROS, and the chemistry induced in biological liquids by those ROS. In this context, we have measured the absolute density of the main ROS created in three different atmospheric pressure plasma sources: two geometrically distinct RF-driven microplasma jets (μ-APPJ [1] and kinpen [2]), and an array of microcathode sustained discharges [3]. Optical diagnostics of the plasma volumes and effluent regions have been performed: UV absorption for O3 and IR emission for O2(a^1δ) [4]. High concentrations of both ROS have been obtained (10^14--10^17cm-3). The effect of different parameters, such as gas flows and mixtures and power coupled to the plasmas, has been studied. For plasma biomedicine, the determination of the reactive species present in plasma-treated liquids is of great importance. In this work, we focused on the measurement of the concentration of H2O2 and NOX radicals, generated in physiological solutions like NaCl and PBS.[4pt] [1] N. Knake et al., J. Phys. D: App. Phys. 41, 194006 (2008)[0pt] [2] K.D. Weltmann et al., Pure Appl. Chem. 82, 1223 (2010)[0pt] [3] J.S. Sousa et al., Appl. Phys. Lett. 97, 141502 (2010)[0pt] [4] J.S. Sousa et al., Appl. Phys. Lett. 93, 011502 (2008)

  14. Effects of argatroban, danaparoid, and fondaparinux on trombin generation in heparin-induced thrombocytopenia.

    PubMed

    Tardy-Poncet, Brigitte; Combe, Marion; Piot, Michèle; Chapelle, Céline; Akrour, Majid; Tardy, Bernard

    2013-03-01

    There is no in vitro data on the comparison of the effects of danaparoid, argatroban and fondaparinux on thrombin generation in patients with heparin-induced thrombocytopenia. It was the study objective to compare the in vitro anticoagulant potential of argatroban, danaparoid and fondaparinux using a thrombin generation assay TGA on a mixture of control platelet-rich plasma (PRP) and HIT patient platelet-poor plasma (PPP). The plasma of seven patients with a clear HIT diagnosed at our institution was selected. Mixtures of donor PRP and patient PPP were incubated with unfractionated heparin 0.2 U.mL⁻¹, argatroban at 600 ng.mL⁻¹, argatroban at 400 ng.mL⁻¹, danaparoid at 0.65 IU.mL⁻¹ and fondaparinux at 1 μg.mL⁻¹. Thrombin generation was assessed by calibrated thrombinography. The percentage of inhibition of the endogenous thrombin potential observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with fondaparinux (median: 53.6% vs. 3.9%; p=0.031) but not compared with argatroban at 400 ng.mL⁻¹ and danaparoid. The percentage of inhibition of the thrombin peak observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with danaparoid (median: 71.2 vs. 56.8; p=0.031) and fondaparinux (mean: 71.2 vs. 30; p=0.031) but not with argatroban at 400 ng.mL⁻¹. In conclusion, the in vitro effect of argatroban and danaparoid on thrombin generation seems to corroborate the results of clinical studies of these drugs in the treatment of HIT in term of efficiency. Fondaparinux showed a very small effect on thrombin generation evaluated by calibrated thrombinography.

  15. Fibrinogen γ' increases the sensitivity to activated protein C in normal and factor V Leiden plasma.

    PubMed

    Omarova, Farida; Uitte de Willige, Shirley; Simioni, Paolo; Ariëns, Robert A S; Bertina, Rogier M; Rosing, Jan; Castoldi, Elisabetta

    2014-08-28

    Activated protein C (APC) resistance, often associated with the factor V (FV) Leiden mutation, is the most common risk factor for venous thrombosis. We observed increased APC resistance in carriers of fibrinogen γ gene (FGG) haplotype 2, which is associated with reduced levels of the alternatively spliced fibrinogen γ' chain. This finding prompted us to study the effects of fibrinogen and its γ' chain on APC resistance. Fibrinogen, and particularly the γA/γ' isoform, improved the response of plasma to added APC in the thrombin generation-based assay. Similarly, a synthetic peptide mimicking the C-terminus of the fibrinogen γ' chain, which binds thrombin and inhibits its activities, greatly increased the APC sensitivity of normal and FV Leiden plasma, likely due to its ability to inhibit thrombin-mediated activation of FV and FVIII. Although the fibrinogen γ' peptide also inhibited protein C activation by the thrombin/thrombomodulin complex, it still increased the sensitivity of plasma to endogenously formed APC when thrombin generation was measured in the presence of soluble thrombomodulin. We conclude that fibrinogen, and particularly fibrinogen γ', increases plasma APC sensitivity. The fibrinogen γ' peptide might form the basis for pharmacologic interventions to counteract APC resistance. © 2014 by The American Society of Hematology.

  16. The Interaction of Explosively Generated Plasma with Explosives

    NASA Astrophysics Data System (ADS)

    Tasker, Douglas; LANL Team

    2015-06-01

    It has been shown that the temperature of explosively generated plasma (EGP) is of the order of 1 eV and plasma ejecta can be focused to achieve velocities as high as 25 km/s. These high velocity plasma can readily penetrate a wide range of materials including metals. Proof-of-principle tests were performed to determine if EGP could be used for explosive ordnance demolition and other applications. The test goals were: to benignly disable ordnance containing relatively sensitive high performance explosives (PBX-9501); and to investigate the possibility of interrupting an ongoing detonation in a powerful high explosive (again PBX-9501) with EGP. Experiments were performed to establish the optimum sizes of plasma generators for the benign deactivation of high explosives, i.e., the destruction of the ordnance without initiating a detonation or comparable violent event. These experiments were followed by attempts to interrupt an ongoing detonation by the destruction of the unreacted explosive in its path. The results were encouraging. First, it was demonstrated that high explosives could be destroyed without the initiation of a detonation or high order reaction. Second, ongoing detonations were successfully interrupted with EGP. LA-UR-15-20612.

  17. Status of the plasma generator of the superconducting proton linac

    SciTech Connect

    Kronberger, M.; Lettry, J.; Paoluzzi, M.; Pereira, H.; Arias, J. Sanchez; Schmitzer, C.; Scrivens, R.; Faircloth, D.

    2012-02-15

    In the framework of the superconducting proton linac (SPL) study at CERN, a new non-cesiated H{sup -} plasma generator driven by an external 2 MHz RF antenna has been developed and successfully operated at repetition rates of 50 Hz, pulse lengths of up to 3 ms, and average RF powers of up to 3 kW. The coupling efficiency of RF power into the plasma was determined by the cooling water temperatures and the analysis of the RF forward and reflected power and the antenna current and amounts to 50%-60%. The plasma resistance increases between 10 kW and 40 kW RF power from about 0.45 {Omega} to 0.65 {Omega}. Measurements of RF power dissipated in the ferrites and the magnets on a test bench show a 5-fold decrease of the power losses for the magnets when they are contained in a Cu box, thus validating the strategy of shielding the magnets with a high electrical conductivity material. An air cooling system was installed in the SPL plasma generator to control the temperatures of the ferrites despite hysteresis losses of several Watts.

  18. Mechanism for blob generation in the TORPEX toroidal plasma

    SciTech Connect

    Furno, I.; Labit, B.; Fasoli, A.; Poli, F. M.; Ricci, P.; Theiler, C.; Brunner, S.; Diallo, A.; Graves, J. P.; Podesta, M.; Mueller, S. H.

    2008-05-15

    The mechanism for blob generation is detailed in the toroidal magnetized plasma of the TORPEX device [Fasoli et al., Phys. Plasmas 13, 055902 (2006)] using an experimental configuration, which features a plasma region dominated by a coherent wave and a region on the low field side characterized by the propagation of blobs. Predictions from linearized 2D drift-reduced Braginskii equations are compared with experimental data, revealing the interchange nature of the coherent wave. The dynamics of blob formation is investigated using time-resolved measurements of two-dimensional profiles of electron density, temperature, plasma potential and ExB velocity. Blobs form from radially elongated structures associated with the interchange wave. When a blob is generated, the following sequence of events is observed: 1) A decrease of local pressure gradient length provides an increase of the interchange mode drive; 2) in response, the interchange mode increases in amplitude and expands in the radial direction forming a radially elongated structure from the wave crest; 3) the elongated structure is convected by the ExB flow and is eventually sheared off, forming a blob on the low field side. The dependence of the blob amplitude upon the minimum pressure radial scale length before the blob ejection is also investigated.

  19. Generation and Diagnostics of Microwave Discharge Expanding Nitrogen Plasma

    NASA Astrophysics Data System (ADS)

    Shibata, Tomohiko; Yoshida, Kazuyuki; Nezu, Atsushi; Matsuura, Haruaki; Akatsuka, Hiroshi

    2008-10-01

    We examine a microwave discharge expanding nitrogen plasma on its vibrational and rotational temperatures (Tv, Tr) by using optical emission spectroscopy (OES), and on its electron density and temperature by using a double probe. In the present study, we generated microwave discharge plasma in a cylindrical quartz tube (26 mm i.d.) and the plasma flowed and expanded rapidly into a rarefied gas wind tunnel with its pressure 2.6x10-3 torr. The microwave output power was set at 300 W. The gas flow rate was set at 300 ml/min. In OES measurement, we measured the band spectra of 1stPS and 2ndPS. We compare the experimentally measured spectrum with the calculate one to determine Tv and Tr of the generated plasma. Electron temperature did not reduce monotonically, which is due to complicated energy relaxation process contributed by metastables or vibrational levels. Intensity of 2ndPS decreased more rapidly than that of 1stPS, which is considered to be mainly due to the lowering of Te. We found different way of variation in Tv of 1stPS and that of 2ndPS.

  20. Method for generating a plasma wave to accelerate electrons

    DOEpatents

    Umstadter, Donald; Esarey, Eric; Kim, Joon K.

    1997-01-01

    The invention provides a method and apparatus for generating large amplitude nonlinear plasma waves, driven by an optimized train of independently adjustable, intense laser pulses. In the method, optimal pulse widths, interpulse spacing, and intensity profiles of each pulse are determined for each pulse in a series of pulses. A resonant region of the plasma wave phase space is found where the plasma wave is driven most efficiently by the laser pulses. The accelerator system of the invention comprises several parts: the laser system, with its pulse-shaping subsystem; the electron gun system, also called beam source, which preferably comprises photo cathode electron source and RF-LINAC accelerator; electron photo-cathode triggering system; the electron diagnostics; and the feedback system between the electron diagnostics and the laser system. The system also includes plasma source including vacuum chamber, magnetic lens, and magnetic field means. The laser system produces a train of pulses that has been optimized to maximize the axial electric field amplitude of the plasma wave, and thus the electron acceleration, using the method of the invention.

  1. Method for generating a plasma wave to accelerate electrons

    DOEpatents

    Umstadter, D.; Esarey, E.; Kim, J.K.

    1997-06-10

    The invention provides a method and apparatus for generating large amplitude nonlinear plasma waves, driven by an optimized train of independently adjustable, intense laser pulses. In the method, optimal pulse widths, interpulse spacing, and intensity profiles of each pulse are determined for each pulse in a series of pulses. A resonant region of the plasma wave phase space is found where the plasma wave is driven most efficiently by the laser pulses. The accelerator system of the invention comprises several parts: the laser system, with its pulse-shaping subsystem; the electron gun system, also called beam source, which preferably comprises photo cathode electron source and RF-LINAC accelerator; electron photo-cathode triggering system; the electron diagnostics; and the feedback system between the electron diagnostics and the laser system. The system also includes plasma source including vacuum chamber, magnetic lens, and magnetic field means. The laser system produces a train of pulses that has been optimized to maximize the axial electric field amplitude of the plasma wave, and thus the electron acceleration, using the method of the invention. 21 figs.

  2. Improved Magnetic Field Generation Efficiency and Higher Temperature Spheromak Plasmas

    SciTech Connect

    Wood, R D; Hill, D N; McLean, H S; Hooper, E B; Hudson, B F; Moller, J M; Romero-Talamas, C A

    2008-09-15

    New understanding of the mechanisms governing the observed magnetic field generation limits on the sustained spheromak physics experiment has been obtained. Extending the duration of magnetic helicity injection during the formation of a spheromak and optimizing the ratio of injected current to bias flux produce higher magnetic field plasmas with record spheromak electron temperatures. To explore magnetic field buildup efficiency limits, the confinement region geometry was varied resulting in improved field buildup efficiencies.

  3. Flowing dusty plasma experiments: generation of flow and measurement techniques

    NASA Astrophysics Data System (ADS)

    Jaiswal, S.; Bandyopadhyay, P.; Sen, A.

    2016-12-01

    A variety of experimental techniques for the generation of subsonic/supersonic dust fluid flows and means of measuring such flow velocities are presented. The experiments have been carried out in a \\Pi -shaped dusty plasma experimental device with micron size kaolin/melamine formaldehyde particles embedded in a background of argon plasma created by a direct current glow discharge. A stationary dust cloud is formed over the cathode region by precisely balancing the pumping speed and gas flow rate. A flow of dust particles/fluid is generated by additional gas injection from a single or dual locations or by altering the dust confining potential. The flow velocity is then estimated by three different techniques, namely, by super particle identification code, particle image velocimetry analysis and the excitation of dust acoustic waves. The results obtained from these three different techniques along with their merits and demerits are discussed. An estimation of the neutral drag force responsible for the generation as well as the attenuation of the dust fluid flow is made. These techniques can be usefully employed in laboratory devices to investigate linear and non-linear collective excitations in a flowing dusty plasma.

  4. Nonthermal Argon Plasma Generator and Some Potential Applications

    NASA Astrophysics Data System (ADS)

    Bunoiu, M.; Jugunaru, I.; Bica, I.; Balasoiu, M.

    2015-12-01

    A laboratory - made nonthermal plasma generator is presented. It has a diameter of 0.020 m and length of 0.155 m and contains two electrodes. The first electrode is a 2% Th-W alloy, 0.002 m in diameter bar, centred inside the generator's body by means of a four channel teflon piece; the other three channels, 0.003 m in diameter, are used for Ar supply. The second electrode is a nozzle of 0.002 m - 0.008 m diameter and 0.005m length. A ~500 kV/m electric field is generated between the two electrodes by a high frequency source (13.56 MHz ±5%), equipped with a OT-1000 (Tungsram) power triode. For Ar flows ranging from 0.00008 m3/s to 0.00056 m3/s, a plasma jet of length not exceeding 0.015 m and temperature below 315 K is obtained. Anthurium andraeanumis sample , blood matrix, human hair and textile fibers may be introduced in the plasma jet. For time periods of 30 s and 60 s, various effects like, cell detexturization, fast blood coagulation or textile fiber or hair cleaning and smoothing are obtained. These effects are presented and discussed in the paper.

  5. Determination of Plasma Screening Effects for Thermonuclear Reactions in Laser-generated Plasmas

    NASA Astrophysics Data System (ADS)

    Wu, Yuanbin; Pálffy, Adriana

    2017-03-01

    Due to screening effects, nuclear reactions in astrophysical plasmas may behave differently than in the laboratory. The possibility to determine the magnitude of these screening effects in colliding laser-generated plasmas is investigated theoretically, having as a starting point a proposed experimental setup with two laser beams at the Extreme Light Infrastructure facility. A laser pulse interacting with a solid target produces a plasma through the Target Normal Sheath Acceleration scheme, and this rapidly streaming plasma (ion flow) impacts a secondary plasma created by the interaction of a second laser pulse on a gas jet target. We model this scenario here and calculate the reaction events for the astrophysically relevant reaction 13C(4He, n)16O. We find that it should be experimentally possible to determine the plasma screening enhancement factor for fusion reactions by detecting the difference in reaction events between two scenarios of ion flow interacting with the plasma target and a simple gas target. This provides a way to evaluate nuclear reaction cross-sections in stellar environments and can significantly advance the field of nuclear astrophysics.

  6. STIM1 and Orai1 mediate thrombin-induced Ca(2+) influx in rat cortical astrocytes.

    PubMed

    Moreno, Claudia; Sampieri, Alicia; Vivas, Oscar; Peña-Segura, Claudia; Vaca, Luis

    2012-12-01

    In astrocytes, thrombin leads to cytoplasmic Ca(2+) elevations modulating a variety of cytoprotective and cytotoxic responses. Astrocytes respond to thrombin stimulation with a biphasic Ca(2+) increase generated by an interplay between ER-Ca(2+) release and store-operated Ca(2+) entry (SOCE). In many cell types, STIM1 and Orai1 have been demonstrated to be central components of SOCE. STIM1 senses the ER-Ca(2+) depletion and binds Orai1 to activate Ca(2+) influx. Here we used immunocytochemistry, overexpression and siRNA assays to investigate the role of STIM1 and Orai1 in the thrombin-induced Ca(2+) response in primary cultures of rat cortical astrocytes. We found that STIM1 and Orai1 are endogenously expressed in cortical astrocytes and distribute accordingly with other mammalian cells. Importantly, native and overexpressed STIM1 reorganized in puncta under thrombin stimulation and this reorganization was reversible. In addition, the overexpression of STIM1 and Orai1 increased by twofold the Ca(2+) influx evoked by thrombin, while knockdown of endogenous STIM1 and Orai1 significantly decreased this Ca(2+) influx. These results indicate that STIM1 and Orai1 underlie an important fraction of the Ca(2+) response that astrocytes exhibit in the presence of thrombin. Thrombin stimulation in astrocytes leads to ER-Ca(2+) release which causes STIM1 reorganization allowing the activation of Orai1 and the subsequent Ca(2+) influx.

  7. Thrombin-unique coagulation system protein with multifaceted impacts on cancer and metastasis.

    PubMed

    Wojtukiewicz, Marek Z; Hempel, Dominika; Sierko, Ewa; Tucker, Stephanie C; Honn, Kenneth V

    2016-06-01

    The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.

  8. Thrombin selectively induces transcription of genes in human monocytes involved in inflammation and wound healing.

    PubMed

    López, Mercedes L; Bruges, Gustavo; Crespo, Gustavo; Salazar, Victor; Deglesne, Pierre-Antoine; Schneider, Heike; Cabrera-Fuentes, Hector; Schmitz, M Lienhard; Preissner, Klaus T

    2014-11-01

    Thrombin is essential for blood coagulation but functions also as a mediator of cellular signalling. Gene expression microarray experiments in human monocytes revealed thrombin-induced upregulation of a limited subset of genes, which are almost exclusively involved in inflammation and wound healing. Among these, the expression of F3 gene encoding for tissue factor (TF) was enhanced indicating that this physiological initiator of coagulation cascade may create a feed-forward loop to enhance blood coagulation. Activation of protease-activated receptor type 1 (PAR1) was shown to play a main role in promoting TF expression. Moreover, thrombin induced phosphorylation of ERK1/2, an event that is required for expression of thrombin-regulated genes. Thrombin also increased the expression of TF at the protein level in monocytes as evidenced by Western blot and immunostaining. Furthermore, FXa generation induced by thrombin-stimulated monocytes was abolished by a TF blocking antibody and therefore it is entirely attributable to the expression of tissue factor. This cellular activity of thrombin provides a new molecular link between coagulation, inflammation and wound healing.

