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  1. von Willebrand Disease

    PubMed Central

    Goodeve, Anne C.

    2013-01-01

    von Willebrand disease (VWD) is a common inherited bleeding disorder characterized by excessive mucocutaneous bleeding. Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery and/or childbirth and in severe cases, bleeding into joints and soft tissues. There are three subtypes: types 1 and 3 represent quantitative variants and type 2 is a group of four qualitative variants: 1) type 2A - characterized by defective von Willebrand factor (VWF) -dependent platelet adhesion because of decreased high molecular weight (HMW) VWF multimers, 2) type 2B - caused by pathologically increased VWF-platelet interactions, 3) type 2M - caused by decreased VWF-platelet interactions not based on the loss of HMW multimers and 4) type 2N - characterized by abnormal binding of VWF to FVIII. The diagnosis of VWD requires specialized assays of von Willebrand factor (VWF) and/or molecular genetic testing of VWF. Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally-inactivated plasma-derived clotting factor concentrates containing both VWF and FVIII. Depending on the VWD type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. Other treatments that can reduce symptoms include fibrinolytic inhibitors and hormones for menorrhagia. PMID:21289515

  2. Type 2M and Type 2A von Willebrand Disease: Similar but Different.

    PubMed

    Favaloro, Emmanuel J; Pasalic, Leonardo; Curnow, Jennifer

    2016-07-01

    Analogous to the differentiation between hemophilia A and B, respectively, reflecting deficiency in factor VIII (FVIII) and FIX, and increasing being recognized as reflecting clinically different disorders, types 2A and 2M von Willebrand disease (VWD) can also be shown to express both similarities and differences in their prevalence, genetic defects, laboratory test results, clinical features, and treatment responses. In this narrative review, we explore these two "subtypes" of type 2 VWD, identifying parallels and dissimilarities in various aspects of their presentation to clinicians and to scientists/laboratories. This differential will become increasingly important as we strive to provide personalized approaches to future management of patients with VWD, particularly in the emerging landscape of recombinant von Willebrand factor. PMID:27148841

  3. Von Willebrand factor and von Willebrand disease.

    PubMed

    Budde, U; Schneppenheim, R

    2001-12-01

    von Willebrand disease (vWD) is caused by quantitative and/or qualitative defects of the von Willebrand factor (vWF), a multimeric high molecular weight glycoprotein. Typically, it affects the primary hemostatic system, which results in a mucocutaneous bleeding tendency simulating a platelet function defect. The vWF promotes its function in two ways: (i) by initiating platelet adhesion to the injured vessel wall under conditions of high shear forces, and (ii) by its carrier function for factor VIII in plasma. Accumulating knowledge of the different clinical phenotypes and the pathophysiological basis of the disease translated into a classification that differentiated between quantitative and qualitative defects by means of quantitative and functional parameters, and by analyzing the electrophoretic pattern of vWF multimers. The advent of molecular techniques provided the opportunity for conducting genotype-phenotype studies which have recently helped, not only to elucidate or confirm important functions of vWF and its steps in post-translational processing, but also many disease causing defects. Acquired von Willebrand syndrome (avWS) has gained more attention during the recent years. An international registry was published and recommendation by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis in 2000. It concluded that avWS, although not a frequent disease, is nevertheless probably underdiagnosed. This should be addressed in future prospective studies. The aim of treatment is the correction of the impaired hemostatic system of the patient, ideally including the defects of both primary and secondary hemostasis. Desmopressin is the treatment of choice in about 70% of patients, mostly with type 1, while the others merit treatment with concentrates containing vWF. PMID:11844133

  4. [Acquired von Willebrand syndrome].

    PubMed

    Franchini, Massimo

    2006-01-01

    Acquired von Willebrand syndrome (aVWS) is a rare, but probably underestimated, bleeding disorder that mimics the congenital form of von Willebrand disease (VWD) in terms of laboratory findings and clinical presentation. However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. AVWS occurs in association with a variety of underlying disorders, including lymphoproliferative disorders, myeloproliferative disorders and cardiovascular diseases. The main pathogenic, clinical, laboratory and therapeutic aspects of this syndrome are concisely reported in this review. PMID:16913181

  5. von Willebrand Disease (For Parents)

    MedlinePlus

    ... Type 2A or Type 2B. People with Type 3 (and some with Type 2A and 2B) will need treatment with Humate-P, an intravenous medication derived from human plasma that contains factor VIII and von Willebrand factor. ...

  6. Acquired von Willebrand disease.

    PubMed

    Petrini, P

    1999-05-01

    Acquired von Willebrand disease (AvWD) is a syndrome that has clinical and laboratory features similar to hereditary vWD. In contrast to the latter it occurs in patients without a family history of previous bleeding tendency. PMID:23401904

  7. von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor.

    PubMed

    Brehm, M A; Huck, V; Aponte-Santamaría, C; Obser, T; Grässle, S; Oyen, F; Budde, U; Schneppenheim, S; Baldauf, C; Gräter, F; Schneider, S W; Schneppenheim, R

    2014-07-01

    The bleeding disorder von Willebrand disease (VWD) is caused by mutations of von Willebrand factor (VWF), a multimeric glycoprotein essential for platelet-dependent primary haemostasis. VWD type 2A-associated mutations each disrupt VWF biosynthesis and function at different stages, depending on the VWF domain altered by the mutation. These effects cause considerable heterogeneity in phenotypes and symptoms. To characterise the molecular mechanisms underlying the specific VWF deficiencies in VWD 2A/IIC, IID and IIE, we investigated VWF variants with patient-derived mutations either in the VWF pro-peptide or in domains D3 or CK. Additionally to static assays and molecular dynamics (MD) simulations we used microfluidic approaches to perform a detailed investigation of the shear-dependent function of VWD 2A mutants. For each group, we found distinct characteristics in their intracellular localisation visualising specific defects in biosynthesis which are correlated to respective multimer patterns. Using microfluidic assays we further determined shear flow-dependent characteristics in polymer-platelet-aggregate formation, platelet binding and string formation for all mutants. The phenotypes observed under flow conditions were not related to the mutated VWF domain. By MD simulations we further investigated how VWD 2A/IID mutations might alter the ability of VWF to form carboxy-terminal dimers. In conclusion, our study offers a comprehensive picture of shear-dependent and shear-independent dysfunction of VWD type 2A mutants. Furthermore, our microfluidic assay might open new possibilities for diagnosis of new VWD phenotypes and treatment choice for VWD patients with shear-dependent VWF dysfunctions that are currently not detectable by static tests. PMID:24598842

  8. [Inborn and acquired von Willebrand disease].