  9. Laser plasma simulations of the generation processes of Alfven and collisionless shock waves in space plasma

    NASA Astrophysics Data System (ADS)

    Prokopov, P. A.; Zakharov, Yu P.; Tishchenko, V. N.; Shaikhislamov, I. F.; Boyarintsev, E. L.; Melekhov, A. V.; Ponomarenko, A. G.; Posukh, V. G.; Terekhin, V. A.

    2016-11-01

    Generation of Alfven waves propagating along external magnetic field B0 and Collisionless Shock Waves propagating across B0 are studied in experiments with laser- produced plasma and magnetized background plasma. The collisionless interaction of interpenetrating plasma flows takes place through a so-called Magnetic Laminar Mechanism (MLM) or Larmor Coupling. At the edge of diamagnetic cavity LP-ions produce induction electric field Eφ which accelerates BP-ions while LP-ions rotate in opposite direction. The ions movement generates sheared azimuthal magnetic field Bφ which could launches torsional Alfven wave. In previous experiments at KI-1 large scale facility a generation of strong perturbations propagating across B0 with magnetosonic speed has been studied at a moderate value of interaction parameter δ∼0.3. In the present work we report on experiments at conditions of 5∼R2 and large Alfven-Mach number MA∼10 in which strong transverse perturbations traveling at a scale of ∼1 m in background plasma at a density of ∼3*1013 cm-3 is observed. At the same conditions but smaller MA ∼ 2 a generation, the structure and dynamic of Alfven wave with wavelength ∼0.5 m propagating along fields B0∼100÷500 G for a distance of ∼2.5 m is studied.

  10. Nonlinear currents generated in plasma by a radiation pulse with a frequency exceeding the electron plasma frequency

    SciTech Connect

    Grishkov, V. E.; Uryupin, S. A.

    2016-09-15

    It is shown that the nonlinear currents generated in plasma by a radiation pulse with a frequency exceeding the electron plasma frequency change substantially due to a reduction in the effective electron–ion collision frequency.

  11. A method to measure thrombin activity in a mixture of fibrinogen and thrombin powders

    PubMed Central

    DeAnglis, Ashley P.; Nur, Israel; Gorman, Anne J.; Meidler, Roberto

    2017-01-01

    Thrombin and fibrinogen powders are the active components of advanced surgical hemostasis products including the EVARREST Fibrin Sealant Patch. Measuring the enzymatic activity of thrombin in the presence of fibrinogen is challenging, as hydration of the powders in a neutral aqueous environment will cause the enzyme to rapidly react with the fibrinogen to form a fibrin clot, which in turn binds and entraps the enzyme thus preventing subsequent measurement of thrombin activity. A novel approach has been developed to overcome this challenge. After isolation of the mixture of powders, an alkaline carbonate solution is used to solubilize the proteins, while reversibly inhibiting the activity of thrombin and preventing clot formation. Once the powders have been fully solubilized, thrombin activity can be restored by neutralization in a buffered fibrinogen solution resulting in fibrin clot formulation. The rate of clot formation can be quantified in a coagulometer to determine the thrombin activity of the original powder. Samples coated with powders containing fibrinogen and varying amounts of thrombin were tested using the method described herein. The results demonstrated that the method could consistently measure the activity of (alpha) thrombin in the presence of fibrinogen over a broad range of thrombin activity levels. The test was successfully validated according to International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines and thus is suitable for use as part of a commercial manufacturing process. A method has been developed that enables thrombin activity to be measured in a mixture of fibrinogen and thrombin powders. PMID:26991860

  12. A method to measure thrombin activity in a mixture of fibrinogen and thrombin powders.

    PubMed

    DeAnglis, Ashley P; Nur, Israel; Gorman, Anne J; Meidler, Roberto

    2017-03-01

    Thrombin and fibrinogen powders are the active components of advanced surgical hemostasis products including the EVARREST Fibrin Sealant Patch. Measuring the enzymatic activity of thrombin in the presence of fibrinogen is challenging, as hydration of the powders in a neutral aqueous environment will cause the enzyme to rapidly react with the fibrinogen to form a fibrin clot, which in turn binds and entraps the enzyme thus preventing subsequent measurement of thrombin activity. A novel approach has been developed to overcome this challenge. After isolation of the mixture of powders, an alkaline carbonate solution is used to solubilize the proteins, while reversibly inhibiting the activity of thrombin and preventing clot formation. Once the powders have been fully solubilized, thrombin activity can be restored by neutralization in a buffered fibrinogen solution resulting in fibrin clot formulation. The rate of clot formation can be quantified in a coagulometer to determine the thrombin activity of the original powder. Samples coated with powders containing fibrinogen and varying amounts of thrombin were tested using the method described herein. The results demonstrated that the method could consistently measure the activity of (alpha) thrombin in the presence of fibrinogen over a broad range of thrombin activity levels. The test was successfully validated according to International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines and thus is suitable for use as part of a commercial manufacturing process. A method has been developed that enables thrombin activity to be measured in a mixture of fibrinogen and thrombin powders.

  13. Laser-plasma mirrors: from electron acceleration to harmonics generation

    NASA Astrophysics Data System (ADS)

    Thévenet, Maxence; Bocoum, Maïmouna; Faure, Jérôme; Leblanc, Adrien; Vincenti, Henri; Quéré, Fabien

    2016-10-01

    Accelerating electrons in the > 10 TV/m fields inside an ultrashort ultraintense laser pulse has been a long-standing goal in experimental physics, motivated by promising theoretical predictions. The biggest hurdle was to have electrons injected in the center of the laser pulse. Recent experimental and numerical results showed that this problem could be solved using a plasma mirror, i.e. an overdense plasma with a sharp (generation mechanisms on plasma mirrors, giving new insights into the motion of the plasma mirror surface. funded by the European Research Council, Contract No. 306708, ERC Starting Grant FEMTOELEC.

  14. Electron beam generated plasmas for the processing of graphene

    NASA Astrophysics Data System (ADS)

    Walton, S. G.; Hernández, S. C.; Boris, D. R.; Petrova, Tz B.; Petrov, G. M.

    2017-09-01

    The Naval Research Laboratory (NRL) has developed a processing system based on an electron beam-generated plasma and applied it to the processing of graphene. Unlike conventional discharges produced by electric fields (DC, RF, microwave, etc), the plasma is driven by a high-energy (~few keV) electron beam, an approach that simplifies the relative production of species while providing comparatively high ion-to-radical production rates. The resulting plasmas are characterized by high charged particle densities (1010-1011 cm-3) and electron temperatures that are typically about 1.0 eV or lower. Accordingly, the flux to adjacent surfaces is generally dominated by ions with kinetic energies in the range of 1-5 eV, a value at or near the bond strength of most materials. This provides the potential for controllably engineering materials with monolayer precision, an attribute attractive for the processing of atomically thin material systems. This work describes the attributes of electron beam driven plasma processing system and its use in modification of graphene.

  15. Aptamer Based Microsphere Biosensor for Thrombin Detection

    PubMed Central

    Zhu, Hongying; Suter, Jonathan D.; White, Ian M.; Fan, Xudong

    2006-01-01

    We have developed an optical microsphere resonator biosensor using aptamer as receptor for the measurement of the important biomolecule thrombin. The sphere surface is modified with anti-thrombin aptamer, which has excellent binding affinity and selectivity for thrombin. Binding of the thrombin at the sphere surface is monitored by the spectral position of the microsphere's whispering gallery mode resonances. A detection limit on the order of 1 NIH Unit/mL is demonstrated. Control experiments with non-aptamer oligonucleotide and BSA are also carried out to confirm the specific binding between aptamer and thrombin. We expect that this demonstration will lead to the development of highly sensitive biomarker sensors based on aptamer with lower cost and higher throughput than current technology.

  16. Theoretical and numerical predictions of hypervelocity impact-generated plasma

    NASA Astrophysics Data System (ADS)

    Li, Jianqiao; Song, Weidong; Ning, Jianguo

    2014-08-01

    The hypervelocity impact generated plasmas (HVIGP) in thermodynamic non-equilibrium state were theoretically analyzed, and a physical model was presented to explore the relationship between plasma ionization degree and internal energy of the system by a group of equations including a chemical reaction equilibrium equation, a chemical reaction rate equation, and an energy conservation equation. A series of AUTODYN 3D (a widely used software in dynamic numerical simulations and developed by Century Dynamic Inc.) numerical simulations of the impacts of hypervelocity Al projectile on its targets at different incident angles were performed. The internal energy and the material density obtained from the numerical simulations were then used to calculate the ionization degree and the electron temperature. Based on a self-developed 2D smooth particle hydrodynamic (SPH) code and the theoretical model, the plasmas generated by 6 hypervelocity impacts were directly simulated and their total charges were calculated. The numerical results are in good agreements with the experimental results as well as the empirical formulas, demonstrating that the theoretical model is justified by the AUTODYN 3D and self-developed 2D SPH simulations and applicable to predict HVIGPs. The study is of significance for astrophysical and cosmonautic researches and safety.

  17. Material for electrodes of low temperature plasma generators

    DOEpatents

    Caplan, Malcolm; Vinogradov, Sergel Evge'evich; Ribin, Valeri Vasil'evich; Shekalov, Valentin Ivanovich; Rutberg, Philip Grigor'evich; Safronov, Alexi Anatol'evich

    2008-12-09

    Material for electrodes of low temperature plasma generators. The material contains a porous metal matrix impregnated with a material emitting electrons. The material uses a mixture of copper and iron powders as a porous metal matrix and a Group IIIB metal component such as Y.sub.2O.sub.3 is used as a material emitting electrons at, for example, the proportion of the components, mass %: iron: 3-30; Y.sub.2O.sub.3:0.05-1; copper: the remainder. Copper provides a high level of heat conduction and electric conductance, iron decreases intensity of copper evaporation in the process of plasma creation providing increased strength and lifetime, Y.sub.2O.sub.3 provides decreasing of electronic work function and stability of arc burning. The material can be used for producing the electrodes of low temperature AC plasma generators used for destruction of liquid organic wastes, medical wastes, and municipal wastes as well as for decontamination of low level radioactive waste, the destruction of chemical weapons, warfare toxic agents, etc.

  18. Material for electrodes of low temperature plasma generators

    DOEpatents

    Caplan, Malcolm; Vinogradov, Sergel Evge'evich; Ribin, Valeri Vasil'evich; Shekalov, Valentin Ivanovich; Rutberg, Philip Grigor'evich; Safronov, Alexi Anatol'evich; Shiryaev, Vasili Nikolaevich

    2010-03-02

    Material for electrodes of low temperature plasma generators. The material contains a porous metal matrix impregnated with a material emitting electrons. The material uses a mixture of copper and iron powders as a porous metal matrix and a Group IIIB metal component such as Y.sub.2O.sub.3 is used as a material emitting electrons at, for example, the proportion of the components, mass %: iron:3-30; Y.sub.2O.sub.3:0.05-1; copper: the remainder. Copper provides a high level of heat conduction and electric conductance, iron decreases intensity of copper evaporation in the process of plasma creation providing increased strength and lifetime, Y.sub.2O.sub.3 provides decreasing of electronic work function and stability of arc burning. The material can be used for producing the electrodes of low temperature AC plasma generators used for destruction of liquid organic wastes, medical wastes, municipal wastes as well as for decontamination of low level radioactive waste, the destruction of chemical weapons, warfare toxic agents, etc.

  19. Zero-plasma-current equilibria generated by tilted planar coils

    NASA Astrophysics Data System (ADS)

    Li, J.; Israeli, B.; Hammond, K. C.; Volpe, F. A.

    2016-10-01

    It is known that a periodic toroidal arrangement of tilted planar coils, combined with vertical field coils, can generate a helical magnetic field. One question, though, is: is this coil-set a generator or an amplifier of rotational transform? In other words, is a finite plasma-current needed? A numerical scan of coil-currents shows that configurations exist, for which no plasma-current is needed, and yet torsatron plasmas of finite volume can be obtained. The case of six tilted circular coils has been examined in great detail because of its relevance to the CIRCUS device operated by Columbia, a generalization of the two-tilted-coil CNT stellarator, also at Columbia. More axisymmetric configurations featuring a higher number of tilted circular coils are also being investigated. The calculations are performed with the aid of a numerical field-line tracer and the VMEC equilibrium solver, slightly modified to reflect the simplicity of the coil geometry: the coils are not discretized; instead, their field is evaluated by means of analytical expressions. This allows for faster calculations and rapid, fine scans of large parameter spaces.

  20. The interaction of explosively generated plasma with explosives

    NASA Astrophysics Data System (ADS)

    Tasker, Douglas G.; Whitley, Von H.; Johnson, Carl E.

    2017-01-01

    It has been shown that the temperature of explosively generated plasma (EGP) is of the order of 1 eV and plasma ejecta can be focused to achieve velocities as high as 25 km/s. Proof-of-principle tests were performed to determine if EGP could be used for explosive ordnance demolition and other applications. The goals were: to benignly disable ordnance containing relatively sensitive high performance explosives (PBX-9501); and to investigate the possibility of interrupting an ongoing detonation in a powerful high explosive (again PBX-9501) with EGP. Experiments were performed to establish the optimum sizes of plasma generators for the benign deactivation of high explosives, i.e., the destruction of the ordnance without initiating a detonation or comparable violent event. These experiments were followed by attempts to interrupt an ongoing detonation by the benign disruption of the unreacted explosive in its path. The results were encouraging. First, it was demonstrated that high explosives could be destroyed without the initiation of a detonation or high order reaction. Second, ongoing detonations were successfully interrupted with EGP. [LA-UR-15-25350

  1. Theoretical and numerical predictions of hypervelocity impact-generated plasma

    SciTech Connect

    Li, Jianqiao; Song, Weidong Ning, Jianguo

    2014-08-15

    The hypervelocity impact generated plasmas (HVIGP) in thermodynamic non-equilibrium state were theoretically analyzed, and a physical model was presented to explore the relationship between plasma ionization degree and internal energy of the system by a group of equations including a chemical reaction equilibrium equation, a chemical reaction rate equation, and an energy conservation equation. A series of AUTODYN 3D (a widely used software in dynamic numerical simulations and developed by Century Dynamic Inc.) numerical simulations of the impacts of hypervelocity Al projectile on its targets at different incident angles were performed. The internal energy and the material density obtained from the numerical simulations were then used to calculate the ionization degree and the electron temperature. Based on a self-developed 2D smooth particle hydrodynamic (SPH) code and the theoretical model, the plasmas generated by 6 hypervelocity impacts were directly simulated and their total charges were calculated. The numerical results are in good agreements with the experimental results as well as the empirical formulas, demonstrating that the theoretical model is justified by the AUTODYN 3D and self-developed 2D SPH simulations and applicable to predict HVIGPs. The study is of significance for astrophysical and cosmonautic researches and safety.

  2. Laser propagation and soliton generation in strongly magnetized plasmas

    SciTech Connect

    Feng, W.; Li, J. Q.; Kishimoto, Y.

    2016-03-15

    The propagation characteristics of various laser modes with different polarization, as well as the soliton generation in strongly magnetized plasmas are studied numerically through one-dimensional (1D) particle-in-cell (PIC) simulations and analytically by solving the laser wave equation. PIC simulations show that the laser heating efficiency substantially depends on the magnetic field strength, the propagation modes of the laser pulse and their intensities. Generally, large amplitude laser can efficiently heat the plasma with strong magnetic field. Theoretical analyses on the linear propagation of the laser pulse in both under-dense and over-dense magnetized plasmas are well confirmed by the numerical observations. Most interestingly, it is found that a standing or moving soliton with frequency lower than the laser frequency is generated in certain magnetic field strength and laser intensity range, which can greatly enhance the laser heating efficiency. The range of magnetic field strength for the right-hand circularly polarized (RCP) soliton formation with high and low frequencies is identified by solving the soliton equations including the contribution of ion's motion and the finite temperature effects under the quasi-neutral approximation. In the limit of immobile ions, the RCP soliton tends to be peaked and stronger as the magnetic field increases, while the enhanced soliton becomes broader as the temperature increases. These findings in 1D model are well validated by 2D simulations.

  3. Two color laser driven THz generation in clustered plasma

    NASA Astrophysics Data System (ADS)

    Malik, Rakhee; Uma, R.; Kumar, Pawan

    2017-07-01

    A scheme of terahertz (THz) generation, using nonlinear mixing of two color laser (fundamental ω1 and slightly frequency shifted second harmonic ω2 ) in clustered plasma, is investigated. The lasers exert ponderomotive force on cluster electrons and drive density perturbations at 2 ω1 and ω2-ω1 . The density perturbations beat with the oscillatory velocities to produce nonlinear current at ω2-2 ω1 , generating THz radiation. The radiation is enhanced due to cluster plasmon resonance and by phase matching introduced through a density ripple. The generation involves third order nonlinearity and does not require a magnetic field or inhomogeneity to sustain it. We report THz power conversion efficiency ˜ 10-4 at 1 μm and 0.5 μm wavelengths with intensity ˜ 3 ×1014W/cm 2 .

  4. Apparatus for recording emissions from a rapidly generated plasma from a single plasma producing event

    DOEpatents

    Tan, Tai Ho; Williams, Arthur H.

    1985-01-01

    An optical fiber-coupled detector visible streak camera plasma diagnostic apparatus. Arrays of optical fiber-coupled detectors are placed on the film plane of several types of particle, x-ray and visible spectrometers or directly in the path of the emissions to be measured and the output is imaged by a visible streak camera. Time and spatial dependence of the emission from plasmas generated from a single pulse of electromagnetic radiation or from a single particle beam burst can be recorded.

  5. Apparatus for recording emissions from a rapidly generated plasma from a single plasma producing event

    DOEpatents

    Tan, T.H.; Williams, A.H.

    An optical fiber-coupled detector visible streak camera plasma diagnostic apparatus. Arrays of optical fiber-coupled detectors are placed on the film plane of several types of particle, x-ray and visible spectrometers or directly in the path of the emissions to be measured and the output is imaged by a visible streak camera. Time and spatial dependence of the emission from plasma generated from a single pulse of electromagnetic radiation or from a single particle beam burst can be recorded.

  6. SOLAR WIND STRAHL BROADENING BY SELF-GENERATED PLASMA WAVES

    SciTech Connect

    Pavan, J.; Gaelzer, R.; Vinas, A. F.; Yoon, P. H.; Ziebell, L. F. E-mail: rudi@ufpel.edu.br E-mail: yoonp@umd.edu

    2013-06-01

    This Letter reports on the results of numerical simulations which may provide a possible explanation for the strahl broadening during quiet solar conditions. The relevant processes involved in the broadening are due to kinetic quasi-linear wave-particle interaction. Making use of static analytical electron distribution in an inhomogeneous field, it is found that self-generated electrostatic waves at the plasma frequency, i.e., Langmuir waves, are capable of scattering the strahl component, resulting in energy and pitch-angle diffusion that broadens its velocity distribution significantly. The present theoretical results provide an alternative or complementary explanation to the usual whistler diffusion scenario, suggesting that self-induced electrostatic waves at the plasma frequency might play a key role in broadening the solar wind strahl during quiet solar conditions.

  7. Plasma generating device with hairpin-shaped cathode filaments

    DOEpatents

    Ehlers, Kenneth W.

    1979-01-01

    A device for generating a homogeneous ion-electron plasma from which a large ion beam can be extracted. The device utilizes hairpin-shaped filaments lining at least portions of the wall of the chamber which have been rotated 90 degrees from prior known approaches. This provides a very significant result in that the DC current flowing through the filaments produces a small solenoidal magnetic field that impedes the emitted electrons from striking the walls of the chamber, which may be of a cylindrical or rectangular configuration. This improves the efficiency of the ion source and provides additional space for more filaments, while providing a very uniform plasma density profile which is noise-free.

  8. High-order Harmonic Generation in Ultra Thin Plasma Foil

    NASA Astrophysics Data System (ADS)

    Shuai, Bin; Shen, Baifei; Li, Ruxin; Xu, Zhizhan

    Via l-D Particle In Cell (PIC) simulations, we investigated the high-order harmonic emission from flim plasma foils irradiated by two circular- polarized, counter-propagating laser pulses with their electrical vectors rotating in different directions. More than 200 harmonics can be generated with a laser intensity of 1021 W/cm2. When the duration of laser gets shorter, the frequencies of harmonics were severely modulated due to the Doppler shift caused by the movement of the plasma boundary when the foil is being compressed. The Doppler shift can be estimated by the simulation results, and this effect can also be reduced or modified by introducing frequency chirping to the pump pulse.

  9. On the generation of plasma waves in Saturn's inner magnetosphere

    NASA Astrophysics Data System (ADS)

    Barbosa, D. D.; Kurth, W. S.

    1993-06-01

    Voyager 1 plasma wave measurements of Saturn's inner magnetosphere are reviewed with regard to interpretative aspects of the wave spectrum. A comparison of the wave emission profile with the electron plasma frequency obtained from in situ measurements of the thermal ion density shows good agreement with various features in the wave data identified as electrostatic modes and electromagnetic radio waves. Theoretical calculations of the critical flux of superthermal electrons able to generate whistler-mode waves and electrostatic electron cyclotron harmonic waves through a loss-cone instability are presented. The comparison of model results with electron measurements shows excellent agreement, thereby lending support to the conclusion that a moderate perpendicular anisotropy in the hot electron distribution is present in the equatorial region of L = 5-8.

  10. Solar Wind Strahl Broadening by Self-Generated Plasma Waves

    NASA Technical Reports Server (NTRS)

    Pavan, J.; Vinas, A. F.; Yoon, P. H.; Ziebell, L. F.; Gaelzer, R.

    2013-01-01

    This Letter reports on the results of numerical simulations which may provide a possible explanation for the strahl broadening during quiet solar conditions. The relevant processes involved in the broadening are due to kinetic quasi-linear wave-particle interaction. Making use of static analytical electron distribution in an inhomogeneous field, it is found that self-generated electrostatic waves at the plasma frequency, i.e., Langmuir waves, are capable of scattering the strahl component, resulting in energy and pitch-angle diffusion that broadens its velocity distribution significantly. The present theoretical results provide an alternative or complementary explanation to the usual whistler diffusion scenario, suggesting that self-induced electrostatic waves at the plasma frequency might play a key role in broadening the solar wind strahl during quiet solar conditions.

  11. Electromagnetic Properties of Impact-Generated Plasma, Vapor and Debris

    SciTech Connect

    Crawford, D.A.; Schultz, P.H.

    1998-11-02

    Plasma, vapor and debris associated with an impact or explosive event have been demonstrated in the laboratory to produce radiofrequency and optical electromagnetic emissions that can be diagnostic of the event. Such effects could potentially interfere with communications or remote sensing equipment if an impact occurred, for example, on a satellite. More seriously, impact generated plasma could end the life of a satellite by mechanisms that are not well understood and not normally taken into account in satellite design. For example, arc/discharge phenomena resulting from highly conductive plasma acting as a current path across normally shielded circuits may have contributed to the loss of the Olympus experimental communications satellite on August 11, 1993. The possibility of significant storm activity during the Leonid meteor showers of November 1998, 1999 and 2000 (impact velocity, 72 km/s) has heightened awareness of potential vulnerabilities from hypervelocity electromagnetic effects to orbital assets. The concern is justified. The amount of plasma, electrostatic charge and the magnitude of the resulting currents and electric fields scale nearly as the cube of the impact velocity. Even for microscopic Leonid impacts, the amount of plasma approaches levels that could be dangerous to spacecraft electronics. The degree of charge separation that occurs during hypervelocity impacts scales linearly with impactor mass. The resulting magnetic fields increase linearly with impactor radius and could play a significant role in our understanding of the paleomagnetism of planetary surfaces. The electromagnetic properties of plasma produced by hypervelocity impact have been exploited by researchers as a diagnostic tool, invoked to potentially explain the magnetically jumbled state of the lunar surface and blamed for the loss of the Olympus experimental communications satellite. The production of plasma in and around an impact event can lead to several effects: (1) the

  12. Thrombin Production and Human Neutrophil Elastase Sequestration by Modified Cellulosic Dressings and Their Electrokinetic Analysis

    PubMed Central

    Edwards, Judson Vincent; Prevost, Nicolette

    2011-01-01

    Wound healing is a complex series of biochemical and cellular events. Optimally, functional material design addresses the overlapping acute and inflammatory stages of wound healing based on molecular, cellular, and bio-compatibility issues. In this paper the issues addressed are uncontrolled hemostasis and inflammation which can interfere with the orderly flow of wound healing. In this regard, we review the serine proteases thrombin and elastase relative to dressing functionality that improves wound healing and examine the effects of charge in cotton/cellulosic dressing design on thrombin production and elastase sequestration (uptake by the wound dressing). Thrombin is central to the initiation and propagation of coagulation, and elastase is released from neutrophils that can function detrimentally in a stalled inflammatory phase characteristic of chronic wounds. Electrokinetic fiber surface properties of the biomaterials of this study were determined to correlate material charge and polarity with function relative to thrombin production and elastase sequestration. Human neutrophil elastase sequestration was assessed with an assay representative of chronic wound concentration with cotton gauze cross-linked with three types of polycarboxylic acids and one phosphorylation finish; thrombin production, which was assessed in a plasma-based assay via a fluorogenic peptide substrate, was determined for cotton, cotton-grafted chitosan, chitosan, rayon/polyester, and two kaolin-treated materials including a commercial hemorrhage control dressing (QuickClot Combat Gauze). A correlation in thrombin production to zeta potential was found. Two polycarboxylic acid cross linked and a phosphorylated cotton dressing gave high elastase sequestration. PMID:24956451

  13. Thrombin production and human neutrophil elastase sequestration by modified cellulosic dressings and their electrokinetic analysis.

    PubMed

    Edwards, Judson Vincent; Prevost, Nicolette

    2011-12-15

    Wound healing is a complex series of biochemical and cellular events. Optimally, functional material design addresses the overlapping acute and inflammatory stages of wound healing based on molecular, cellular, and bio-compatibility issues. In this paper the issues addressed are uncontrolled hemostasis and inflammation which can interfere with the orderly flow of wound healing. In this regard, we review the serine proteases thrombin and elastase relative to dressing functionality that improves wound healing and examine the effects of charge in cotton/cellulosic dressing design on thrombin production and elastase sequestration (uptake by the wound dressing). Thrombin is central to the initiation and propagation of coagulation, and elastase is released from neutrophils that can function detrimentally in a stalled inflammatory phase characteristic of chronic wounds. Electrokinetic fiber surface properties of the biomaterials of this study were determined to correlate material charge and polarity with function relative to thrombin production and elastase sequestration. Human neutrophil elastase sequestration was assessed with an assay representative of chronic wound concentration with cotton gauze cross-linked with three types of polycarboxylic acids and one phosphorylation finish; thrombin production, which was assessed in a plasma-based assay via a fluorogenic peptide substrate, was determined for cotton, cotton-grafted chitosan, chitosan, rayon/polyester, and two kaolin-treated materials including a commercial hemorrhage control dressing (QuickClot Combat Gauze). A correlation in thrombin production to zeta potential was found. Two polycarboxylic acid cross linked and a phosphorylated cotton dressing gave high elastase sequestration.

  14. Thrombin use in surgery: an evidence-based review of its clinical use

    PubMed Central

    Ham, Sung W; Lew, Wesley K; Weaver, Fred A

    2010-01-01

    When surgical ligation of bleeding fails, or is not possible, surgeons rely on a number of hemostatic aids, including thrombin. This review discusses the history, pharmacology and clinical application of thrombin as a surgical hemostat. The initial thrombin was bovine in origin, but its use has been complicated by the formation of antibodies that cross-react with human coagulation factors. This has been associated with life-threatening bleeding and in some circumstances anaphylaxis and death. Human thrombin, isolated from pooled plasma of donors, was developed in an effort to minimize these risks, but its downsides are its limited availability and the potential for transmitting blood-borne pathogens. Recently a recombinant thrombin has been developed, and approved for use by the FDA. It has the advantage of being minimally antigenic and devoid of the risk of viral transmission. Thrombin is often used in conjunction with other hemostatic aids, including absorbable agents such as Gelfoam, and with fibrinogen in fibrin glues. The last part of this review will discuss these agents in detail, and review their clinical applications. PMID:22282693

  15. A reusable aptasensor of thrombin based on DNA machine employing resonance light scattering technique.

    PubMed

    Hou, Yining; Liu, Jifeng; Hong, Min; Li, Xia; Ma, Yanhua; Yue, Qiaoli; Li, Chen-Zhong

    2017-06-15

    The design of molecular nanodevices attracted great interest in these years. Herein, a reusable, sensitive and specific aptasensor was constructed based on an extension-contraction movement of DNA interconversion for the application of human thrombin detection. The present biosensor was based on resonance light scattering (RLS) using magnetic nanoparticles (MNPs) as the RLS probe. MNPs coated with streptavidin can combine with biotin labeled thrombin aptamers. The combined nanoparticles composite is monodispersed in aqueous medium. When thrombin was added a sandwich structure can form on the surface of MNPs, which induced MNPs aggregation. RLS signal was therefore enhanced, and there is a linear relationship between RLS increment and thrombin concentration in the range of 60pM-6.0nM with a limit of detection at 3.5pM (3.29SB/m, according to the recent recommendation of IUPAC). The present aptasensor can be repeatedly used for at least 6 cycling times by heat to transfer G-quadruplex conformation to single strand of DNA sequence and release thrombin. MNPs can be captured by applying the external magnetic field. Furthermore, the proposed biosensor was successfully applied to detect thrombin in human plasma.

  16. Shock Generation and Control Using DBD Plasma Actuators

    NASA Technical Reports Server (NTRS)

    Patel, Mehul P.; Cain, Alan B.; Nelson, Christopher C.; Corke, Thomas C.; Matlis, Eric H.

    2012-01-01

    This report is the final report of a NASA Phase I SBIR contract, with some revisions to remove company proprietary data. The Shock Boundary Layer Interaction (SBLI) phenomena in a supersonic inlet involve mutual interaction of oblique shocks with boundary layers, forcing the boundary layer to separate from the inlet wall. To improve the inlet efficiency, it is desired to prevent or delay shock-induced boundary layer separation. In this effort, Innovative Technology Applications Company (ITAC), LLC and the University of Notre Dame (UND) jointly investigated the use of dielectric-barrier-discharge (DBD) plasma actuators for control of SBLI in a supersonic inlet. The research investigated the potential for DBD plasma actuators to suppress flow separation caused by a shock in a turbulent boundary layer. The research involved both numerical and experimental investigations of plasma flow control for a few different SBLI configurations: (a) a 12 wedge flow test case at Mach 1.5 (numerical and experimental), (b) an impinging shock test case at Mach 1.5 using an airfoil as a shock generator (numerical and experimental), and (c) a Mach 2.0 nozzle flow case in a simulated 15 X 15 cm wind tunnel with a shock generator (numerical). Numerical studies were performed for all three test cases to examine the feasibility of plasma flow control concepts. These results were used to guide the wind tunnel experiments conducted on the Mach 1.5 12 degree wedge flow (case a) and the Mach 1.5 impinging shock test case (case b) which were at similar flow conditions as the corresponding numerical studies to obtain experimental evidence of plasma control effects for SBLI control. The experiments also generated data that were used in validating the numerical studies for the baseline cases (without plasma actuators). The experiments were conducted in a Mach 1.5 test section in the University of Notre Dame Hessert Laboratory. The simulation results from cases a and b indicated that multiple

  17. Reversibility of thrombin-induced decrease in platelet glycoprotein Ib function.

    PubMed

    Lu, H; Menashi, S; Garcia, I; Cramer, E M; Li, H; Tenza, D; De Romeuf, C; Soria, J; Soria, C

    1993-09-01

    Thrombin induces a redistribution of glycoprotein (GP) Ib/GP IX complex from the platelet surface into the surface connected canalicular system (SCCS). This redistribution results in a reduced interaction of platelet GP Ib with von Willebrand factor (vWF) bound to subendothelium leading to impaired platelet adhesion. In this study we show that the platelet aggregation and degranulation require concentrations of thrombin above 0.05 U/ml, while the decrease in GP Ib function (about 50% of control value), as determined by ristocetin induced platelet agglutination, can be induced by lower concentrations (0.01-0.04 U/ml). Moreover, we show that when adding thrombin inhibitors to the platelets preincubated with < 0.04 U/ml thrombin for 5 min, their agglutinability by ristocetin was gradually recovered within 30 min, indicating that in these conditions the decrease in platelet adhesiveness is reversible. Immuno-electromicroscopic study showed that this restoration of platelet GP Ib function was associated with a reversed translocation of GP Ib from the SCCS to the plasma membrane. The data obtained from counting gold particles showed that the ratio of GP Ib immunolabelling on the external membrane versus that on the SCCS was 3.31 +/- 0.90 for resting platelets, down-regulated to 0.84 +/- 0.13 (P < 0.05 versus resting platelets) for the platelets treated with 0.04 U/ml thrombin and returned to 2.63 +/- 2.21 (P > 0.05 versus resting platelets) after incubation for 30 min with hirudin. However, the translocation of GP Ib was poorly reversed by thrombin inhibitors when higher concentrations of thrombin were used which induced platelet aggregation and large extent of degranulation. We conclude that thrombin affects platelets in a dose dependent manner, and that at low concentrations the decrease in platelet GP Ib related function is a reversible phenomenon.

  18. Defect generation in electronic devices under plasma exposure: Plasma-induced damage

    NASA Astrophysics Data System (ADS)

    Eriguchi, Koji

    2017-06-01

    The increasing demand for higher performance of ULSI circuits requires aggressive shrinkage of device feature sizes in accordance with Moore’s law. Plasma processing plays an important role in achieving fine patterns with anisotropic features in metal-oxide-semiconductor field-effect transistors (MOSFETs). This article comprehensively addresses the negative aspect of plasma processing — plasma-induced damage (PID). PID naturally not only modifies the surface morphology of materials but also degrades the performance and reliability of MOSFETs as a result of defect generation in the materials. Three key mechanisms of PID, i.e., physical, electrical, and photon-irradiation interactions, are overviewed in terms of modeling, characterization techniques, and experimental evidence reported so far. In addition, some of the emerging topics — control of parameter variability in ULSI circuits caused by PID and recovery of PID — are discussed as future perspectives.

  19. Theoretical modeling and experimental validation of surface stress in thrombin aptasensor.

    PubMed

    Lim, Yang Choon; Kouzani, Abbas Z; Kaynak, Akif; Dai, Xiujuan J; Littlefair, Guy; Duan, Wei

    2014-12-01

    Adsorption of target molecules on the immobilized microcantilever surface produced beam displacement due to the differential surface stress generated between the immobilized and non-immobilized surface. Surface stress is caused by the intermolecular forces between the molecules. Van der Waals, electrostatic forces, hydrogen bonding, hydrophobic effect and steric hindrance are some of the intermolecular forces involved. A theoretical framework describing the adsorption-induced microcantilever displacement is derived in this paper. Experimental displacement of thrombin aptamer-thrombin interactions was carried out. The relation between the electrostatic interactions involved between adsorbates (thrombin) as well as adsorbates and substrates (thrombin aptamer) and the microcantilever beam displacement utilizing the proposed mathematical model was quantified and compared to the experimental value. This exercise is important to aid the designers in microcantilever sensing performance optimization.

  20. Electron distribution function in a plasma generated by fission fragments

    NASA Technical Reports Server (NTRS)

    Hassan, H. A.; Deese, J. E.

    1976-01-01

    A Boltzmann equation formulation is presented for the determination of the electron distribution function in a plasma generated by fission fragments. The formulation takes into consideration ambipolar diffusion, elastic and inelastic collisions, recombination and ionization, and allows for the fact that the primary electrons are not monoenergetic. Calculations for He in a tube coated with fissionable material shows that, over a wide pressure and neutron flux range, the distribution function is non-Maxwellian, but the electrons are essentially thermal. Moreover, about a third of the energy of the primary electrons is transferred into the inelastic levels of He. This fraction of energy transfer is almost independent of pressure and neutron flux.

  1. Magnetic field generation during intense laser channelling in underdense plasma

    SciTech Connect

    Smyth, A. G.; Sarri, G.; Doria, D.; Kar, S.; Borghesi, M.; Vranic, M.; Guillaume, E.; Silva, L. O.; Vieira, J.; Heathcote, R.; Norreys, P. A.; Hicks, G.; Najmudin, Z.; Nakamura, H.