    PubMed

    Schneppenheim, R; Budde, U

    2008-12-01

    Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented. PMID:19132162

  9. [Inborn and acquired von Willebrand disease].

    PubMed

    Schneppenheim, R; Barthels, M; Budde, U

    2005-11-01

    Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practitioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented. PMID:16395486

  10. Acquired von Willebrand disease.

    PubMed

    Kumar, Shaji; Pruthi, Rajiv K; Nichols, William L

    2002-02-01

    Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history. Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD. Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients. Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management. PMID:11838652

  11. Treatment of von Willebrand Disease.

    PubMed

    Curnow, Jennifer; Pasalic, Leonardo; Favaloro, Emmanuel J

    2016-03-01

    Congenital von Willebrand disease (VWD) and acquired von Willebrand syndrome (AVWS) reflect conditions caused by von Willebrand factor (VWF) deficiency and/or defects. VWD is the most common inherited bleeding disorder and AVWS arises from a variety of causes. Since VWF stabilizes and protects factor VIII (FVIII) in the circulation, this is also reduced in many patients with VWD. The treatment of VWD and AVWS therefore primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding. This may entail the use of VWF concentrates (currently plasma-derived) and/or FVIII concentrates (currently plasma-derived or more increasingly recombinant forms), and/or desmopressin to release endogenous VWF in subgroups of patients. For AVWS additional treatment of the underlying condition is also required. Adjunct therapies include antifibrinolytics. Globally, various formulations exist for both VWF and FVIII concentrates and are differentially available based on manufacturer marketing or regulatory approvals/clearances in different geographies. Also, guidelines for treatment of VWD vary for different localities and recombinant VWF is undergoing clinical trials. The current review provides an overview of the treatment of VWD as currently practiced in developed countries, and also provides a glimpse towards the future. PMID:26838696

  12. Severe nose bleeding after intake of acetylsalicylic acid: von Willebrand disease type 2A. Case 9.

    PubMed

    von der Weid, N X; Mansouri Taleghani, B; Wuillemin, W A

    2003-08-01

    This case report of a school boy with a history of severe and repeated episodes of epistaxis presents a short overview of the clinical and laboratory findings which lead to confirm the suspected diagnosis of von Willebrand disease (vWD). Suspicion of defective primary haemostasis should arise when unusual (because of their number or duration) mucosal bleeds appear in an otherwise normal and healthy patient. Because of its definitive inhibitory effect on platelet aggregation, acetylsalicylic acid (more than other non-steroidal anti-inflammatory drugs exerting unselective inhibition of cyclooxygenase) is a strong factor in triggering or sustaining the bleeding disorders in these patients. Among the congenital disorder of primary haemostasis, vWD is by far the most frequent one. The difficulties of laboratory diagnosis of vWD are stressed; the promises and pitfalls of new in vitro methods for measuring primary haemostasis (PFA-100 analyzer) are discussed. An accurate diagnosis of the specific type of vWD is of critical importance for correct patient management as well as for genetic counseling. PMID:12923584

  13. Diagnosis of von Willebrand disease.

    PubMed

    Ingerslev, J; Gürsel, T

    1999-05-01

    The haemorrhagic diathesis in von Willebrand disease (vWD) is caused by a quantitative deficiency or a qualitative defect in the von Willebrand factor (vWF) in plasma and/or platelets causing insufficient primary haemostasis. Since vWF binds and protects factor VIII (FVIII) towards random proteolysis, coagulation may also be impaired in patients with a low plasma level of vWF, and in instances where vWF displays insufficient binding capacity to FVIII. The entity of vWD displays a vast heterogeneity. Apart from rarely occurring acquired cases, vWD is an inherited disorder of autosomal linkage. The major clinical hallmark in vWD is an increased tendency to mucocutaneous bleeding that rarely reach life-threatening proportions, unless vWF is severely reduced or completely absent. Increased bleeding may also occur in sites such as muscles and joints when the level of FVIII is particularly low. Significant progress has recently been achieved through extensive molecular genetic exploration of various forms of vWD. In order to guide treatment and to form a platform for genetic investigation, however, accuracy in diagnosis and phenotypic characterization is important. By means of various laboratory methods, major subclasses of vWD can be differentiated, as presented in another article of this series. Whereas most of the cases of vWD can quite easily be diagnosed and classified using today's diagnostic methods, the most frequently occurring bleeding disorder of all, vWd type 1 of mild degree, continues to challenge clinicians and diagnostic laboratories. The aim of this paper is to review the laboratory methods most commonly used in diagnostic investigation of the patient suspected of vWD. PMID:23401900

  14. How Is von Willebrand Disease Diagnosed?

    MedlinePlus

    ... of your von Willebrand factor. The test helps your doctor diagnose what type of VWD you have. Platelet function test. This test measures how well your platelets are working. You may have these tests ...

  15. Interactions of von Willebrand factor and ADAMTS13 in von Willebrand disease and thrombotic thrombocytopenic purpura.