    2016-06-15

    Channel formation during the propagation of a high-energy (120 J) and long duration (30 ps) laser pulse through an underdense deuterium plasma has been spatially and temporally resolved via means of a proton imaging technique, with intrinsic resolutions of a few μm and a few ps, respectively. Conclusive proof is provided that strong azimuthally symmetric magnetic fields with a strength of around 0.5 MG are created inside the channel, consistent with the generation of a collimated beam of relativistic electrons. The inferred electron beam characteristics may have implications for the cone-free fast-ignition scheme of inertial confinement fusion.

  2. Plasma motor generator tether system for orbit reboost

    NASA Technical Reports Server (NTRS)

    Hulkower, Neal D.; Rusch, Roger J.

    1988-01-01

    This paper describes a comprehensive study of an electrodynamic tether used as a Plasma Motor Generator (PMG). The paper summarizes the work performed in the study and includes: (1) a detailed design of a 2 kW PMG tether system to be used for orbit reboost, (2) the selection of the Orbiting Maneuvering Vehicle (OMV) and the European Retrievable Carrier (EURECA) as the primary candidate spacecraft to host the experimental system, (3) analysis of the integration of the PMG tether system with these two spacecraft, (4) the simulation of the deployment of the tether, and (5) an engineering design and development plan leading to a flight demonstration of this PMG tether.

  3. Plasma motor generator tether system for orbit reboost

    NASA Technical Reports Server (NTRS)

    Hulkower, Neal D.; Rusch, Roger J.

    1988-01-01

    This paper describes a comprehensive study of an electrodynamic tether used as a Plasma Motor Generator (PMG). The paper summarizes the work performed in the study and includes: (1) a detailed design of a 2 kW PMG tether system to be used for orbit reboost, (2) the selection of the Orbiting Maneuvering Vehicle (OMV) and the European Retrievable Carrier (EURECA) as the primary candidate spacecraft to host the experimental system, (3) analysis of the integration of the PMG tether system with these two spacecraft, (4) the simulation of the deployment of the tether, and (5) an engineering design and development plan leading to a flight demonstration of this PMG tether.

  4. Electron distribution function in a plasma generated by fission fragments

    NASA Technical Reports Server (NTRS)

    Hassan, H. A.; Deese, J. E.

    1976-01-01

    A Boltzmann equation formulation is presented for the determination of the electron distribution function in a plasma generated by fission fragments. The formulation takes into consideration ambipolar diffusion, elastic and inelastic collisions, recombination and ionization, and allows for the fact that the primary electrons are not monoenergetic. Calculations for He in a tube coated with fissionable material shows that, over a wide pressure and neutron flux range, the distribution function is non-Maxwellian, but the electrons are essentially thermal. Moreover, about a third of the energy of the primary electrons is transferred into the inelastic levels of He. This fraction of energy transfer is almost independent of pressure and neutron flux.

  5. Closed cycle MHD generator with nonuniform gas-plasma flow driving recombinated plasma clots

    SciTech Connect

    Slavin, V.S.; Danilov, V.V.; Sokolov, V.S.

    1996-12-31

    A new concept of a closed cycle MHD generator without alkali seed has been suggested. The essence of it is the phenomenon of frozen conductivity for recombined plasma which appears for noble gas at T{sub e} > 4,000 K. At the inlet of the MHD channel in supersonic flow of noble gas (He or Ar) the plasma clots with electron density about 10{sup 15} cm{sup {minus}3} are formed by pulsed intense electron beam with energy about 300 keV. Gas flow drives these clots in a cross magnetic field along the MHD channel which has electrodes connected with the load by Faraday scheme. The gas flow pushes plasma layers and produces electric power at the expense of enthalpy extraction. The numerical simulation has shown that a supersonic gas flow, containing about 4 plasma layers in the MHD channel simultaneously, is braked without shock waves creation. This type of the MHD generator can provide more than 30% enthalpy extraction ratio and about 80% isentropic efficiency. The advantages of the new concept are the following: (a) possibility of working at higher pressure and lower temperature, (b) operation with alkali seed.

  6. Thrombin impairs human endometrial endothelial angiogenesis; implications for progestin-only contraceptive-induced abnormal uterine bleeding.

    PubMed

    Shapiro, John P; Guzeloglu-Kayisli, Ozlem; Kayisli, Umit A; Semerci, Nihan; Huang, S Joseph; Arlier, Sefa; Larsen, Kellie; Fadda, Paolo; Schatz, Frederick; Lockwood, Charles J

    2017-06-01

    Progestin-only contraceptives induce abnormal uterine bleeding, accompanied by prothrombin leakage from dilated endometrial microvessels and increased thrombin generation by human endometrial stromal cell (HESC)-expressed tissue factor. Initial studies of the thrombin-treated HESC secretome identified elevated levels of cleaved chondroitin sulfate proteoglycan 4 (CSPG4), impairing pericyte-endothelial interactions. Thus, we investigated direct and CSPG4-mediated effects of thrombin in eliciting abnormal uterine bleeding by disrupting endometrial angiogenesis. Liquid chromatography/tandem mass spectrometry, enzyme-linked immunosorbent assay (ELISA) and quantitative real-time-polymerase chain reaction (PCR) evaluated conditioned medium supernatant and cell lysates from control versus thrombin-treated HESCs. Pre- and post-Depo medroxyprogesterone acetate (DMPA)-administered endometria were immunostained for CSPG4. Proliferation, apoptosis and tube formation were assessed in human endometrial endothelial cells (HEECs) incubated with recombinant human (rh)-CSPG4 or thrombin or both. Thrombin induced CSPG4 protein expression in cultured HESCs as detected by mass spectrometry and ELISA (p<.02, n=3). Compared to pre-DMPA endometria (n=5), stromal cells in post-DMPA endometria (n=5) displayed stronger CSPG4 immunostaining. In HEEC cultures (n=3), total tube-formed mesh area was significantly higher in rh-CSPG4 versus control (p<.05). However, thrombin disrupted HEEC tube formation by a concentration- and time-dependent reduction of angiogenic parameters (p<.05), whereas CSPG4 co-treatment did not reverse these thrombin-mediated effects. These results suggest that disruption of HEEC tube formation by thrombin induces aberrant angiogenesis and abnormal uterine bleeding in DMPA users. Mass spectrometry analysis identified several HESC-secreted proteins regulated by thrombin. Therapeutic agents blocking angiogenic effects of thrombin in HESCs can prevent or minimize progestin

  7. Platelet-rich plasma stimulated by pulse electric fields: Platelet activation, procoagulant markers, growth factor release and cell proliferation.

    PubMed

    Frelinger, A L; Torres, A S; Caiafa, A; Morton, C A; Berny-Lang, M A; Gerrits, A J; Carmichael, S L; Neculaes, V B; Michelson, A D

    2016-01-01

    Therapeutic use of activated platelet-rich plasma (PRP) has been explored for wound healing, hemostasis and antimicrobial wound applications. Pulse electric field (PEF) stimulation may provide more consistent platelet activation and avoid complications associated with the addition of bovine thrombin, the current state of the art ex vivo activator of therapeutic PRP. The aim of this study was to compare the ability of PEF, bovine thrombin and thrombin receptor activating peptide (TRAP) to activate human PRP, release growth factors and induce cell proliferation in vitro. Human PRP was prepared in the Harvest SmartPreP2 System and treated with vehicle, PEF, bovine thrombin, TRAP or Triton X-100. Platelet activation and procoagulant markers and microparticle generation were measured by flow cytometry. Released growth factors were measured by ELISA. The releasates were tested for their ability to stimulate proliferation of human epithelial cells in culture. PEF produced more platelet-derived microparticles, P-selectin-positive particles and procoagulant annexin V-positive particles than bovine thrombin or TRAP. These differences were associated with higher levels of released epidermal growth factor after PEF than after bovine thrombin or TRAP but similar levels of platelet-derived, vascular-endothelial, and basic fibroblast growth factors, and platelet factor 4. Supernatant from PEF-treated platelets significantly increased cell proliferation compared to plasma. In conclusion, PEF treatment of fresh PRP results in generation of microparticles, exposure of prothrombotic platelet surfaces, differential release of growth factors compared to bovine thrombin and TRAP and significant cell proliferation. These results, together with PEF's inherent advantages, suggest that PEF may be a superior alternative to bovine thrombin activation of PRP for therapeutic applications.

  8. Charge-exchange plasma generated by an ion thruster

    NASA Technical Reports Server (NTRS)

    Kaufman, H. R.

    1975-01-01

    The use of high voltage solar arrays greatly reduces or eliminates power processing requirements in space electric propulsion systems. This use also requires substantial areas of solar array to be at high positive potential relative to space and most of the spacecraft. The charge exchange plasma conducts electrons from the ion beam to such positive surfaces, and thereby electrically load the high voltage solar array. To evaluate this problem, the charge-exchange plasma generated by an ion beam was investigated experimentally. Based upon the experimental data, a simple model was derived for the charge-exchange plasma. This model is conservative in the sense that both the electron/ion density and the electron current density should be equal to, or less than, the preducted value for all directions in the hemisphere upstream of the ion beam direction. Increasing the distance between a positive potential surface (such as a high voltage solar array) and the thruster is the simplest way to control interactions. Both densities and currents vary as the inverse square of this distance.

  9. Slow electrostatic fluctuations generated by beam-plasma interaction

    NASA Astrophysics Data System (ADS)

    Pommois, Karen; Valentini, Francesco; Pezzi, Oreste; Veltri, Pierluigi

    2017-01-01

    Eulerian simulations of the Vlasov-Poisson equations have been employed to analyze the excitation of slow electrostatic fluctuations (with phase speed close to the electron thermal speed), due to a beam-plasma interaction, and their propagation in linear and nonlinear regimes. In 1968, O'Neil and Malmberg [Phys. Fluids 11, 1754 (1968)] dubbed these waves "beam modes." In the present paper, previous analytical results on the beam modes in both linear and nonlinear regimes have been revisited numerically, pointing out that, when an electron beam is launched in a plasma of Maxwellian electrons and motionless protons and this initial equilibrium is perturbed by a monochromatic density disturbance, the electric field amplitude grows exponentially in time and then undergoes nonlinear saturation, associated with the kinetic effects of particle trapping and phase space vortex generation. Moreover, new numerical results give evidence that, when the initial density perturbation is setup in the form of a low amplitude random phase noise, the whole Fourier spectrum of wavenumbers is excited. As a result, the electric field profile appears as a train of isolated pulses, each of them being associated with a phase space vortex in the electron distribution function. At later times, these vortical structures tend to merge and, correspondingly, the electric pulses collapse, showing the tendency towards a time asymptotic configuration characterized by the appearance of electric soliton-like pulses. This dynamical evolution is driven by purely kinetic processes, possibly at work in many space and laboratory plasma environments.

  10. THz Radiation Generation via Laser Plasma Interaction Experiments

    NASA Astrophysics Data System (ADS)

    Yugami, Noboru; Higashiguchi, Takeshi

    2008-12-01

    Recently radiation generation from the interaction between laser and plasma is studied. Terahertz radiation from photo-conductive antenna which is based on semiconductor technology is widely used, The power is in the order of nano-watt level so that it is hard to use for application. On the other hand, terahertz radiation from laser plasma interaction is much higher than that of semiconductor technology. In our experiments, we have studied by use DARC (dc to ac radiation converter) mechanism by using YAG laser with nano-second pulse duration. DARC is novel radiation source using the interaction between laser-created ionization front and static electric field. The frequency of radiation is determined by both plasma density of ionization front and the geometry of DARC structure. We observed radiation pulse of frequency of 1.2 THz and pulse duration of 2 ps with ZnSe crystal as media detected by EO (electro-optics) sampling technique. Note from Publisher: This article contains the abstract only.

  11. Plasma Generation and Mass Separation in the Archimedes Demonstration Unit

    NASA Astrophysics Data System (ADS)

    Winslow, D. L.; Agnew, S. F.; Anderegg, F.; Cluggish, B. P.; Freeman, R. L.; Gilleland, J.; Hilsabeck, T. J.; Isler, R. C.; Lee, W. D.; Litvak, A.; Miller, R. L.; Ohkawa, T.; Putvinski, S.; Umstadter, K. R.; Zhang, J.

    2004-11-01

    The Archimedes Demonstration Unit (ADU) is a large scale (L = 4 m, a = 0.37 m) cylindrical device built to demonstrate Plasma Mass Filter^1 operation. The ADU utilizes crossed electric and magnetic fields to generate a low-pass filter on atomic mass, facilitating a reduction of the volume of high level nuclear waste at the Hanford site in Richland, Washington. During the last year, high density (ne ≤ 2.2 × 10^19m-3) and low temperature (Te ˜ 3 eV) noble gas target discharges have been attained with B ≤ 1.5 kG and P_RF ≤ 1.6 MW. Rotation and separation of noble gases and injected trace metals have been observed, and scaling of separation with magnetic field and ion mass has been measured. Experiments are underway to study formation and rotation of sodium plasmas fueled by ICP torch injection of sodium hydroxide (a primary constituent of the Hanford waste). ^1T. Ohkawa, "Plasma Mass Filter", U.S. Patent 6 096 220, August 1, 2000.

  12. Plasma Streamwise Vortex Generators in an Adverse Pressure Gradient

    NASA Astrophysics Data System (ADS)

    Kelley, Christopher; Corke, Thomas; Thomas, Flint

    2013-11-01

    A wind tunnel experiment was conducted to compare plasma streamwise vortex generators (PSVGs) and passive vortex generators (VGs). These devices were installed on a wing section by which the angle of attack could be used to vary the streamwise pressure gradient. The experiment was performed for freestream Mach numbers 0.1-0.2. Three-dimensional velocity components were measured using a 5-hole Pitot probe in the boundary layer. These measurements were used to quantify the production of streamwise vorticity and the magnitude of the reorientation term from the vorticity transport equation. The effect of Mach number, pressure gradient, operating voltage, and electrode length was then investigated for the PSVGs. The results indicate that the PSVGs could easily outperform the passive VGs and provide a suitable alternative for flow control.

  13. Ge laser-generated plasma for ion implantation

    NASA Astrophysics Data System (ADS)

    Giuffrida, L.; Torrisi, L.; Czarnecka, A.; Wołowski, J.; Quarta, Ge; Calcagnile, L.; Lorusso, A.; Nassisi, V.

    Laser-generated plasma obtained by Ge ablation in vacuum was investigated with the aim to implant energetic Ge ions in light substrates (C, Si, SiO2). Different intensities of laser sources were employed for these experiments: Nd:Yag of Catania-LNS; Nd:Yag of Warsaw-IPPL; excimer laser of Lecce-INFN; iodine laser of Prague-PALS. Different experimental setups were used to generate multiple ion stream emissions, multiple ion energetic distributions, high implantation doses, thin film deposition and post-acceleration effects. `On line' measurements of ion energy were obtained with ion collectors and ion energy analyzer in time-of-flight configuration. `Off line' measurement of Ge implants were obtained with 2.25 MeV helium beam in Rutherford backscattering spectrometry. Results indicated that ion implants show typical deep profiles only for substrates placed along the normal to the target surface at which the ion energy is maximum.

  14. Peculiarities of Efficient Plasma Generation in Air and Water by Short Duration Laser Pulses

    NASA Technical Reports Server (NTRS)

    Adamovsky, Grigory; Floyd, Bertram M.

    2017-01-01

    We have conducted experiments to demonstrate an efficient generation of plasma discharges by focused nanosecond pulsed laser beams in air and provided recommendations on the design of optical systems to implement such plasma generation. We have also demonstrated generation of the secondary plasma discharge using the unused energy from the primary one. Focused nanosecond pulsed laser beams have also been utilized to generate plasma in water where we observed self-focusing and filamentation. Furthermore, we applied the laser generated plasma to the decomposition of methylene blue dye diluted in water.

  15. Thrombin and brain recovery after intracerebral hemorrhage

    PubMed Central

    Hua, Ya; Keep, Richard F.; Gu, Yuxiang; Xi, Guohua

    2009-01-01

    Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke and produces severe neurological deficits in survivors. At present, there is lack of effective treatments that improve outcome in ICH. A neglected aspect of ICH research is the development of approaches that can be effectively used to improve recovery. Although previous studies have showed that thrombin induces blood-brain barrier leakage, brain edema and neuronal death after intracerebral hemorrhage (ICH), our recent studies have shown that thrombin may have a role in brain recovery after ICH. An understanding of the mechanisms by which thrombin affects neurogenesis, angiogenesis and plasticity may facilitate brain recovery after ICH. PMID:19064789

  16. Bernstein wave aided laser third harmonic generation in a plasma

    NASA Astrophysics Data System (ADS)

    Tyagi, Yachna; Tripathi, Deepak; Kumar, Ashok

    2016-09-01

    The process of Bernstein wave aided resonant third harmonic generation of laser in a magnetized plasma is investigated. The extra-ordinary mode (X-mode) laser of frequency ω 0 and wave number k → 0 , travelling across the magnetic field in a plasma, exerts a second harmonic ponderomotive force on the electrons imparting them an oscillatory velocity v → 2 ω0 , 2 k → 0 . This velocity beats with the density perturbation due to the Bernstein wave to produce a density perturbation at cyclotron frequency shifted second harmonic. The density perturbation couples with the oscillatory velocity v → ω0 , k → 0 of X-mode of the laser to produce the cyclotron frequency shifted third harmonic current density leading to harmonic radiation. The phase matching condition for the up shifted frequency is satisfied when the Bernstein wave is nearly counter-propagating to the laser. As the transverse wave number of the Bernstein wave is large, it is effective in the phase matched third harmonic generation, when the laser frequency is not too far from the upper hybrid frequency.

  17. Ion Beam Analysis applied to laser-generated plasmas

    NASA Astrophysics Data System (ADS)

    Cutroneo, M.; Macková, A.; Havranek, V.; Malinsky, P.; Torrisi, L.; Kormunda, M.; Barchuk, M.; Ullschmied, J.; Dudzak, R.