    PubMed

    Budde, U; Schneppenheim, R

    2014-01-01

    The function of von Willebrand factor (VWF), a huge multimeric protein and a key factor in platelet dependent primary haemostasis, is regulated by its specific protease ADAMTS13. The ADAMTS13 dependent degradation of VWF to its proteolytic fragments can be visualized as a characteristic so-called triplet structure of individual VWF oligomers by multimer analysis. Lack of VWF high molecular weight multimers (VWF-HMWM) or their pathologically enhanced degradation underlies a particular type of von Willebrand disease, VWD type 2A with a significant bleeding tendency, and may also be observed in acquired von Willebrand syndrome due to cardiovascular disease. In these conditions multimer analysis is an obligatory and powerful tool for diagnosis of VWD. The opposite condition, the persistence of ultralarge VWF (UL-VWF) multimers may cause the microangiopathic life-threatening disorder thrombotic thrombocytopenic purpura (TTP). During the course of active TTP, UL-VWF is consumed in the hyaline thrombi formed in the microvasculature which will ultimately result in the loss of UL-VWF and VWF-HMWM. Therefore, VWF multimer analysis is not a valid tool to diagnose TTP in the active phase of disease but may be helpful for the diagnosis of TTP patients in remission. PMID:25010251

  16. The functions of the A1A2A3 domains in von Willebrand factor include multimerin 1 binding.

    PubMed

    Parker, D'Andra N; Tasneem, Subia; Farndale, Richard W; Bihan, Dominique; Sadler, J Evan; Sebastian, Silvie; de Groot, Philip G; Hayward, Catherine P M

    2016-07-01

    Multimerin 1 (MMRN1) is a massive, homopolymeric protein that is stored in platelets and endothelial cells for activation-induced release. In vitro, MMRN1 binds to the outer surfaces of activated platelets and endothelial cells, the extracellular matrix (including collagen) and von Willebrand factor (VWF) to support platelet adhesive functions. VWF associates with MMRN1 at high shear, not static conditions, suggesting that shear exposes cryptic sites within VWF that support MMRN1 binding. Modified ELISA and surface plasmon resonance were used to study the structural features of VWF that support MMRN1 binding, and determine the affinities for VWF-MMRN1 binding. High shear microfluidic platelet adhesion assays determined the functional consequences for VWF-MMRN1 binding. VWF binding to MMRN1 was enhanced by shear exposure and ristocetin, and required VWF A1A2A3 region, specifically the A1 and A3 domains. VWF A1A2A3 bound to MMRN1 with a physiologically relevant binding affinity (KD: 2.0 ± 0.4 nM), whereas the individual VWF A1 (KD: 39.3 ± 7.7 nM) and A3 domains (KD: 229 ± 114 nM) bound to MMRN1 with lower affinities. VWF A1A2A3 was also sufficient to support the adhesion of resting platelets to MMRN1 at high shear, by a mechanism dependent on VWF-GPIbα binding. Our study provides new information on the molecular basis of MMRN1 binding to VWF, and its role in supporting platelet adhesion at high shear. We propose that at sites of vessel injury, MMRN1 that is released following activation of platelets and endothelial cells, binds to VWF A1A2A3 region to support platelet adhesion at arterial shear rates. PMID:27052467

  17. Treatment of the acquired von Willebrand syndrome.

    PubMed

    Budde, Ulrich; Scheppenheim, Sonja; Dittmer, Rita

    2015-12-01

    Acquired von Willebrand syndrome (aVWS) accounts for 22% of patients with abnormal von Willebrand factor. Most patients with known pathophysiological mechanisms suffer from cardiovascular, myeloproliferative and lymphoproliferative disorders. Less frequent associations are of autoimmune origin, due to hyperfibrinolysis, adsorption to tumor cells, reduced synthesis and prolonged circulation. The mechanisms leading to aVWS is hitherto not known in patients with liver and kidney diseases, drug use, glycogen storage disease, virus infections and at least 18 other disease entities. Diagnosis is complicated by the battery of tests needed, and their inherent rather low sensitivity and specificity for aVWS. Thus, even in acute bleeding situations it may take days until a firm diagnosis is settled and specific therapies can be initiated. The main aim is to shed more light onto this, compared with inherited von Willebrand disease, rare disease which affects at least 2-3% of the older population. PMID:26577336

  18. Studies of the human factor VIII/von Willebrand factor protein. III. Qualitative defects in von Willebrand's disease.

    PubMed Central

    Gralnick, H R; Coller, B S; Sultan, Y

    1975-01-01

    The Factor VIII/von Willebrand factor protein was characterized in two unrelated patients with von Willebrand's disease in whom procoagulant and Factor VIII/von Willebrand factor antigen levels were normal. In both patients evidence of an abnormal protein was observed on crossed antigen-antibody electrophoresis. In one patient the Factor VIII/von Willebrand factor protein eluted from Sepharose 4B in a position and distribution identical to normal with normal levels of procoagulant activity and antigen. However, the partially purified Factor VIII/von Willebrand factor protein had markedly reduced von Willebrand factor activity in a ristocetin assay. In the second patient the peak of Factor VIII/von Willebrand factor protein, antigen, and procoagulant activity eluted from a Sepharose 4B column with an estimated molecular weight of approximately half that of normal. This protein had no von Willebrand factor activity. In both patients the reduced Factor VIII/von Willebrand factor protein subunit was indistinguishable from normal on polyacrylamide gel electrophoresis. These studies indicate that in some patients with von Willebrand's disease there is a qualitative defect of the Factor VII/von Willebrand factor protein; the total amount of protein, antigen, and procoagulant activity are normal while the von Willebrand factor activity is deficient. Images PMID:1080491

  19. Acquired von Willebrand syndrome: an update.

    PubMed

    Franchini, Massimo; Lippi, Giuseppe

    2007-05-01

    Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. aVWS occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative disorders, myeloproliferative disorders, and cardiovascular diseases. Through an analysis of the more recent literature data, the pathophysiology and the clinical, laboratory, and therapeutic aspects of this syndrome are concisely reported in this review. PMID:17133419

  20. Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands

    SciTech Connect

    Zhang, Z.P.; Blombaeck, M.; Anvret, M. ); Nyman, D. )

    1993-09-01

    Patients with von Willebrand disease in four families in the Aland Islands, including the original family that was described in 1926 by the Finnish physician von Willebrand, were screened for mutations in the Swedish hot-spot' regions (exons 18, 28, 32, 43, and 45) of the von Willebrand factor gene. One cytosine deletion in exon 18 was detected in each of these families. Linkage analysis and genealogical studies suggest that the deletion present in these four families probably has an origin in common with the mutations in the Swedish patients. Apart from the deletion in exon 18, two close transitions (G [yields] A at S1263 and C [yields] T at P1266) in exon 28 on the same chromosome were identified in one individual who married into the original family and in his two children. The transitions could be due to a recombination between the von Willebrand factor gene and its pseudogene. 24 refs., 3 figs., 3 tabs.

  1. Plasma von Willebrand factor concentration and thyroid function in dogs.

    PubMed

    Avgeris, S; Lothrop, C D; McDonald, T P

    1990-03-15

    Plasma von Willebrand factor antigen concentration was determined in 15 dogs with suspected hypothyroidism, in 1 dog with hyperthyroidism, and in 14 euthyroid dogs. The mean +/- SEM von Willebrand factor:antigen concentration in hypothyroid dogs (47.1% +/- 12.6%) was significantly decreased (P less than 0.0005), compared with that in euthyroid dogs (94.7 +/- 5.6%). Four hypothyroid dogs were given thyroxine for 1 month and all 4 had an increase in von Willebrand factor:antigen concentration. The plasma von Willebrand factor:antigen concentration was 200% in the hyperthyroid dog. Seemingly, reduced concentrations of plasma von Willebrand factor:antigen can be found in dogs in association with congenital von Willebrand disease or with von Willebrand disease acquired through hypothyroidism. PMID:2107158

  2. Diagnostic Value of Measuring Platelet Von Willebrand Factor in Von Willebrand Disease

    PubMed Central

    Casonato, Alessandra; Cattini, Maria Grazia; Daidone, Viviana; Pontara, Elena; Bertomoro, Antonella; Prandoni, Paolo

    2016-01-01

    Von Willebrand disease (VWD) may be caused by an impaired von Willebrand factor (VWF) synthesis, its increased clearance or abnormal function, or combinations of these factors. It may be difficult to recognize the different contributions of these anomalies. Here we demonstrate that VWD diagnostics gains from measuring platelet VWF, which can reveal a defective VWF synthesis. Measuring platelet VWF revealed that: severe type 1 VWD always coincided with significantly lower platelet and plasma VWF levels, whereas mild forms revealed low plasma VWF levels associated with low or normal platelet VWF levels, and the latter were associated with a slightly shorter VWF survival; type Vicenza (the archetype VWD caused by a reduced VWF survival) featured normal platelet VWF levels despite significantly reduced plasma VWF levels; type 2B patients could have either normal platelet VWF levels associated with abnormal multimer patterns, or reduced platelet VWF levels associated with normal multimer patterns; type 2A patients could have reduced or normal platelet VWF levels, the former associated mainly with type 2A-I, the latter with type 2A-II; plasma and platelet VWF levels were normal in type 2N, except when the defect was associated with a quantitative VWF mutation. Our findings show that measuring platelet VWF helps to characterize VWD, especially the ambiguous phenotypes, shedding light on the mechanisms underlying the disorder. PMID:27532107

  3. Thrombotic complications in von Willebrand disease.

    PubMed

    Franchini, Massimo

    2006-02-01

    Thrombotic events occur rarely in patients with von Willebrand disease (VWD). In this review we analyze the data reported in the literature, selected through a PubMed search, on thrombotic complications in VWD patients. On the basis of this analysis, we conclude that thrombotic complications in VWD patients often have a multi-factorial pathogenesis resulting from a complex interaction between acquired (coagulation factor replacement, surgery, cardiovascular risk factors) and/or inherited (thrombophilic gene mutations) prothrombotic risk factors. PMID:16522550

  4. Current therapy in children and adolescents with von Willebrand disease

    PubMed Central

    Buga-Corbu, I; Arion, C

    2014-01-01

    Abstract The article represents a review of recent data about the therapy of von Willebrand disease in children and adolescents (hereditary as well as acquired forms of the disease). The treatment of bleeding events in these patients, the indications in different subtypes, and the future lines of research are mentioned. Abbreviations: Ag VWF = von Willebrand antigen, VWD = von Willebrand disease, DDAVP = arginine-vasopressin, EACA = epsilon aminocaproic acid, VWF = von Willebrand factor, VIIc F = the VIIth factor of coagulation, VIIIc F = the VIIIth factor of coagulation, IgG = immunoglobulin G, T/2 = half-time, WVF – Rco = the ristocetin cofactor. PMID:25408737

  5. Marshall-Stickler phenotype associated with von Willebrand disease

    SciTech Connect

    MacDonald, M.R.; Baker, K.S.; Schaefer, G.B.

    1997-01-20

    We report on 6 individuals from three different kindreds with Marshall-Stickler (MS) phenotype, with characteristic orofacial abnormalities, arthropathy, deafness, and eye findings, all of whom were discovered to have a mild bleeding diathesis and coagulation-study findings consistent with mild von Willebrand disease (vWD). MS syndrome has been linked in some cases to the type II procollagen gene (COL2A1) on chromosome 12q, and to the collagen XI gene (COL11A2) on chromosome 6. The von Willebrand factor (vWF) is encoded by a 180-Kb gene located on the short arm of chromosome 12. This is the first reported association of these two disorders. 26 refs., 5 figs., 1 tab.