    2016-04-01

    This paper presents the research activity on Ion Beam Analysis methods performed at Tandetron Laboratory (LT) of the Institute of Nuclear Physics AS CR, Rez, Czech Republic. Recently, many groups are paying attention to implantation by laser generated plasma. This process allows to insert a controllable amount of energetic ions into the surface layers of different materials modifying the physical and chemical properties of the surface material. Different substrates are implanted by accelerated ions from plasma through terawatt iodine laser, at nominal intensity of 1015 W/cm2, at the PALS Research Infrastructure AS CR, in the Czech Republic. This regime of the laser matter interaction generates, multi-MeV proton beams, and multi-charged ions that are tightly confined in time (hundreds ps) and space (source radius of a few microns). These ion beams have a much lower transverse temperature, a much shorter duration and a much higher current than those obtainable from conventional accelerators. The implementation of protons and ions acceleration driven by ultra-short high intensity lasers is exhibited by adopting suitable irradiation conditions as well as tailored targets. An overview of implanted targets and their morphological and structural characterizations is presented and discussed.

  18. High duty factor plasma generator for CERN's Superconducting Proton Linac.

    PubMed

    Lettry, J; Kronberger, M; Scrivens, R; Chaudet, E; Faircloth, D; Favre, G; Geisser, J-M; Küchler, D; Mathot, S; Midttun, O; Paoluzzi, M; Schmitzer, C; Steyaert, D

    2010-02-01

    CERN's Linac4 is a 160 MeV linear accelerator currently under construction. It will inject negatively charged hydrogen ions into CERN's PS-Booster. Its ion source is a noncesiated rf driven H(-) volume source directly inspired from the one of DESY and is aimed to deliver pulses of 80 mA of H(-) during 0.4 ms at a 2 Hz repetition rate. The Superconducting Proton Linac (SPL) project is part of the luminosity upgrade of the Large Hadron Collider. It consists of an extension of Linac4 up to 5 GeV and is foreseen to deliver protons to a future 50 GeV synchrotron (PS2). For the SPL high power option (HP-SPL), the ion source would deliver pulses of 80 mA of H(-) during 1.2 ms and operate at a 50 Hz repetition rate. This significant upgrade motivates the design of the new water cooled plasma generator presented in this paper. Its engineering is based on the results of a finite element thermal study of the Linac4 H(-) plasma generator that identified critical components and thermal barriers. A cooling system is proposed which achieves the required heat dissipation and maintains the original functionality. Materials with higher thermal conductivity are selected and, wherever possible, thermal barriers resulting from low pressure contacts are removed by brazing metals on insulators. The AlN plasma chamber cooling circuit is inspired from the approach chosen for the cesiated high duty factor rf H(-) source operating at SNS.

  19. PREFACE: Acceleration and radiation generation in space and laboratory plasmas

    NASA Astrophysics Data System (ADS)

    Bingham, R.; Katsouleas, T.; Dawson, J. M.; Stenflo, L.

    1994-01-01

    Sixty-six leading researchers from ten nations gathered in the Homeric village of Kardamyli, on the southern coast of mainland Greece, from August 29-September 4, 1993 for the International Workshop on Acceleration and Radiation Generation in Space and Laboratory Plasmas. This Special Issue represents a cross-section of the presentations made at and the research stimulated by that meeting. According to the Iliad, King Agamemnon used Kardamyli as a dowry offering in order to draw a sulking Achilles into the Trojan War. 3000 years later, Kardamyli is no less seductive. Its remoteness and tranquility made it an ideal venue for promoting the free exchange of ideas between various disciplines that do not normally interact. Through invited presen tations, informal poster discussions and working group sessions, the Workshop brought together leaders from the laboratory and space/astrophysics communities working on common problems of acceleration and radiation generation in plasmas. It was clear from the presentation and discussion sessions that there is a great deal of common ground between these disciplines which is not at first obvious due to the differing terminologies and types of observations available to each community. All of the papers in this Special Issue highlight the role collective plasma processes play in accelerating particles or generating radiation. Some are state-of-the-art presentations of the latest research in a single discipline, while others investi gate the applicability of known laboratory mechanisms to explain observations in natural plasmas. Notable among the latter are the papers by Marshall et al. on kHz radiation in the magnetosphere ; Barletta et al. on collective acceleration in solar flares; and by Dendy et al. on ion cyclotron emission. The papers in this Issue are organized as follows: In Section 1 are four general papers by Dawson, Galeev, Bingham et al. and Mon which serves as an introduction to the physical mechanisms of acceleration

  20. Utility of dual frequency hybrid source for plasma and radical generation in plasma enhanced chemical vapor deposition process

    NASA Astrophysics Data System (ADS)

    Shin, Kyung Sik; Bhusan Sahu, Bibhuti; Geon Han, Jeon; Hori, Masaru

    2015-07-01

    Looking into the aspect of material processing, this work evaluates alternative plasma concepts in SiH4/H2 plasmas to investigate the radical and plasma generation in the plasma enhanced chemical vapor deposition (PECVD) synthesis of nanocrystalline Si (nc-Si:H). Simultaneous measurements by vacuum ultraviolet absorption spectroscopy (VUVAS), optical emission spectroscopy (OES), and radio frequency (RF) compensated Langmuir probe (LP) reveal that RF/ultrahigh frequency (UHF) hybrid source can efficiently produce H radicals and plasmas that are accountable for nc-Si:H film synthesis. The efficacy of hybrid plasmas is also discussed.

  1. Significance of thrombin-receptors of thrombocytes for the interaction of heparins and low-molecular-weight heparin in human whole blood clotting.

    PubMed

    Harenberg, J; Schuler, M; Zimmermann, R; Heptner, W

    1988-01-01

    We describe in the present paper the results of the influence of normal and low-molecular-weight heparin on the interaction of human fibrinogen and thrombocytes in human whole blood cotting ex vivo. During the coagulation process sequential measurements of fibrinopeptide A reflect fibrin formation and determination of platelet factor 4 indicate activation of thrombocytes. The data show that low-molecular-weight heparin inhibits plasma thrombin generation in vivo for longer than normal heparin and it affects the fibrinogen platelet binding less. There is good evidence that a lonely factor Xa inhibition mediates this anticoagulant mechanism. Therefore, these data favor the hypothesis that antifactor Xa activity prevents indeed blood clotting.

  2. Promoting Plasma Physics as a Career: A Generational Approach

    NASA Astrophysics Data System (ADS)

    Morgan, James

    2005-10-01

    A paradigm shift is occurring in education physics programs. Educators are shifting from the traditional teaching focus to concentrate on student learning. Students are unaware of physics as a career, plasma physics or the job opportunities afforded to them with a physics degree. The physics profession needs to promote itself to the younger generations, or specifically the millennial generation (Born in the 1980's-2000's). Learning styles preferred by ``Millennials'' include a technological environment that promotes learning through active task performance rather than passive attendance at lectures. Millennials respond well to anything experiential and will be motivated by opportunities for creativity and challenging learning environments. The open-ended access to information, the ability to tailor learning paths, and continuous and instantaneous performance assessment offer flexibility in the design of curricula as well as in the method of delivery. Educators need to understand the millennial generation, appeal to their motivations and offer a learning environment designed for their learning style. This poster suggests promoting a physics career by focusing on generational learning styles and preferences.

  3. Hemostatic properties and protein expression profile of therapeutic apheresis plasma treated with amotosalen and ultraviolet A for pathogen inactivation.

    PubMed

    Ohlmann, Philippe; Hechler, Béatrice; Chafey, Philippe; Ravanat, Catherine; Isola, Hervé; Wiesel, Marie-Louise; Cazenave, Jean-Pierre; Gachet, Christian

    2016-09-01

    The INTERCEPT Blood System (IBS) using amotosalen-HCl and ultraviolet (UV)A inactivates a large spectrum of microbial pathogens and white blood cells in therapeutic plasma. Our aim was to evaluate to what extent IBS modifies the capacity of plasma to generate thrombin and induces qualitative or quantitative modifications of plasma proteins. Plasma units from four donors were collected by apheresis. Samples were taken before (control [CTRL]) and after IBS treatment and stored at -80°C until use. The activities of plasma coagulation factors and inhibitors and the thrombin generation potential were determined using assays measuring clotting times and the calibrated automated thrombogram (CAT), respectively. The proteomic profile of plasma proteins was examined using a two-dimensional differential in-gel electrophoresis (2D-DIGE) method. Nearly all of the procoagulant and antithrombotic factors tested retained at least 78% of their initial pre-IBS activity. Only FVII and FVIII displayed a lower level of conservation (67%), which nevertheless remained within the reference range for conventional plasma coagulation factors. The thrombin generation profile of plasma was conserved after IBS treatment. Among the 1331 protein spots revealed by 2D-DIGE analysis, only four were differentially expressed in IBS plasma compared to CTRL plasma and two were identified by mass spectrometric analysis as transthyretin and apolipoprotein A1. The IBS technique for plasma moderately decreases the activities of plasma coagulation factors and antithrombotic proteins, with no impact on the thrombin generation potential of plasma and very limited modifications of the proteomic profile. © 2016 AABB.

  4. Enhanced Plasma Lifetime of Air Plasmas Generated by Electron Beam Excitation

    NASA Astrophysics Data System (ADS)

    Vidmar, Robert; Stalder, Kenneth

    2002-10-01

    A kinetic model with an improved set of reaction rate coefficients for air constituents will be discussed. The model includes rates that vary with E/N for electron temperature, momentum transfer, three body attachment, singlet-delta formation, electron detachment from O2-, and ionization of O2. The electric field is assumed uniform and sustained either by external electrodes or return currents generated in an electron beam. Calculations show the plasma lifetime increases as E/N increases by reducing attachment, increasing detachment, and increasing ionization. Electric-field-free plasma lifetimes of 10-20 ns for air at sea level (depending on initial electron density) can be increased by a factor of almost 5 with an E/N of about 2 x 10-16 volt cm^2. The plasma lifetime at altitudes of 30,000 feet corresponds to 60-100 ns without electric field and increases by a factor of 5-20 with an E/N of 5 x 10-17 volt cm^2. The power to maintain these E/N values and to sustain a given level of plasma density will be discussed. This research is sponsored by the Air Force Research Laboratory, under agreement number F49620-01-1-0414.

  5. Reversal of trauma-induced amnesia in mice by a thrombin receptor antagonist.

    PubMed

    Itzekson, Zeev; Maggio, Nicola; Milman, Anat; Shavit, Efrat; Pick, Chaim G; Chapman, Joab

    2014-05-01

    Minimal traumatic brain injury (mTBI) is associated with the existence of retrograde amnesia and microscopic bleeds containing activated coagulation factors. In an mTBI model, we report that thrombin induces amnesia through its receptor protease-activated receptor 1 (PAR-1). Thrombin activity was significantly elevated (32 %, p < 0.05) 5 min following mTBI compared to controls. Amnesia was assessed by the novel object recognition test in mTBI animals and in animals injected intracerebroventricularly (ICV) with either thrombin or a PAR-1 agonist 1 h after the acquisition phase. Saline-injected controls had a preference index of over 0.3 while mTBI animals and those injected with thrombin or the PAR-1 agonist spent equal time with both objects indicating no recall of the object presented to them 24 h previously (p < 0.05). Co-injecting a PAR-1 antagonist (SCH79797) completely blocked the amnestic effects of mTBI, thrombin, and the PAR-1 agonist. Long-term potentiation, measured in hippocampal slices 24 h after mTBI, ICV thrombin or the PAR-1 agonist, was significantly impaired and this effect was completely reversed by the PAR-1 antagonist. The results support a crucial role for PAR-1 in the generation of amnesia following mTBI, revealing a novel therapeutic target for the cognitive effects of brain trauma.

  6. Magnetohydrodynamic Power Generation in the Laboratory Simulated Martian Entry Plasma

    NASA Technical Reports Server (NTRS)

    Vuskovic, L.; Popovic, S.; Drake, J.; Moses, R. W.

    2005-01-01

    This paper addresses the magnetohydrodynamic (MHD) conversion of the energy released during the planetary entry phase of an interplanetary vehicle trajectory. The effect of MHD conversion is multi-fold. It reduces and redirects heat transferred to the vehicle, and regenerates the dissipated energy in reusable and transportable form. A vehicle on an interplanetary mission carries about 10,000 kWh of kinetic energy per ton of its mass. This energy is dissipated into heat during the planetary atmospheric entry phase. For instance, the kinetic energy of Mars Pathfinder was about 4220 kWh. Based on the loss in velocity, Mars Pathfinder lost about 92.5% of that energy during the plasma-sustaining entry phase that is approximately 3900 kWh. An ideal MHD generator, distributed over the probe surface of Mars Pathfinder could convert more than 2000 kWh of this energy loss into electrical energy, which correspond to more than 50% of the kinetic energy loss. That means that the heat transferred to the probe surface can be reduced by at least 50% if the converted energy is adequately stored, or re-radiated, or directly used. Therefore, MHD conversion could act not only as the power generating, but also as the cooling process. In this paper we describe results of preliminary experiments with light and microwave emitters powered by model magnetohydrodynamic generators and discuss method for direct use of converted energy.

  7. Enhanced ionospheric plasma bubble generation in more active ITCZ

    NASA Astrophysics Data System (ADS)

    Li, Guozhu; Otsuka, Yuichi; Ning, Baiqi; Abdu, M. A.; Yamamoto, M.; Wan, Weixing; Liu, Libo; Abadi, Prayitno

    2016-03-01

    A close link between the atmospheric Intertropical Convergence Zone (ITCZ) and ionospheric plasma bubble has been proposed since the last century. But this relationship has often appeared to be less than convincing due to the simultaneous roles played by several other factors in shaping the global distribution of ionospheric bubbles. From simultaneous collaborative radar multibeam steering measurements at Kototabang (0.2°S, 100.3°E) and Sanya (18.4°N, 109.6°E), conducted during September-October of 2012 and 2013, we find that the total numbers of nights with bubble (i.e., occurrence rates) at the two closely located longitudes (Kototabang and Sanya) are comparable. But interestingly, the total number of nights with locally generated bubble (i.e., generation rate) over Kototabang is clearly more than that over Sanya. Further analysis reveals that a more active ITCZ is situated around the longitude of Kototabang. We surmise that the enhanced ionospheric bubble generation at Kototabang longitude could be caused by a higher gravity wave activity associated with the more active ITCZ.

  8. Protein C inhibits endocytosis of thrombin-thrombomodulin complexes in A549 lung cancer cells and human umbilical vein endothelial cells

    SciTech Connect

    Maruyama, I.; Majerus, P.W.

    1987-05-01

    We investigated the effect of protein C on the endocytosis of thrombin-thrombomodulin complexes. We previously showed that exposure of umbilical vein endothelial cells to thrombin stimulated the internalization and degradation of thrombin. A similar internalization was stimulated by a monoclonal antithrombomodulin antibody. We have repeated these studies in the presence of protein C and found that endocytosis of /sup 125/I-thrombin-thrombomodulin complexes, but not /sup 125/I-antithrombomodulin-thrombomodulin complexes, is inhibited. Activated protein C did not inhibit endocytosis of thrombin-thrombomodulin complexes. Protein C inhibited both internalization and degradation of /sup 125/I-thrombin and diisopropylphosphoryl (DIP) /sup 125/I-thrombin in human lung cancer cells (A549). These effects were observed at protein C concentrations found in human plasma. Protein S had no effect on the inhibition of endocytosis of thrombin-thrombomodulin complexes by protein C. We propose that protein C may regulate the rate of endocytosis of thrombin-thrombomodulin complexes in vivo and thereby control the capacity for endothelium to activate protein C.

  9. Mechanisms of polymer degradation using an oxygen plasma generator

    NASA Technical Reports Server (NTRS)

    Colony, Joe A.; Sanford, Edward L.

    1987-01-01

    An RF oxygen plasma generator was used to produce polymer degradation which appears to be similar to that which has been observed in low Earth orbit. Mechanisms of this type of degradation were studied by collecting the reaction products in a cryogenic trap and identifying the molecular species using infrared, mass spectral, and X-ray diffraction techniques. No structurally dependent species were found from Kapton, Teflon, or Saran polymers. However, very reactive free radical entities are produced during the polymer degradation, as well as carbon dioxide and water. Reactions of the free radicals with the glass reaction vessel, with copper metal in the cold trap, and with a triphenyl phosphate scavenger in the cold trap, demonstrated the reactivity of the primary products.

  10. Silicon carbide detector for laser-generated plasma radiation

    NASA Astrophysics Data System (ADS)

    Bertuccio, Giuseppe; Puglisi, Donatella; Torrisi, Lorenzo; Lanzieri, Claudio

    2013-05-01

    We present the performance of a Silicon Carbide (SiC) detector in the acquisition of the radiation emitted by laser generated plasmas. The detector has been employed in time of flight (TOF) configuration within an experiment performed at the Prague Asterix Laser System (PALS). The detector is a 5 mm2 area 100 nm thick circular Nisbnd SiC Schottky junction on a high purity 4Hsbnd SiC epitaxial layer 115 μm thick. Current signals from the detector with amplitudes up to 1.6 A have been measured, achieving voltage signals over 80 V on a 50 Ω load resistance with excellent signal to noise ratios. Resolution of few nanoseconds has been experimentally demonstrated in TOF measurements. The detector has operated at 250 V DC bias under extreme operating conditions with no observable performance degradation.

  11. Numerical Model of the Plasma Sheath Generated by the Plasma Source Instrument Aboard the Polar Satellite

    NASA Technical Reports Server (NTRS)

    Singh, N.; Leung, W. C.; Moore, T. E.; Craven, P. D.

    2001-01-01

    The plasma sheath generated by the operation of the Plasma Source Instrument (PSI) aboard the Polar satellite is studied by using a three-dimensional particle-in-cell (PIC) code. When the satellite passes through the region of low-density plasma, the satellite charges to positive potentials as high as 40-50 V, owing to the photoelectron emission. In such a case, ambient core ions cannot accurately be measured or detected. The goal of the onboard PSI is to reduce the floating potential of the satellite to a sufficiently low value so that the ions in the polar wind become detectable. When the PSI is operated, ion-rich xenon plasma is ejected from the satellite, such that the floating potential of the satellite is reduced and is maintained at approximately 2 V. Accordingly, in our three-dimensional PIC simulation we considered that the potential of the satellite is 2 V as a fixed bias. Considering the relatively high density of the xenon plasma in the sheath (10-10(exp 3)/cc), the ambient plasma of low density (<1/cc) is neglected. In the simulations the electric fields and plasma dynamics are calculated self-consistently. We found that an 'apple'-shape positive potential sheath forms surrounding the satellite. In the region near the PSI emission a high positive potential hill develops. Near the Thermal Ion Dynamics Experiment detector away from the PSI, the potentials are sufficiently low for the ambient polar wind ions to reach it. In the simulations it takes only about a couple of tens of electron gyroperiods for the sheath to reach a quasi steady state. This time is approximately the time taken by the heavy Xe(+) ions to expand up to about one average Larmor radius of electrons from the satellite surface. After this time the expansion of the sheath in directions transverse to the ambient magnetic field slows down because the electrons are magnetized. Using the quasi steady sheath, we performed trajectory calculations to characterize the detector response to a

  12. Numerical Model of the Plasma Sheath Generated by the Plasma Source Instrument Aboard the Polar Satellite

    NASA Technical Reports Server (NTRS)

    Leung, Wing C.; Singh, Nagendra; Moore, Thomas E.; Craven, Paul D.