  6. Rapid discrimination of the phenotypic variants of von Willebrand disease.

    PubMed

    Roberts, Jonathan C; Morateck, Patti A; Christopherson, Pamela A; Yan, Ke; Hoffmann, Raymond G; Gill, Joan Cox; Montgomery, Robert R

    2016-05-19

    Approximately 20% to 25% of patients with von Willebrand disease (VWD) have a qualitative defect of the von Willebrand factor (VWF) protein activities. Variant VWD typically is classified as type 1C, 2A, 2B, 2M, or 2N depending on the VWF activity defect. Traditionally, diagnosis has relied on multiple clinical laboratory assays to assign VWD phenotype. We developed an enzyme-linked immunosorbent assay (ELISA) to measure the various activities of VWF on a single plate and evaluated 160 patient samples enrolled in the Zimmerman Program for the Molecular and Clinical Biology of von Willebrand Disease with type 2 VWD. Using linear discriminate analysis (LDA), this assay was able to identify type 1C, 2A, 2B, 2M, or 2N VWD with an overall accuracy of 92.5% in the patient study cohort. LDA jackknife analysis, a statistical resampling technique, identified variant VWD with an overall accuracy of 88.1%, which predicts the assay's performance in the general population. In addition, this assay demonstrated correlation with traditional clinical laboratory VWF assays. The VWF multiplex activity assay may be useful as a same-day screening assay when considering the diagnosis of variant VWD in an individual patient. PMID:26917779

  7. Congenital von Willebrand's disease and clinical hypothyroidism.

    PubMed

    Hassan, S; Qureshi, W; Donthireddy, V; Kuriakose, P

    2013-03-01

    Data from case reports and systematic reviews suggest an association of Hypothyroidism and Acquired von Willebrand's syndrome. It is not known if congenital von Willebrand's disease is associated with hypothyroidism in a similar way. The aim of this study was to identify the association of congenital von Willebrand's disease (VWD) with clinical hypothyroidism. A total of 350 cases of congenital VWD were initially screened from our institution database from 1985 to 2010. A careful review of patient records was carried out to see if patients truly had congenital VWD and coexisting clinical hypothyroidism. Patients with uncertain diagnoses or other bleeding disorders were excluded, leading to 197 patients remaining in the final sample. A random age- and sex-matched parallel control group was also obtained from the hospital database. Of 197 patients (mean age 43.8 ± 17.5 years, women 72%) of congenital VWD, 32/197 (16%) were diagnosed with clinical hypothyroidism, while only 11/197 (5.6%) of the matched controls were clinically hypothyroid. Univariate and multivariate analysis demonstrated that VWD was an independent predictor of developing clinical hypothyroidism (OR 3.45; 95% CI 1.65-7.22, P = 0.001). The proportion of patients diagnosed with clinical hypothyroidism was more in the VWD group (P < 0.0001). Our analysis shows a strong association of clinical hypothyroidism in patients with congenital VWD, but future studies will be required to delineate a pathological mechanism. In our opinion, clinicians should consider checking thyroid function in the newly diagnosed and established cases of congenital VWD. PMID:23171382

  8. Acquired von Willebrand syndrome: von Willebrand factor propeptide to von Willebrand factor antigen ratio predicts remission status

    PubMed Central

    Lee, Adrienne; Sinclair, Gary; Valentine, Karen; James, Paula

    2014-01-01

    We investigated a case of acquired von Willebrand syndrome (AVWS) secondary to a nonneutralizing anti-von Willebrand factor (VWF) antibody associated with an autoimmune disorder. At diagnosis, VWF activity (VWF:Act), antigen (VWF:Ag), multimers, and factor VIII coagulant activity were virtually absent. VWF propeptide (VWFpp) was elevated with an infinitely high VWFpp to VWF:Ag ratio (VWFpp:Ag) consistent with rapid VWF clearance. Immunosuppressive treatment resulted in phenotypic remission 1 with normalization of VWF/factor VIII levels and multimer pattern. However, VWFpp:Ag remained elevated (∼2× normal), consistent with ongoing VWF clearance by the remaining anti-VWF antibody still present by enzyme-linked immunosorbent assay. This suggests that increased VWF secretion was compensating for the incomplete remission state. Relapse occurred when VWFpp:Ag was again infinitely high, with associated decreased VWFpp but unchanged anti-VWF titers; switching the balance to favor VWF clearance over secretion. Complete remission with undetectable anti-VWF occurred only when VWFpp:Ag was normal. This case of relapsing-remitting AVWS demonstrates the use of VWFpp:Ag for predicting remission status. PMID:24951428

  9. Report on von Willebrand Disease in Malaysia

    PubMed Central

    Periayah, Mercy Halleluyah; Halim, Ahmad Sukari; Saad, Arman Zaharil Mat; Yaacob, Nik Soriani; Karim, Faraizah Abdul

    2016-01-01

    BACKGROUND: Von Willebrand disease (vWD) is an inherited hemostatic disorder that affects the hemostasis pathway. The worldwide prevalence of vWD is estimated to be 1% of the general population but only 0.002% in Malaysia. AIM: Our present paper has been written to disclose the statistical counts on the number of vWD cases reported from 2011 to 2013. MATERIAL AND METHODS: This article is based on sociodemographic data, diagnoses and laboratory findings of vWD in Malaysia. A total of 92 patients were reported to have vWD in Malaysia from 2011 to 2013. RESULTS: Sociodemographic-analysis revealed that 60% were females, 63% were of the Malay ethnicity, 41.3% were in the 19-44 year old age group and 15.2% were from Sabah, with the East region having the highest registered number of vWD cases. In Malaysia, most patients are predominately affected by vWD type 1 (77.2%). Factor 8, von Willebrand factor: Antigen and vWF: Collagen-Binding was the strongest determinants in the laboratory profiles of vWD. CONCLUSION: This report has been done with great interest to provide an immense contribution from Malaysia, by revealing the statistical counts on vWD from 2011-2013. PMID:27275342

  10. [Molecular biology of von Willebrand disease].