    2000-01-01

    The plasma sheath generated by the operation of the Plasma Source Instrument (PSI) aboard the POLAR satellite is studied by using a 3-dimensional Particle-In-Cell (PIC) code. When the satellite passes through the region of low density plasma, the satellite charges to positive potentials as high as 4050Volts due to the photoelectrons emission. In such a case, ambient core ions cannot accurately be measured or detected. The goal of the onboard PSI is to reduce the floating potential of the satellite to a sufficiently low value so that the ions in the polar wind become detectable. When the PSI is operated, an ion-rich Xenon plasma is ejected from the satellite, such that the floating potential of the satellite is reduced and is maintained at about 2Volts. Accordingly, in our 3-dimensional PIC simulation, we considered that the potential of the satellite is 2Volts as a fixed bias. Considering the relatively high density of the Xenon plasma in the sheath (approx. 10 - 10(exp 3)/cc), the ambient plasma of low density (less than 1/cc) is neglected. In the simulations, the electric fields and plasma dynamics are calculated self-consistently. We found that an "Apple" shape positive potential sheath forms surrounding the satellite. In the region near the PSI emission, a high positive potential hill develops. Near the Thermal Ion Detection Experiment (TIDE) detector away from the PSI, the potentials are sufficiently low for the ambient polar wind ions to reach it. In the simulations, it takes about a hundred electron gyroperiods for the sheath to reach a quasi-steady state. This time is approximately the time taken by the heavy Xe(+) ions to expand up to about one average Larmor radius of electrons from the satellite surface. Using the steady state sheath, we performed trajectory calculations to characterize the detector response to a highly supersonic polar wind flow. The detected ions' velocity distribution shows significant deviations from a shifted Maxwellian in the

  13. Numerical Model of the Plasma Sheath Generated by the Plasma Source Instrument Aboard the Polar Satellite

    NASA Technical Reports Server (NTRS)

    Singh, N.; Leung, W. C.; Moore, T. E.; Craven, P. D.

    2001-01-01

    The plasma sheath generated by the operation of the Plasma Source Instrument (PSI) aboard the Polar satellite is studied by using a three-dimensional particle-in-cell (PIC) code. When the satellite passes through the region of low-density plasma, the satellite charges to positive potentials as high as 40-50 V, owing to the photoelectron emission. In such a case, ambient core ions cannot accurately be measured or detected. The goal of the onboard PSI is to reduce the floating potential of the satellite to a sufficiently low value so that the ions in the polar wind become detectable. When the PSI is operated, ion-rich xenon plasma is ejected from the satellite, such that the floating potential of the satellite is reduced and is maintained at approximately 2 V. Accordingly, in our three-dimensional PIC simulation we considered that the potential of the satellite is 2 V as a fixed bias. Considering the relatively high density of the xenon plasma in the sheath (10-10(exp 3)/cc), the ambient plasma of low density (<1/cc) is neglected. In the simulations the electric fields and plasma dynamics are calculated self-consistently. We found that an 'apple'-shape positive potential sheath forms surrounding the satellite. In the region near the PSI emission a high positive potential hill develops. Near the Thermal Ion Dynamics Experiment detector away from the PSI, the potentials are sufficiently low for the ambient polar wind ions to reach it. In the simulations it takes only about a couple of tens of electron gyroperiods for the sheath to reach a quasi steady state. This time is approximately the time taken by the heavy Xe(+) ions to expand up to about one average Larmor radius of electrons from the satellite surface. After this time the expansion of the sheath in directions transverse to the ambient magnetic field slows down because the electrons are magnetized. Using the quasi steady sheath, we performed trajectory calculations to characterize the detector response to a

  14. Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin

    SciTech Connect

    Maraganore, J.M.; Bourdon, P.; Jablonski, J.; Ramachandran, K.L. ); Fenton, J.W. II )

    1990-07-31

    A novel class of synthetic peptides has been designed that inhibit the thrombin catalytic site and exhibit specificity for the anion-binding exosite (ABE) of {alpha}-thrombin. These peptides, called hirulogs, consist of (i) an active-site specificity sequence with a restricted Arg-Pro scissile bond, (ii) a polymeric linker of glycyl residues from 6 to 18 {angstrom} in length, and (iii) an ABE recognition sequence such as that in the hirudin C-terminus. Hirulog-1 ((D-Phe)-Pro-Arg-Pro-(Gly){sub 4}-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Tyr-Leu) inhibits the thrombin-catalyzed hydrolysis of a tripeptide p-nitroanilide substrate with K{sub i} = 2.3 nM. In contrast, the synthetic C-terminal hirudin peptide S-Hir{sub 53-64}, which binds to the thrombin ABE, blocked the fibrinogen clotting activity of the enzyme with K{sub i} = 144 nM but failed to inhibit the hydrolysis of p-nitroanilide substrates at concentrations as high as 1 mM. Hirulog-1, but not S-Hir{sub 53-64}, was found to inhibit the incorporation of ({sup 14}C)diisopropyl fluorophosphate in thrombin. Hirulog-1 appears specific for thrombin as it lacks inhibitory activities toward human factor Xa, human plasmin, and bovine trypsin at inhibitor:enzyme concentrations 3 orders of magnitude higher than those required to inhibit thrombin. The optimal inhibitory activity of hirulog-1 depends upon all three components of its structure. Comparison of anticoagulant activities of hirulog-1, hirudin, and S-Hir{sub 53-64} showed that the synthetic hirulog-1 is 2-fold more potent than hirudin and 100-fold more active than S-Hir{sub 53-64} in increasing the activated partial thromboplastin time of normal human plasma.

  15. Plasma-Enhanced Chemical Vapor Deposition of SiOx Films Using Electron Beam Generated Plasmas

    DTIC Science & Technology

    2009-09-28

    the films was large (> 130 nm/min), which implied a high porosity for all cases except for low TEOS flow (≤ 2 sccm) at the higher (300 °C) temperature...special relation to the substrate or e-beam. A total flow of 100 sccm was used in all cases . For the gas flows mentioned above, the individual flows...beam generated plasmas. In this case , molecular hydrogen, formed primarily by recombination of atomic hydrogen on system walls, will not be

  16. Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human platelet aggregation in vitro: comparison with direct inhibitors of factor VIIa, XIa and thrombin.

    PubMed

    Wong, Pancras C; Jiang, Xiaosui

    2010-08-01

    Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development. This study evaluated the in vitro effect of apixaban on human platelet aggregation induced by thrombin derived via the extrinsic pathway. Direct inhibitors of FXa (rivaroxaban), FVIIa (BMS-593214), thrombin (dabigatran, argatroban) and FXIa (BMS-262084) were included for comparison. Citrated human platelets-rich plasma (PRP) was treated with 50 mg/ml corn trypsin inhibitor (to block the contact factor pathway) and 3 mM H-Gly-Pro-Arg-Pro-OH-AcOH (to prevent fibrin polymerisation). Human tissue factor (TF) (Innovin; dilution 1:1,000 to 1:1,500) plus 7.5 mM CaCl2 was added to PRP pre-incubated with vehicle or increasing concentrations of inhibitors. The TF-induced platelet aggregation was measured by optical aggregometry. TF produced 85 +/- 3% aggregation of human platelets in the vehicle-treated group (n=10). Apixaban and other factor inhibitors, except the FXIa inhibitor, inhibited TF-induced platelet aggregation with IC50 (nM) values as follows: 4 +/- 1 (apixaban), 8 +/- 2 (rivaroxaban), 13 +/- 1 (BMS-593214), 46 +/- 1 (dabigatran) and 79 +/- 1 (argatroban). BMS-262084 (IC50 = 2.8 nM vs. human FXIa) had no effect on TF-induced platelet aggregation at 10 microM. These inhibitors at 10 microM had no effect on platelet aggregation induced by ADP and collagen, as expected from their mechanism of action. This study demonstrates that inhibition of thrombin generation by blocking upstream proteases (FVIIa and FXa) in the blood coagulation cascade is as effective as direct thrombin inhibition in preventing TF-induced platelet aggregation. Under these experimental conditions, a FXIa inhibitor did not prevent TF-induced platelet aggregation.

  17. Preparation of recombinant alpha-thrombin: high-level expression of recombinant human prethrombin-2 and its activation by recombinant ecarin.

    PubMed

    Yonemura, Hiroshi; Imamura, Takayuki; Soejima, Kenji; Nakahara, Yo; Morikawa, Wataru; Ushio, Yoshitaka; Kamachi, Yasuharu; Nakatake, Hiroshi; Sugawara, Keishin; Nakagaki, Tomohiro; Nozaki, Chikateru

    2004-05-01

    We have established a large-scale manufacturing system to produce recombinant human alpha-thrombin. In this system, a high yield of alpha-thrombin is prepared from prethrombin-2 activated by recombinant ecarin. We produced human prethrombin-2 using mouse myeloma cells and an expression plasmid carrying the chicken beta-actin promoter and mutant dihydrofolate reductase gene for gene amplification. To increase prethrombin-2 expression further, we performed fed-batch cultivation with the addition of vegetable peptone in 50 liters of suspension culture. After five feedings of vegetable peptone, the expression level of the recombinant prethrombin-2 reached 200 micro g/ml. Subsequently, the recombinant prethrombin-2 could be activated to alpha-thrombin by recombinant ecarin expressed in a similar manner. Finally, recombinant alpha-thrombin was purified to homogeneity by affinity chromatography using a benzamidine-Sepharose gel. The yield from prethrombin-2 in culture medium was approximately 70%. The activity of the purified recombinant alpha-thrombin, including hydrolysis of a chromogenic substrate, release of fibrinopeptide A, and activation of protein C, was indistinguishable from that of plasma-derived alpha-thrombin. Our system is suitable for the large-scale production of recombinant alpha-thrombin, which can be used in place of clinically available alpha-thrombin derived from human or bovine plasma.

  18. Application of the three phase AC plasma generator for drug destruction

    SciTech Connect

    Polovtsev, I.S.

    1996-12-31

    Experiments for gas destruction with the help of the new three phase AC plasma generator were performed. Advantages of the new type plasma generator were studied. It was shown that this generator can be successfully used for destruction of hazardous wastes. Tests on methane, freon and malathion were performed. Results of the tests show complete destruction of the injected gases.

  19. A mathematical model of thrombin production in blood coagulation, Part I: The sparsely covered membrane case.

    PubMed

    Baldwin, S A; Basmadjian, D

    1994-01-01

    This paper presents the first attempt to model the blood coagulation reactions in flowing blood. The model focuses on the common pathway and includes activation of factor X and prothrombin, including feedback activation of cofactors VIII and V by thrombin, and plasma inhibition of factor Xa and thrombin. In this paper, the first of two, the sparsely covered membrane (SCM) case is presented. This considers the limiting situation where platelet membrane binding sites are in excess, such that no membrane saturation or binding competition occurs. Under these conditions, the model predicts that the two positive feedback loops lead to multiple steady-state behavior in the range of intermediate mass transfer rates. It will be shown that this results in three parameter regions exhibiting very different thrombin production patterns. The model predicts the effect of flow on steady-state and dynamic thrombin production and attempts to explain the difference between venous and arterial thrombi. The reliance of thrombin production on precursor procoagulant protein concentrations is also assessed.

  20. Bufadienolides from Kalanchoe daigremontiana as thrombin inhibitors-In vitro and in silico study.

    PubMed

    Kolodziejczyk-Czepas, Joanna; Sieradzka, Malgorzata; Moniuszko-Szajwaj, Barbara; Pecio, Łukasz; Ponczek, Michal B; Nowak, Pawel; Stochmal, Anna

    2017-06-01

    Thrombin is an active plasma coagulation factor II, critical for the formation of fibrin clot during blood coagulation. For that reason, this protein is also a crucial target for different anti-thrombotic therapies. The work is based on in vitro evaluation of the inhibitory effect of bufadienolide-rich fraction, isolated from roots of Kalanchoe daigremontiana (1-50μg/ml) on enzymatic properties of a serine proteinase - thrombin. The efficacy of the inhibition of amidolytic activity of thrombin (measured as a hydrolysis of the chromogenic substrate S-2238, Chromogenix) attained about 10 and 66%, respectively. The IC50, established for the examined bufadienolide fraction was 2.79μg/ml, while the IC50 calculated for argatroban (reference compound) was 0.78μg/ml. Linearization conducted using Lineweaver-Burk plot indicated that the K. daigremontiana fraction contains compounds that are uncompetitive inhibitors of thrombin. K. daigremontiana fraction was also able to reduce the proteolytic activity of thrombin towards its physiological substrate, i.e. fibrinogen. Additionally, this study is supported by in silico analysis of interactions of the most common compounds, identified in the examined in Kalanchoe extract to crystal structure of this enzyme.

  1. Generation of low-temperature plasma by low-pressure arcs for synthesis of nitride coatings

    NASA Astrophysics Data System (ADS)

    Krysina, O. V.; Koval, N. N.; Lopatin, I. V.; Shugurov, V. V.; Kovalsky, S. S.

    2016-01-01

    Experiments were performed to study gas, metal, and mixed metal-gas plasmas. The plasmas were generated with the use of an arc evaporator and a gas-plasma source with a hot filament and hollow cathode that were operated independently or simultaneously. It has been revealed that the arc current of gas-plasma source affects the parameters of the metal-gas plasma and the element concentrations in the coatings. It has been demonstrated that the characteristics of the nitride coatings produced by plasma-assisted vacuum-arc deposition can be controlled by varying the parameters of the arc in the gas-plasma source.

  2. Microwave plasmas generated in bubbles immersed in liquids for hydrocarbons reforming

    NASA Astrophysics Data System (ADS)

    Levko, Dmitry; Sharma, Ashish; Raja, Laxminarayan L.

    2016-06-01

    We present a computational modeling study of microwave plasma generated in cluster of atmospheric-pressure argon bubbles immersed in a liquid. We demonstrate that the use of microwaves allows the generation of a dense chemically active non-equilibrium plasma along the gas-liquid interface. Also, microwaves allow generation of overdense plasma in all the bubbles considered in the cluster which is possible because the collisional skin depth of the wave exceeds the bubble dimension. These features of microwave plasma generation in bubbles immersed in liquids are highly desirable for the large-scale liquid hydrocarbon reforming technologies.

  3. Terahertz generation by beating two Langmuir waves in a warm and collisional plasma

    SciTech Connect

    Zhang, Xiao-Bo; Qiao, Xin; Cheng, Li-Hong; Tang, Rong-An; Zhang, Ai-Xia; Xue, Ju-Kui

    2015-09-15

    Terahertz (THz) radiation generated by beating of two Langmuir waves in a warm and collisional plasma is discussed theoretically. The critical angle between the two Langmuir waves and the critical wave-length (wave vector) of Langmuir waves for generating THz radiation are obtained analytically. Furthermore, the maximum radiation energy is obtained. We find that the critical angle, the critical wave-length, and the generated radiation energy strongly depend on plasma temperature and wave-length of the Langmuir waves. That is, the THz radiation generated by beating of two Langmuir waves in a warm and collisional plasma can be controlled by adjusting the plasma temperature and the Langmuir wave-length.

  4. The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability.

    PubMed

    Wielders, S; Mukherjee, M; Michiels, J; Rijkers, D T; Cambus, J P; Knebel, R W; Kakkar, V; Hemker, H C; Béguin, S

    1997-04-01

    The area under the thrombin generation curve (the endogenous thrombin potential; ETP) has been proposed as a parameter for plasma-based hypercoagulability and to monitor anticoagulant treatment. We present an ETP assay for the routine laboratory using a centrifugal analyser. Throughput is 30 samples/h, within and between run imprecision is 4-5.6%. Suitable substrates were developed for the ranges of 10-500% and 2-100% of normal. Independent of tissue factor concentration (if > 4 pM), the normal value of the extrinsic ETP is 384.8 +/- 51.7 nM.min. The intrinsic ETP, triggered by ellagic acid, is 414 +/- 41 nM.min. The ETP is decreased to 15 and 35% of normal by oral anticoagulation (INR 2.5-4.0) and by heparin administration (APTT 1.5-2.5 x control). The ETP is increased in untreated subjects with congenital antithrombin deficiency and in women using oral contraceptives. In deep vein thrombosis (phlebographically confirmed), it is increased by 29.4% (extrinsic) and 53% (intrinsic). In (angiographically assessed) coronary artery disease the increase is by 10% and 17% respectively.

  5. On the Internal Gas Dynamics and Efficiency of a Vortex Water-Vapor Plasma Generator

    NASA Astrophysics Data System (ADS)

    Charakhovski, L.; Essiptchouk, A.; Otani, C.; Petraconi, G.; Marquesi, A.; Sauchyn, V.; Khvedchyn, I.; Olenovich, A.; Liavonchyk, A.; Skamarokhau, D.; Halinouski, A.

    2017-05-01

    Results of experimental investigations of a new-type generator of an arc water plasma, having a high thermal efficiency close to 100%, are presented. This generator represents a system comprising a vortex arc plasma generator, in which an electric arc is stabilized by water vapor and a straight-through-flow tubular electric steam generator. Such a high efficiency of the plasma generator system was achieved due to the refinement of the internal gas dynamics of the plasma generator and the heat and mass transfer in its discharge channel as a result of the improvement of the vortex stabilization and thermal insulation of an arc discharge in it by the specially organized ″instantly permeable″ channel wall cooled by only the working water used for generation of the plasma.

  6. Plasma generation in mass-limited water targets

    NASA Astrophysics Data System (ADS)

    Hah, Jungmoo; Liberty, Kirk; Nees, John; Krushelnick, Karl; Thomas, Alexander

    2014-10-01

    One major problem associated with high repetition-rate experiment is obtaining a suitable new target for each shot, while maintaining shot-to-shot spatial stability. For high repetition-rate laser experiments with solid targets, rotating stage is usually used for moving a target point, which causes stability and size problems. To solve these problems, some researchers have tried to replace solid targets with liquid stream or droplet. Here, we use a syringe pump, a piezoelectric device and a tungsten needle to make continuous and stable water droplets with a diameter of ~ 2 μm. These mass-limited water droplets as a target have some advantages. First, heat dissipation is blocked, so the target is entirely heated. Second, effective spatial contrast is improved by reducing the interaction between lower intensity spatial wings of the beam and a single-micron target. Third, at the relativistic laser intensities, a smaller target allows for higher electron densities at the target's back surface, which enhances field's strength for ion acceleration. For these advantages, it is required that we understand plasma generation processes. Therefore, we investigate the processes by irradiating fs laser pulses to mass-limited droplets and these interactions are captured by CCD.