    PubMed

    Melo-Nava, Brenda; Peñaloza, Rosenda

    2007-01-01

    Von Willebrand Factor (VWF) is a large multimeric glycoprotein expressed in the megakaryocytes and endothelial cells of all vertebrates. It participates fundamentally in the primary and secondary hemostasis because it induces the adhesion of platelets to vascular subendothelium and promotes aggregation of platelets when blood vessels and capillaries are damaged. In addition, VWF links to factor VIII which avoids its proteolysis. The deficiency or the inadequate synthesis of the VWF causes von Willebrand disease (VWD), which is the most common hereditary bleeding disorder in humans principally from mucous and cutaneous sites. VWD is difficult to detect with accuracy due to interrelation among VWF with different components of hemostasis, although it is performed by different tests of haemostatic system, and the basic mechanisms in VWD are herein emphasized. The diagnosis of VWD is difficult due to the heterogeneous manifestation of the disease, which also complicates its classification. This article focuses on the molecular aspects of the disease and discusses their possible clinical implications. PMID:18268896

  11. Von Willebrand Factor, Angiodysplasia and Angiogenesis

    PubMed Central

    Randi, Anna M.; Laffan, Mike A.; Starke, Richard D.

    2013-01-01

    The large multimeric glycoprotein Von Willebrand factor (VWF) is best known for its role in haemostasis; however in recent years other functions of VWF have been identified, indicating that this protein is involved in multiple vascular processes. We recently described a new role for VWF in controlling angiogenesis, which may have significant clinical implications for patients with Von Willebrand disease (VWD), a genetic or acquired condition caused by the deficiency or dysfunction of VWF. VWD can be associated with angiodysplasia, a condition of degenerative blood vessels often present in the gastrointestinal tract, linked to dysregulated angiogenesis. Angiodysplasia can cause severe intractable bleeding, often refractory to conventional VWD treatments. In this review we summarise the evidence showing that VWF controls angiogenesis, and review the angiogenic pathways which have been implicated in this process. We discuss the possible mechanisms though which VWF regulates angiopoietin-2 (Ang-2) and integrin αvβ3, leading to signalling through vascular endothelial growth factor receptor-2 (VEGFR2), one of the most potent activators of angiogenesis. We also review the evidence that links VWF with angiodysplasia, and how the newly identified function of VWF in controlling angiogenesis may pave the way for the development of novel therapies for the treatment of angiodysplasia in congenital VWD and in acquired conditions such as Heyde syndrome. PMID:24106610

  12. Therapeutic approaches to acquired von Willebrand syndrome.

    PubMed

    Federici, A B

    2000-02-01

    Acquired von Willebrand syndrome (AVWS) is a rare acquired bleeding disorder similar to the congenital von Willebrand disease (VWD) in terms of laboratory findings. Diagnosis of AVWS can be very difficult, with treatment normally taking an empirical form. Although more than 200 cases have been reported since 1968, no retrospective or prospective studies are available on AVWS. Recently, an International Registry on AVWS, gathering data directly from worldwide Departments of Haematology-Oncology and Haemophilia Centres, has been organised by a group working on behalf of the Subcommittee on VWF in the Scientific Standardisation Committee (SSC) of International Society on Thrombosis and Haemostasis (ISTH). Information about an additional 211 AVWS patients is now available, with more detailed data on demography, type of haemorrhage, diagnostic tests for AVWS and management of bleeding episodes. The additional 211 AVWS cases are associated with lymphoproliferative (47%) or myeloproliferative (19%) disorders, cardiovascular diseases, neoplasia (7%) and other miscellaneous diseases (14%). Bleeding episodes of AVWS patients were managed by different compounds including desmopressin (22%), FVIII/VWF concentrates (26%) and high-dose immunoglobulin (10%), plasmapheresis (2%), steroids (5%) and immunosuppressive drugs (20%). Based on complied data, we can conclude that none of the therapeutic approaches proposed are 100% effective in all AVWS cases. Therefore, treatment must be customized for each patient according to the underlying disorder, as well as to the type and the severity of bleeding episode and must be targeted to each specific case. PMID:11060681

  13. Von Willebrand factor, angiodysplasia and angiogenesis.

    PubMed

    Randi, Anna M; Laffan, Mike A; Starke, Richard D

    2013-01-01

    The large multimeric glycoprotein Von Willebrand factor (VWF) is best known for its role in haemostasis; however in recent years other functions of VWF have been identified, indicating that this protein is involved in multiple vascular processes. We recently described a new role for VWF in controlling angiogenesis, which may have significant clinical implications for patients with Von Willebrand disease (VWD), a genetic or acquired condition caused by the deficiency or dysfunction of VWF. VWD can be associated with angiodysplasia, a condition of degenerative blood vessels often present in the gastrointestinal tract, linked to dysregulated angiogenesis. Angiodysplasia can cause severe intractable bleeding, often refractory to conventional VWD treatments. In this review we summarise the evidence showing that VWF controls angiogenesis, and review the angiogenic pathways which have been implicated in this process. We discuss the possible mechanisms though which VWF regulates angiopoietin-2 (Ang-2) and integrin αvβ3, leading to signalling through vascular endothelial growth factor receptor-2 (VEGFR2), one of the most potent activators of angiogenesis. We also review the evidence that links VWF with angiodysplasia, and how the newly identified function of VWF in controlling angiogenesis may pave the way for the development of novel therapies for the treatment of angiodysplasia in congenital VWD and in acquired conditions such as Heyde syndrome. PMID:24106610

  14. von Willebrand disease: a laboratory approach.

    PubMed

    Trasi, Sucheta; Ghosh, Kanjaksha; Shetty, Shrimati; Mohanty, Dipika

    2005-01-01

    von Willebrand disease (VWD) is a common inherited bleeding disorder. Accurate diagnosis and classification of VWD is crucial for clinical management. A detailed clinical history, including that of bleeding, is required. A family and drug history are also important. Genetic factors such as blood group, and environmental factors such as stress, trauma, pregnancy and inflammation should also be considered. The age, ethnic group and hormonal status could also affect the von Willebrand factor (VWF) levels. No single test is robust enough to detect all variants of VWD. In view of the heterogeneity of the disease and limitations in assays, a battery of tests should be performed before a final diagnosis can be reached. These include the screening coagulation tests, factor VIII:C assay, VWF antigen assay, assessment of functional VWF which includes VWF ristocetin cofactor assays, VWF collagen binding assay, ristocetin-induced platelet aggregation and VWF multimer analysis. The newer ELISA techniques based on VWF binding with factor VIII glycoprotein (Gp) 1b and cerebrosides have also helped in determining certain unusual forms of VWD. The advent of new systems such as platelet function analysers (PFA), thromboelastography (TEG) and clot signature analysers (CSA), which are designed to assess either the primary platelet function or as a global haemostasis screen, have facilitated and simplified the diagnosis. However, few centres all over the world can perform all these expensive tests to provide a final diagnosis of VWD. We reviewed the laboratory investigations required for a diagnosis of VWD. Apart from congenital VWD, the possibility of acquired VWD should be considered in those with a negative past history of bleeding or in the presence of an underlying disease. PMID:15981443

  15. Lack of multimer organization of von Willebrand factor in an acquired von Willebrand syndrome.

    PubMed

    Casonato, A; Pontara, E; Doria, A; Bertomoro, A; Cattini, M G; Gambari, P F; Girolami, A

    2002-03-01

    We report a case of acquired von Willebrand syndrome (AVWS) in a 20-year-old-woman with systemic lupus erythematosus, in whom severe bleeding complications followed kidney biopsy. Coagulation studies demonstrated undetectable levels of ristocetin-induced platelet aggregation (RIPA), von Willebrand factor antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo), associated with significantly prolonged bleeding time; unlike type 3 von Willebrand disease (VWD), platelet VWF was reduced but not undetectable. The plasma VWF multimer pattern was characterized by the presence of only two bands, one of low molecular weight (MW) running as the protomer of plasma VWF in normals, the other of abnormally high MW without detectable intermediate multimers; this pattern resembles that of VWF present in endothelial cells. A search for an anti-VWF antibody demonstrated the presence of an inhibitor at high titre. This anti-VWF antibody did not interfere in the interaction of VWF with platelet glycoprotein (GP) Ib through the A1 domain, and did not react with the A2 domain of VWF; instead, it seemed to modify the relative representation of high and low MW VWF multimers released by normal human umbilical vein endothelial cells (HUVEC). After Azathioprine and corticosteroid treatment, the anti-VWF antibody disappeared and the patient's haemostatic profile normalized, except for the platelet VWF content which still remained decreased. We suggest that the anti-VWF antibody present in the AVWS described compromised both circulating VWF levels and their multimeric organization, inducing the maintenance of the multimer structure that VWF normally has before or in the early phase after secretion from endothelial cells. PMID:11886398

  16. Comparison between von Willebrand factor (VWF) and VWF antigen II in normal individuals and patients with von Willebrand disease.

    PubMed

    de Romeuf, C; Mazurier, C

    1998-07-01

    Von Willebrand disease is characterised by a quantitative (type 1) or qualitative (type 2) decrease in von Willebrand factor (vWF) a multimeric glycoprotein involved in primary haemostasis. The propeptide of von Willebrand, also named vWF antigen II (vWF:AgII), is released from platelets and endothelial cells and circulates in plasma as a glycoprotein of 100 kD. In the present study, we attempted to determine whether vWF:AgII level may provide information on the synthesis of vWF, specially in patients with von Willebrand disease (vWD). To elucidate that point, we developed an ELISA and quantify the vWF:AgII in normal individuals and in various vWD patients. The propeptide molar concentration was found to be 5 nM as compared to 31 nM for mature vWF. In normal individuals, the level of vWF:AgII was significantly decreased in females from O and A blood groups. In type 2 vWD patients the level of plasma vWF:AgII appears normal in the patients with normal level of platelet vWF. In type 2 B vWD characterised by increased affinity of mature vWF for platelet glycoprotein Ib, the vWF:AgII in contrast to the vWF antigen (vWF:Ag) was not decreased. In type 2A vWD patients the level of vWF:AgII was decreased in patients with absence of high molecular weight vWF in platelets and plasma but normal in patients with increased sensitivity to proteolysis. Finally, in type 1 vWD, some studied patients have a parallel decrease in vWF:AgII and vWF:Ag whereas in others, the vWF:Ag levels were much more affected than corresponding vWF:AgII levels, as observed in some type 2 vWD patients. Thus, in contrast to that already described, the plasma vWF:AgII level cannot discriminate type 1 from type 2 vWD patients. We conclude that the vWF:AgII measurement provides additional information on the mechanisms responsible for vWD and might also contribute to the classification of vWD patients. PMID:9684782

  17. Exponential Size Distribution of von Willebrand Factor

    PubMed Central

    Lippok, Svenja; Obser, Tobias; Müller, Jochen P.; Stierle, Valentin K.; Benoit, Martin; Budde, Ulrich; Schneppenheim, Reinhard; Rädler, Joachim O.