  7. Naphthalene and acenaphthene decomposition by electron beam generated plasma application

    SciTech Connect

    Ostapczuk, A.; Hakoda, T.; Shimada, A.; Kojima, T.

    2008-08-15

    The application of non-thermal plasma generated by electron beam (EB) was investigated in laboratory scale to study decomposition of polycyclic aromatic hydrocarbons like naphthalene and acenaphthene in flue gas. PAH compounds were treated by EB with the dose up to 8 kGy in dry and humid base gas mixtures. Experimentally established G-values gained 1.66 and 3.72 mol/100 eV for NL and AC at the dose of 1 kGy. NL and AC removal was observed in dry base gas mixtures showing that the reaction with OH radical is not exclusive pathway to initialize PAH decomposition; however in the presence of water remarkably higher decomposition efficiency was observed. As by-products of NL decomposition were identified compounds containing one aromatic ring and oxygen atoms besides CO and CO{sub 2}. It led to the conclusion that PAH decomposition process in humid flue gas can be regarded as multi-step oxidative de-aromatization analogical to its atmospheric chemistry.

  8. Wakefields generated by collisional neutrinos in neutral-electron-positron plasma

    SciTech Connect

    Tinakiche, Nouara

    2013-02-15

    A classical fluid description is adopted to investigate nonlinear interaction between an electron-type neutrino beam and a relativistic collisionless unmagnetized neutral-electron-positron plasma. In this work, we consider the collisions of the neutrinos with neutrals in the plasma and study their effect on the generation of wakefields in this plasma.

  9. Osteopontin Fragments with Intact Thrombin-Sensitive Site Circulate in Cervical Cancer Patients

    PubMed Central

    Lim, Pak-Leong; Cheung, Tak-Hong; Wong, Raymond R. Y.; Yim, So-Fan; Ng, Margaret H. L.; Tam, Frankie C. H.; Chung, Tony K. H.; Wong, Yick-Fu

    2016-01-01

    We investigated whether circulating osteopontin (OPN) could be used as a biomarker for cervical cancer. We employed a monoclonal antibody (mAb 659) specific for the unique and intact thrombin-sensitive site in OPN using an inhibition ELISA. We found significantly higher levels of OPN in 33 cervical cancer patients in both the plasma (mean +/- SD, 612 +/- 106 ng/mL) and serum (424 +/- 121 ng/mL) compared to healthy subjects [409 +/- 56 ng/mL, from 31 plasma samples (P < 0.0001), and 314 +/- 98 ng/mL, from 32 serum samples (P = 0.0002), respectively]. Similar results were obtained when the plasma from a bigger group (147 individuals) of cervical cancer patients (560 +/- 211 ng/mL) were compared with the same plasma samples of the healthy individuals (P = 0.0014). More significantly, the OPN level was highest in stage III-IV disease (614 +/- 210 ng/mL, from 52 individuals; P = 0.0001) and least and non-discriminatory in stage I (473 +/- 110 ng/mL, from 40 individuals; P = 0.5318). No such discrimination was found when a mAb of a different specificity (mAb 446) was used in a similar inhibition ELISA to compare the two groups in the first study; a commercial capture ELISA also failed. The possibility that the target epitope recognized by the antibody probe in these assays was absent from the circulating OPN due to protein truncation was supported by gel fractionation of the OPN found in patients’ plasma: 60–64 kDa fragments were found instead of the presumably full-length OPN (68 kDa) seen in healthy people. How these fragments are generated and what possible role they play in cancer biology remain interesting questions. PMID:27494141

  10. Analysis of nitrogen plasma generated by a pulsed plasma system near atmospheric pressure

    NASA Astrophysics Data System (ADS)

    Hayakawa, R.; Yoshimura, T.; Ashida, A.; Fujimura, N.; Kitahata, H.; Yuasa, M.

    2004-12-01

    Stable discharging of pure nitrogen can be maintained even at atmospheric pressure when alternative pulsed voltage is applied between two parallel plate electrodes. We evaluated the nitrogen plasma generated by an alternative pulsed voltage system. The excited nitrogen species in a pure nitrogen plasma was evaluated using optical emission spectroscopy. In the discharging space, the largest peak detected corresponded to the N2 second positive system. Additionally, the emission peaks from the excited nitrogen atom were detected at a pressure of as high as 45Torr. In the downstream space, we detected emission peaks from the N2 Herman's infrared system as well as the N2 second positive system. The N2 (AΣu+3) state is considered to be the origin of the N2 Herman's infrared system. The emission intensities from the N2 second positive system and the N2 Herman's infrared system increase with increasing nitrogen gas pressure, whereas the emission intensity from the N2+ first negative system decreases.

  11. Functional assembly of intrinsic coagulation proteases on monocytes and platelets. Comparison between cofactor activities induced by thrombin and factor Xa

    PubMed Central

    1992-01-01

    Generation of coagulation factor Xa by the intrinsic pathway protease complex is essential for normal activation of the coagulation cascade in vivo. Monocytes and platelets provide membrane sites for assembly of components of this protease complex, factors IXa and VIII. Under biologically relevant conditions, expression of functional activity by this complex is associated with activation of factor VIII to VIIIa. In the present studies, autocatalytic regulatory pathways operating on monocyte and platelet membranes were investigated by comparing the cofactor function of thrombin-activated factor VIII to that of factor Xa-activated factor VIII. Reciprocal functional titrations with purified human factor VIII and factor IXa were performed at fixed concentrations of human monocytes, CaCl2, factor X, and either factor IXa or factor VIII. Factor VIII was preactivated with either thrombin or factor Xa, and reactions were initiated by addition of factor X. Rates of factor X activation were measured using chromogenic substrate specific for factor Xa. The K1/2 values, i.e., concentration of factor VIIIa at which rates were half maximal, were 0.96 nM with thrombin- activated factor VIII and 1.1 nM with factor Xa-activated factor VIII. These values are close to factor VIII concentration in plasma. The Vsat, i.e., rates at saturating concentrations of factor VIII, were 33.3 and 13.6 nM factor Xa/min, respectively. The K1/2 and Vsat values obtained in titrations with factor IXa were not significantly different from those obtained with factor VIII. In titrations with factor X, the values of Michaelis-Menten coefficients (Km) were 31.7 nM with thrombin- activated factor VIII, and 14.2 nM with factor Xa-activated factor VIII. Maximal rates were 23.4 and 4.9 nM factor Xa/min, respectively. The apparent catalytic efficiency was similar with either form of factor VIIIa. Kinetic profiles obtained with platelets as a source of membrane were comparable to those obtained with monocytes

  12. Population Inversions in Ablation Plasmas Generated by Intense Electron Beams.

    DTIC Science & Technology

    1986-11-30

    beam driven carbon anode plasmas. Diode closure results ..,.in three phases of beam-plasma evolution which are summarized below: Stage I: Deposited...enough for anode plasma forma- tion before the diode shorts. Spectroscopic data for noncrowbarred shots (dose 1 500-800 J/g) indicate the presence of CII...inconsistent with previously proposed kinetic mechanisms for the N2 laser pumped by helium. With a simple- model of the chemical kinetics, we have shown

  13. Radiofrequency plasma antenna generated by femtosecond laser filaments in air

    SciTech Connect

    Brelet, Y.; Houard, A.; Point, G.; Prade, B.; Carbonnel, J.; Andre, Y.-B.; Mysyrowicz, A.; Arantchouk, L.; Pellet, M.

    2012-12-24

    We demonstrate tunable radiofrequency emission from a meter-long linear plasma column produced in air at atmospheric pressure. A short-lived plasma column is initially produced by femtosecond filamentation and subsequently converted into a long-lived discharge column by application of an external high voltage field. Radiofrequency excitation is fed to the plasma by induction and detected remotely as electromagnetic radiation by a classical antenna.

  14. Cylindrical plasmas generated by an annular beam of ultraviolet light

    SciTech Connect

    Thomas, D. M.; Allen, J. E.

    2015-07-15

    We investigate a cylindrical plasma system with ionization, by an annular beam of ultraviolet light, taking place only in the cylinder's outer region. In the steady state, both the outer and inner regions contain a plasma, with that in the inner region being uniform and field-free. At the interface between the two regions, there is an infinitesimal jump in ion density, the magnitude approaching zero in the quasi-neutral (λ{sub D} → 0) limit. The system offers the possibility of producing a uniform stationary plasma in the laboratory, hitherto obtained only with thermally produced alkali plasmas.

  15. Spatio-temporal optimization of a laser produced Al-plasma: Generation of highly ionized species

    NASA Astrophysics Data System (ADS)

    Smijesh, N.; H. Rao, Kavya; Klemke, N.; Philip, R.; Litvinyuk, I. V.; Sang, R. T.

    2016-11-01

    Laser produced plasmas are transient in nature, and their properties, which depend on the laser parameters as well as the material properties and the irradiation conditions, can be tailored for different applications. Highly ionized Al plasmas generated using 7 ns and negatively chirped 60 ps pulses are optimized for the purpose of generating Al IV and Al III, respectively. The plasma is optimized spatio-temporally for Al IV or Al III with irradiation energy as the control parameter using time-resolved optical emission spectroscopy. Plasmas attuned for higher charged states could be utilized as a good alternative source for the generation of high order harmonics.

  16. Effect of preformed plasma on terahertz-wave emission from the plasma generated by two-color laser pulses

    SciTech Connect

    Minami, Yasuo; Nakajima, Makoto; Suemoto, Tohru

    2011-02-15

    We introduced a weak prepulse 0-2 ns before the main pulse in the formation of a terahertz (THz) wave in air plasma by laser pulses composed of fundamental and second-harmonic waves. The prepulse suppressed the THz wave generated by the main pulse. We analyzed the suppression factor as a function of the time interval between the prepulse and the main pulse and found that the THz wave from the main pulse decreases immediately after the prepulse, recovers partially within several hundred picoseconds, and then recovers slowly. This suppression is attributed to the dense plasma, which absorbs and screens the generated THz wave, since the relaxation time is close to the lifetime of the fluorescence from the plasma. The results support the idea that the major mechanism of THz wave generation is explained by the plasma current model.

  17. Pencil lead plasma for generating multimicrojoule high-order harmonics with a broad spectrum

    SciTech Connect

    Pertot, Y.; Elouga Bom, L. B.; Ozaki, T.; Bhardwaj, V. R.

    2011-03-07

    Using the plasma harmonic method, we show the generation of efficient and intense high-order harmonics from plasma of pencil lead. We demonstrate multimicrojoule energy in each harmonic order for the 11th to the 17th order of a Ti:sapphire laser. By analyzing the target morphology and the plasma composition, we conclude that these intense harmonics are generated from nanoparticles of graphitic carbon.

  18. Hollow Cathode Produced Electron Beams for Plasma Generation: Cathode Operation in Gas Mixtures

    DTIC Science & Technology

    2006-12-15

    Naval Research Laboratory Washington, DC 20375-5320 NRL/MR/6750--06-8992 Hollow Cathode Produced Electron Beams for Plasma Generation: Cathode...Operation in Gas Mixtures Scott Walton Darrin leonharDt richarD FernSler Charged Particle Physics Branch Plasma Physics Division December 15, 2006 Approved...17. LIMITATION OF ABSTRACT Hollow Cathode Produced Electron Beams for Plasma Generation: Cathode Operation in Gas Mixtures Scott Walton, Darrin

  19. Cleavage at Arg-1689 influences heavy chain cleavages during thrombin-catalyzed activation of factor VIII.

    PubMed

    Newell, Jennifer L; Fay, Philip J

    2009-04-24

    The procofactor, factor VIII, is activated by thrombin or factor Xa-catalyzed cleavage at three P1 residues: Arg-372, Arg-740, and Arg-1689. The catalytic efficiency for thrombin cleavage at Arg-740 is greater than at either Arg-1689 or Arg-372 and influences reaction rates at these sites. Because cleavage at Arg-372 appears rate-limiting and dependent upon initial cleavage at Arg-740, we investigated whether cleavage at Arg-1689 influences catalysis at this step. Recombinant B-domainless factor VIII mutants, R1689H and R1689Q were prepared and stably expressed to slow and eliminate cleavage, respectively. Specific activity values for the His and Gln mutations were approximately 50 and approximately 10%, respectively, that of wild type. Thrombin activation of the R1689H variant showed an approximately 340-fold reduction in the rate of Arg-1689 cleavage, whereas the R1689Q variant was resistant to thrombin cleavage at this site. Examination of heavy chain cleavages showed approximately 4- and 11-fold reductions in A2 subunit generation and approximately 3- and 7-fold reductions in A1 subunit generation for the R1689H and R1689Q mutants, respectively. These results suggest a linkage between light chain cleavage and cleavages in heavy chain. Results obtained evaluating proteolysis of the factor VIII mutants by factor Xa revealed modest rate reductions (<5-fold) in generating A2 and A1 subunits and in cleaving light chain at Arg-1721 from either variant, suggesting little dependence upon prior cleavage at residue 1689 as compared with thrombin. Overall, these results are consistent with a competition between heavy and light chains for thrombin exosite binding and subsequent proteolysis with binding of the former chain preferred.

  20. Two distinct Ca2+ compartments show differential sensitivity to thrombin, ADP and vasopressin in human platelets.

    PubMed

    López, Jose J; Redondo, Pedro C; Salido, Ginés M; Pariente, Jose A; Rosado, Juan A

    2006-03-01

    Recent studies propose the existence of two distinct Ca2+ compartments in human platelets based on the expression of different SERCA isoforms with distinct sensitivity to thapsigargin and 2,5-di-(tert-butyl)-1,4-hydroquinone (TBHQ). Using fura-2-loaded human platelets we have found that depletion of the TBHQ sensitive store reduces thrombin--but not ADP--or vasopressin (AVP)-induced Ca2+ release. Redistribution of cytosolic Ca2+ after thrombin stimulation resulted in overloading of the TBHQ-sensitive store. This phenomenon was not observed with ADP or AVP. We found that NAADP decreases the Ca2+ concentration into the stores in permeabilized platelets, which is prevented by depletion of the TBHQ-sensitive store. Nimodipine, an inhibitor of the NAADP receptor, reduced thrombin-induced Ca2+ release from the TBHQ-sensitive stores, without having any effect on the responses elicited by ADP or AVP. Finally, the phospholipase C inhibitor, U-73122, abolished ADP- and AVP-induced Ca2+ release, suggesting that their responses are entirely dependent on IP3 generation. In contrast, treatment with both U-73122 and nimodipine was required to abolish thrombin-induced Ca2+ release. We suggest that thrombin evokes Ca2+ release from TBHQ-sensitive and insensitive stores, which requires both NAADP and IP3, respectively, while ADP and AVP exert an IP3-dependent release of Ca2+ from the TBHQ-insensitive compartment in human platelets.

  1. Thomson scattering measurement of a collimated plasma jet generated by a high-power laser system

    NASA Astrophysics Data System (ADS)

    Ishikawa, T.; Sakawa, Y.; Morita, T.; Yamaura, Y.; Kuramitsu, Y.; Moritaka, T.; Sano, T.; Shimoda, R.; Tomita, K.; Uchino, K.; Matsukiyo, S.; Mizuta, A.; Ohnishi, N.; Crowston, R.; Woolsey, N.; Doyle, H.; Gregori, G.; Koenig, M.; Michaut, C.; Pelka, A.; Yuan, D.; Li, Y.; Zhang, K.; Zhong, J.; Wang, F.; Takabe, H.

    2016-03-01

    One of the important and interesting problems in astrophysics and plasma physics is collimation of plasma jets. The collimation mechanism, which causes a plasma flow to propagate a long distance, has not been understood in detail. We have been investigating a model experiment to simulate astrophysical plasma jets with an external magnetic field [Nishio et al., EPJ. Web of Conferences 59, 15005 (2013)]. The experiment was performed by using Gekko XII HIPER laser system at Institute of Laser Engineering, Osaka University. We shot CH plane targets (3 mm × 3 mm × 10 μm) and observed rear-side plasma flows. A collimated plasma flow or plasma jet was generated by separating focal spots of laser beams. In this report, we measured plasma jet structure without an external magnetic field with shadowgraphy, and simultaneously measured the local parameters of the plasma jet, i.e., electron density, electron and ion temperatures, charge state, and drift velocity, with collective Thomson scattering.

  2. Cavitational Iron Microparticles Generation By Plasma Procedures For Medical Applications

    NASA Astrophysics Data System (ADS)

    Bica, Ioan; Bunoiu, Madalin; Chirigiu, Liviu; Spunei, Marius; Juganaru, Iulius

    2012-12-01

    The paper presents the experimental installation for the production, in argon plasma, of cavitational iron microparticles (pore microspheres, microtubes and octopus-shaped microparticles). Experimental results are presented and discussed and it is shown that absorbant particles with a minimum iron content are obtained by the plasma procedures

  3. A plasma generator utilizing the high intensity ASTROMAG magnets

    NASA Technical Reports Server (NTRS)

    Sullivan, James D.; Post, R. S.; Lane, B. G.; Tarrh, J. M.

    1986-01-01

    The magnet configuration for the proposed particle astrophysics magnet facility (ASTROMAG) on the space station includes a cusp magnetic field with an intensity of a few tesla. With these large magnets (or others) located in the outer ionosphere, many quite interesting and unique plasma physics experiments become possible. First there are studies utilizing the magnet alone to examine the supersonic, sub-Alfvenic interaction with the ambient medium; the scale length for the magnet perturbation is approx. 20 m. The magnetic field geometry when combined with the Earth's and their relative motion will give rise to a host of plasma phenomena: ring nulls, x-points, ion-acoustic and lower-hybrid shocks, electron heating (possible shuttle glow without a surface) launching of Alfvenwaves, etc. Second, active experiments are possible for a controlled study of fundamental plasma phenomena. A controlled variable species plasma can be made by using an RF ion source; use of two soft iron rings placed about the line cusp would give an adequate resonance zone (ECH or ICH) and a confining volume suitable for gas efficiency. The emanating plasma can be used to study free expansion of plasma along and across field lines (polar wind), plasma flows around the space platform, turbulent mixing in the wake region, long wavelength spectrum of convecting modes, plasma-dust interactions, etc.

  4. Generation of reactive species by an atmospheric pressure plasma jet

    NASA Astrophysics Data System (ADS)

    Kelly, S.; Turner, M. M.

    2014-12-01

    The role of gas mixing in reactive species delivery to treatment surfaces for an atmospheric pressure capacitively coupled plasma helium jet is investigated by numerical modelling. Atomic oxygen in the jet effluent is shown to quickly convert to ozone for increasing device to surface separation due to the molecular oxygen present in the gas mixture. Surface profiles of reactive oxygen species show narrow peaks for atomic oxygen and broader surface distributions for ozone and metastable species. Production efficiency of atomic oxygen to the helium plasma jet by molecular oxygen admixture is shown to be dependent on electro-negativity. Excessive molecular oxygen admixture results in negative ion dominance over electrons which eventually quenches the plasma. Interaction of the plasma jet with an aqueous surface showed hydrogen peroxide as the dominant species at this interface. Gas heating by the plasma is found to be dominated by elastic electron collisions and positive ion heating. Comparison with experimental measurements for atomic oxygen shows good agreement.

  5. Microwave plasma generation of hydrogen atoms for rocket propulsion

    NASA Technical Reports Server (NTRS)

    Chapman, R.; Filpus, J.; Morin, T.; Snellenberger, R.; Asmussen, J.; Hawley, M.; Kerber, R.

    1981-01-01

    A flow microwave plasma reaction system is used to study the conversion of hydrogen to hydrogen atoms as a function of pressure, power density, cavity tuning, cavity mode, and time in the plasma zone. Hydrogen atom concentration is measured down-stream from the plasma by NOCl titration. Extensive modeling of the plasma and recombination zones is performed with the plasma zone treated as a backmix reaction system and the recombination zone treated as a plug flow. The thermodynamics and kinetics of the recombination process are examined in detail to provide an understanding of the conversion of recombination energy to gas kinetic energy. It is found that cavity tuning, discharge stability, and optimum power coupling are critically dependent on the system pressure, but nearly independent of the flow rate.

  6. Theoretical model for plasma expansion generated by hypervelocity impact

    SciTech Connect

    Ju, Yuanyuan; Zhang, Qingming Zhang, Dongjiang; Long, Renrong; Chen, Li; Huang, Fenglei; Gong, Zizheng

    2014-09-15

    The hypervelocity impact experiments of spherical LY12 aluminum projectile diameter of 6.4 mm on LY12 aluminum target thickness of 23 mm have been conducted using a two-stage light gas gun. The impact velocity of the projectile is 5.2, 5.7, and 6.3 km/s, respectively. The experimental results show that the plasma phase transition appears under the current experiment conditions, and the plasma expansion consists of accumulation, equilibrium, and attenuation. The plasma characteristic parameters decrease as the plasma expands outward and are proportional with the third power of the impact velocity, i.e., (T{sub e}, n{sub e}) ∝ v{sub p}{sup 3}. Based on the experimental results, a theoretical model on the plasma expansion is developed and the theoretical results are consistent with the experimental data.

  7. Microwave plasma generation of hydrogen atoms for rocket propulsion

    NASA Technical Reports Server (NTRS)

    Chapman, R.; Filpus, J.; Morin, T.; Snellenberger, R.; Asmussen, J.; Hawley, M.; Kerber, R.

    1981-01-01

    A flow microwave plasma reaction system is used to study the conversion of hydrogen to hydrogen atoms as a function of pressure, power density, cavity tuning, cavity mode, and time in the plasma zone. Hydrogen atom concentration is measured down-stream from the plasma by NOCl titration. Extensive modeling of the plasma and recombination zones is performed with the plasma zone treated as a backmix reaction system and the recombination zone treated as a plug flow. The thermodynamics and kinetics of the recombination process are examined in detail to provide an understanding of the conversion of recombination energy to gas kinetic energy. It is found that cavity tuning, discharge stability, and optimum power coupling are critically dependent on the system pressure, but nearly independent of the flow rate.

  8. Evaluation of antithrombotic activity of thrombin DNA aptamers by a murine thrombosis model.

    PubMed

    Zavyalova, Elena; Samoylenkova, Nadezhda; Revishchin, Alexander; Golovin, Andrey; Pavlova, Galina; Kopylov, Alexey

    2014-01-01

    Aptamers are nucleic acid based molecular recognition elements with a high potential for the theranostics. Some of the aptamers are under development for therapeutic applications as promising antithrombotic agents; and G-quadruplex DNA aptamers, which directly inhibit the thrombin activity, are among them. RA-36, the 31-meric DNA aptamer, consists of two thrombin binding pharmacophores joined with the thymine linker. It has been shown earlier that RA-36 directly inhibits thrombin in the reaction of fibrinogen hydrolysis, and also it inhibits plasma and blood coagulation. Studies of both inhibitory and anticoagulation effects had indicated rather high species specificity of the aptamer. Further R&D of RA-36 requires exploring its efficiency in vivo. Therefore the development of a robust and adequate animal model for effective physiological studies of aptamers is in high current demand. This work is devoted to in vivo study of the antithrombotic effect of RA-36 aptamer. A murine model of thrombosis has been applied to reveal a lag and even prevention of thrombus formation when RA-36 was intravenous bolus injected in high doses of 1.4-7.1 µmol/kg (14-70 mg/kg). A comparative study of RA-36 aptamer and bivalirudin reveals that both direct thrombin inhibitors have similar antithrombotic effects for the murine model of thrombosis; though in vitro bivalirudin has anticoagulation activity several times higher compared to RA-36. The results indicate that both RA-36 aptamer and bivalirudin are direct thrombin inhibitors of different potency, but possible interactions of the thrombin-inhibitor complex with other components of blood coagulation cascade level the physiological effects for both inhibitors.

  9. Evaluation of Antithrombotic Activity of Thrombin DNA Aptamers by a Murine Thrombosis Model

    PubMed Central

    Zavyalova, Elena; Samoylenkova, Nadezhda; Revishchin, Alexander; Golovin, Andrey; Pavlova, Galina; Kopylov, Alexey

    2014-01-01

    Aptamers are nucleic acid based molecular recognition elements with a high potential for the theranostics. Some of the aptamers are under development for therapeutic applications as promising antithrombotic agents; and G-quadruplex DNA aptamers, which directly inhibit the thrombin activity, are among them. RA-36, the 31-meric DNA aptamer, consists of two thrombin binding pharmacophores joined with the thymine linker. It has been shown earlier that RA-36 directly inhibits thrombin in the reaction of fibrinogen hydrolysis, and also it inhibits plasma and blood coagulation. Studies of both inhibitory and anticoagulation effects had indicated rather high species specificity of the aptamer. Further R&D of RA-36 requires exploring its efficiency in vivo. Therefore the development of a robust and adequate animal model for effective physiological studies of aptamers is in high current demand. This work is devoted to in vivo study of the antithrombotic effect of RA-36 aptamer. A murine model of thrombosis has been applied to reveal a lag and even prevention of thrombus formation when RA-36 was intravenous bolus injected in high doses of 1.4–7.1 µmol/kg (14–70 mg/kg). A comparative study of RA-36 aptamer and bivalirudin reveals that both direct thrombin inhibitors have similar antithrombotic effects for the murine model of thrombosis; though in vitro bivalirudin has anticoagulation activity several times higher compared to RA-36. The results indicate that both RA-36 aptamer and bivalirudin are direct thrombin inhibitors of different potency, but possible interactions of the thrombin-inhibitor complex with other components of blood coagulation cascade level the physiological effects for both inhibitors. PMID:25192011

  10. The thrombin receptor extracellular domain contains sites crucial for peptide ligand-induced activation.

    PubMed Central

    Bahou, W F; Coller, B S; Potter, C L; Norton, K J; Kutok, J L; Goligorsky, M S

    1993-01-01

    A thrombin receptor (TR) demonstrating a unique activation mechanism has recently been isolated from a megakaryocytic (Dami) cell line. To further study determinants of peptide ligand-mediated activation phenomenon, we have isolated, cloned, and stably expressed the identical receptor from a human umbilical vein endothelial cell (HUVEC) library. Chinese hamster ovary (CHO) cells expressing a functional TR (CHO-TR), platelets, and HUVECs were then used to specifically characterize alpha-thrombin- and peptide ligand-induced activation responses using two different antibodies: anti-TR34-52 directed against a 20-amino acid peptide spanning the thrombin cleavage site, and anti-TR1-160 generated against the NH2-terminal 160 amino acids of the TR expressed as a chimeric protein in Escherichia coli. Activation-dependent responses to both alpha-thrombin (10 nM) and peptide ligand (20 microM) were studied using fura 2-loaded cells and microspectrofluorimetry. Whereas preincubation of CHO-TR with anti-TR34-52 abolished only alpha-thrombin-induced [Ca2+]i transients, preincubation with anti-TR1-160 abrogated both alpha-thrombin- and peptide ligand-induced responses. This latter inhibitory effect was dose dependent and similar for both agonists, with an EC50 of approximately 90 micrograms/ml. Anti-TR1-160 similarly abolished peptide ligand-induced [Ca2+]i transients in platelets and HUVECs, whereas qualitatively different responses characterized by delayed but sustained elevations in [Ca2+]i transients were evident using alpha-thrombin. Platelet aggregation to low concentrations of both ligands was nearly abolished by anti-TR1-160, although some shape change remained; anti-TR34-52 only inhibited alpha-thrombin-induced aggregation. These data establish that a critical recognition sequence for peptide ligand-mediated receptor activation is contained on the NH2-terminal portion of the receptor, upstream from the first transmembrane domain. Furthermore, alpha-thrombin

  11. Generation and remote delivery of plasma activated species

    NASA Astrophysics Data System (ADS)

    Maguire, Paul; Mahony, Charles; Kelsey, Colin; Rutherford, David; Mariotti, Davide; Macias-Montero, Manuel; Perez-Martin, Fatima; Diver, Declan

    2016-09-01

    Plasma interactions with microdroplets offer new opportunities to deliver active chemical agents and nanoparticles to remote substrates downstream with many potential applications from cancer theranostics and wound healing in biomedicine, gentle food decontamination and seed germination in plasma agriculture to catalyst production and photonic structures fabrication, among others. We demonstrate plasma-liquid based pristine nanomaterials synthesis in flight and subsequent delivery up to 120mm from the atmospheric pressure plasma source. Monosized and non-aggregating metal nanoparticles are formed in the rf plasma in less than 100us, representing an increase in precursor reduction rate that is many (>4) orders of magnitude faster than that observed with standard colloidal chemistry or via high energy radiolytic techniques. Also the collection and purification limitations of the latter are avoided. Plasma activated liquid including OH radicals and H2O2 are transported over 120mm and have demonstrated high efficacy bacterial decontamination. These results will be compared with charge species and radical transport from the rf plasma without microdroplets. Reaction models based on high solvated surface electron concentrations will be presented. Funding from EPSRC acknowledged (Grants EP/K006088/1 and EP/K006142/1).

  12. Dust generation at interaction of plasma jet with surfaces

    NASA Astrophysics Data System (ADS)

    Ticos, Catalin; Toader, Dorina; Banu, Nicoleta; Scurtu, Adrian; Oane, Mihai

    2013-10-01

    Coatings of W and C with widths of a few microns will be exposed to plasma jet for studying the erosion of the surface and detachment of micron size dust particles. A coaxial plasma gun has been built inside a vacuum chamber for producing supersonic plasma jets. Its design is based on a 50 kJ coaxial plasma gun which has been successfully used for accelerating hypervelocity dust. Initial shots were carried out for a capacitor bank with C = 12 μF and charged up to 2 kV. Currents of tens of amps were measured with a Rogowsky coil and plasma flow speeds of 4 km/s were inferred from high-speed images of jet propagation. An upgrade consisting in adding capacitors in parallel will be performed in order to increase the energy up to 2 kJ. A coil will be installed at the gun muzzle to compress the plasma flow and increase the energy density of the jet on the sample surface. A CCD camera with a maximum recording speed of 100 k fps and a maximum resolution of 1024 × 1024 pixels was set for image acquisition of the plasma and dust. A laser system used to illuminate the ejected dust from the surface includes a laser diode emitting at 650 nm with a beam power of 25 mW. The authors acknowledge support from EURATOM WP13-IPH-A03-P2-02-BS22.

  13. Spectroscopic determination of temperatures in plasmas generated by arc torches

    NASA Astrophysics Data System (ADS)

    Mašláni, Alan; Sember, Viktor; Hrabovský, Milan

    2017-07-01

    Two different arc plasma torches and especially their plasma jets are studied using optical emission spectra. Results include temperatures obtained from emission lines of atoms, ions and diatomic molecules in various distances along the axes of the plasma jets. Understanding of temperature distributions is complicated mainly in the downstream turbulent regions of the jets. Several common features are found during comparison of emission spectra and corresponding temperatures. It is shown that Boltzmann plot of rotational lines of OH can serve as a good thermometer in the downstream regions of both jets. It seems that even high temperatures exceeding 6000 K may be measured efficiently by this method.

  14. Parasitic current losses due to solar electric propulsion generated plasmas

    NASA Technical Reports Server (NTRS)

    Katz, I.; Parks, D. E.; Mandell, M. J.; Schnuelle, G. W.

    1981-01-01

    Solar electric propulsion is a leading candidate for many upcoming space missions. Under many circumstances plasma produced by charge-exchange reactions within the ion beam dominates the ambient environment near the spacecraft. The calculations presented here contain a predictive hydrodynamic model for the charge-exchange plasma expansion, and a fully three-dimensional model for the structure of the plasma sheath around the solar array wing. Results of calculations for several configurations and voltage levels indicate that with kilovolt biases power losses of approximately 10 percent or more are likely, even with only one engine in operation, and that ameliorative measures should focus on the inboard portion of the solar arrays.

  15. Atmospheric-Pressure Plasma Jet Induces Apoptosis Involving Mitochondria via Generation of Free Radicals

    PubMed Central

    Kim, Geunyoung; Moon, Eunpyo; Yang, Sang Sik; Lee, Jong-Soo

    2011-01-01

    The plasma jet has been proposed as a novel therapeutic method for anticancer treatment. However, its biological effects and mechanism of action remain elusive. Here, we investigated its cell death effects and underlying molecular mechanisms, using air and N2 plasma jets from a micro nozzle array. Treatment with air or N2 plasma jets caused apoptotic death in human cervical cancer HeLa cells, simultaneously with depolarization of mitochondrial membrane potential. In addition, the plasma jets were able to generate reactive oxygen species (ROS), which function as surrogate apoptotic signals by targeting the mitochondrial membrane potential. Antioxidants or caspase inhibitors ameliorated the apoptotic cell death induced by the air and N2 plasma jets, suggesting that the plasma jet may generate ROS as a proapoptotic cue, thus initiating mitochondria-mediated apoptosis. Taken together, our data suggest the potential employment of plasma jets as a novel therapy for cancer. PMID:22140530

  16. Atmospheric-pressure plasma jet induces apoptosis involving mitochondria via generation of free radicals.

    PubMed

    Ahn, Hak Jun; Kim, Kang Il; Kim, Geunyoung; Moon, Eunpyo; Yang, Sang Sik; Lee, Jong-Soo

    2011-01-01

    The plasma jet has been proposed as a novel therapeutic method for anticancer treatment. However, its biological effects and mechanism of action remain elusive. Here, we investigated its cell death effects and underlying molecular mechanisms, using air and N₂ plasma jets from a micro nozzle array. Treatment with air or N₂ plasma jets caused apoptotic death in human cervical cancer HeLa cells, simultaneously with depolarization of mitochondrial membrane potential. In addition, the plasma jets were able to generate reactive oxygen species (ROS), which function as surrogate apoptotic signals by targeting the mitochondrial membrane potential. Antioxidants or caspase inhibitors ameliorated the apoptotic cell death induced by the air and N₂ plasma jets, suggesting that the plasma jet may generate ROS as a proapoptotic cue, thus initiating mitochondria-mediated apoptosis. Taken together, our data suggest the potential employment of plasma jets as a novel therapy for cancer.

  17. System and method for generating steady state confining current for a toroidal plasma fusion reactor

    DOEpatents

    Bers, Abraham

    1981-01-01

    A system for generating steady state confining current for a toroidal plasma fusion reactor providing steady-state generation of the thermonuclear power. A dense, hot toroidal plasma is initially prepared with a confining magnetic field with toroidal and poloidal components. Continuous wave RF energy is injected into said plasma to estalish a spectrum of traveling waves in the plasma, where the traveling waves have momentum components substantially either all parallel, or all anti-parallel to the confining magnetic field. The injected RF energy is phased to couple to said traveling waves with both a phase velocity component and a wave momentum component in the direction of the plasma traveling wave components. The injected RF energy has a predetermined spectrum selected so that said traveling waves couple to plasma electrons having velocities in a predetermined range .DELTA.. The velocities in the range are substantially greater than the thermal electron velocity of the plasma. In addition, the range is sufficiently broad to produce a raised plateau having width .DELTA. in the plasma electron velocity distribution so that the plateau electrons provide steady-state current to generate a poloidal magnetic field component sufficient for confining the plasma. In steady state operation of the fusion reactor, the fusion power density in the plasma exceeds the power dissipated inthe plasma.

  18. System and method for generating steady state confining current for a toroidal plasma fusion reactor

    DOEpatents

    Fisch, Nathaniel J.

    1981-01-01

    A system for generating steady state confining current for a toroidal plasma fusion reactor providing steady-state generation of the thermonuclear power. A dense, hot toroidal plasma is initially prepared with a confining magnetic field with toroidal and poloidal components. Continuous wave RF energy is injected into said plasma to establish a spectrum of traveling waves in the plasma, where the traveling waves have momentum components substantially either all parallel, or all anti-parallel to the confining magnetic field. The injected RF energy is phased to couple to said traveling waves with both a phase velocity component and a wave momentum component in the direction of the plasma traveling wave components. The injected RF energy has a predetermined spectrum selected so that said traveling waves couple to plasma electrons having velocities in a predetermined range .DELTA.. The velocities in the range are substantially greater than the thermal electron velocity of the plasma. In addition, the range is sufficiently broad to produce a raised plateau having width .DELTA. in the plasma electron velocity distribution so that the plateau electrons provide steady-state current to generate a poloidal magnetic field component sufficient for confining the plasma. In steady state operation of the fusion reactor, the fusion power density in the plasma exceeds the power dissipated in the plasma.