    2013-01-01

    Von Willebrand Factor (VWF) is a multimeric protein crucial for hemostasis. Under shear flow, it acts as a mechanosensor responding with a size-dependent globule-stretch transition to increasing shear rates. Here, we quantify for the first time, to our knowledge, the size distribution of recombinant VWF and VWF-eGFP using a multilateral approach that involves quantitative gel analysis, fluorescence correlation spectroscopy, and total internal reflection fluorescence microscopy. We find an exponentially decaying size distribution of multimers for recombinant VWF as well as for VWF derived from blood samples in accordance with the notion of a step-growth polymerization process during VWF biosynthesis. The distribution is solely described by the extent of polymerization, which was found to be reduced in the case of the pathologically relevant mutant VWF-IIC. The VWF-specific protease ADAMTS13 systematically shifts the VWF size distribution toward smaller sizes. This dynamic evolution is monitored using fluorescence correlation spectroscopy and compared to a computer simulation of a random cleavage process relating ADAMTS13 concentration to the degree of VWF breakdown. Quantitative assessment of VWF size distribution in terms of an exponential might prove to be useful both as a valuable biophysical characterization and as a possible disease indicator for clinical applications. PMID:24010664

  18. ADAMTS13 and von Willebrand factor interactions

    PubMed Central

    Zander, Catherine B.; Cao, Wenjing; Zheng, X. Long

    2016-01-01

    Purpose of review ADAMTS13 is a zinc-containing metalloprotease that cleaves von Willebrand factor (VWF). Deficiency of plasma ADAMTS13 activity is accountable for a potentially fatal blood disorder thrombotic thrombocytopenic purpura (TTP). Understanding of ADAMTS13–VWF interaction is essential for developing novel treatments to this disorder. Recent findings Despite the proteolytic activity of ADAMTS13 being restricted to the metalloprotease domain, the ancillary proximal C-terminal domains including the disintegrin domain, first TSP-1 repeat, cysteine-rich region, and spacer domain are all required for cleavage of VWF and its analogs. Recent studies have added to our understandings of the role of the specific regions in the disintegrin domain, the cysteine-rich domain, and the spacer domain responsible for its interaction with VWF. Additionally, regulative functions of the distal portion of ADAMTS13 including the TSP-1 2–8 repeats and the CUB domains have been proposed. Finally, fine mapping of anti-ADAMTS13 antibody epitopes have provided further insight into the essential structural elements in ADAMTS13 for VWF binding and the mechanism of autoantibody-mediated TTP. Summary Significant progress has been made in our understandings of the structure–function relationship of ADAMTS13 in the past decade. To further investigate ADAMTS13–VWF interactions for medical applications, these interactions must be studied under physiological conditions in vivo. PMID:26186678

  19. Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism.

    PubMed

    Hawke, Lindsey; Bowman, Mackenzie L; Poon, Man-Chiu; Scully, Mary-Frances; Rivard, Georges-Etienne; James, Paula D

    2016-07-28

    Approximately 10% of von Willebrand factor (VWF) gene mutations are thought to alter messenger RNA (mRNA) splicing through disruption of consensus splice sites. This mechanism is likely underrecognized and affected by mutations outside consensus splice sites. During VWF synthesis, splicing abnormalities lead to qualitative defects or quantitative deficiencies in VWF. This study investigated the pathologic mechanism acting in 3 von Willebrand disease (VWD) families with putative splicing mutations using patient-derived blood outgrowth endothelial cells (BOECs) and a heterologous human embryonic kidney (HEK 293(T)) cell model. The exonic mutation c.3538G>A causes 3 in-frame splicing variants (23del, 26del, and 23/26del) which cannot bind platelets, blood coagulation factor VIII, or collagen, causing VWD through dominant-negative intracellular retention of coexpressed wild-type (WT) VWF, and increased trafficking to lysosomes. Individuals heterozygous for the c.5842+1G>C mutation produce exon 33 skipping, exons 33-34 skipping, and WT VWF transcripts. Pathogenic intracellular retention of VWF lacking exons 33-34 causes their VWD. The branch site mutation c.6599-20A>T causes type 1 VWD through mRNA degradation of exon 38 skipping transcripts. Splicing ratios of aberrant transcripts and coexpressed WT were altered in the BOECs with exposure to shear stress. This study provides evidence of mutations outside consensus splice sites disrupting splicing and introduces the concept that VWF splicing is affected by shear stress on endothelial cells. PMID:27317792

  20. Biosynthesis of von Willebrand protein by human megakaryocytes.

    PubMed Central

    Sporn, L A; Chavin, S I; Marder, V J; Wagner, D D

    1985-01-01

    Immunofluorescence staining of buffy coat smears from a patient with chronic myelogenous leukemia in accelerated phase showed that approximately 13% of all nucleated cells contained von Willebrand protein and, therefore, appeared to be of megakaryocytic origin. This was confirmed by positive staining with antisera against platelet factor 4 and platelet glycoproteins. Short-term cultures of the buffy coat, which lacked endothelial cells, were metabolically labeled with [35S]methionine, and von Willebrand protein was immunopurified from cell lysates and culture medium. Cultures from this patient synthesized and secreted von Willebrand protein, in contrast with cultures from other patients with leukemia, who lacked circulating megakaryocytes, and from normal volunteers. The subunit composition of the megakaryocytic von Willebrand protein was very similar to that of human umbilical vein endothelial cells. The size of the processed subunit (220 kD) and of the cellular (260 kD) and secreted (275 kD) precursors from the two cell types were indistinguishable by gel electrophoresis. Furthermore, the ratio of precursor to processed subunit and the pattern of cellular and secreted nonreduced multimers were very similar. It appears, therefore, that the processing steps in biosynthesis of von Willebrand protein used by the megakaryocytes are very similar to those of umbilical vein endothelial cells. Images PMID:2413071

  1. Acquired von Willebrand syndrome: diagnostic problems and therapeutic options.

    PubMed

    Eikenboom, Jeroen C J; Tjernberg, Pernilla; Van Marion, Vincent; Heering, Karel J

    2007-01-01

    We present a case of acquired von Willebrand syndrome (AVWS) due to a monoclonal gammopathy of undetermined significance. Initially this case was diagnosed as congenital von Willebrand disease (VWD); however, re-examination of the medical history rendered a congenital bleeding disorder unlikely. A normal plasma von Willebrand factor (VWF) propeptide level and a very short half-life of VWF after a test infusion with factor VIII/VWF concentrate confirmed the diagnosis AVWS. Two major surgical procedures were successfully managed using high-dose intravenous immunoglobulin. The differential diagnosis with congenital VWD and the diagnostic and therapeutic approaches of AVWS are discussed. We conclude that the diagnosis of AVWS relies primarily on clinical suspicion and a careful bleeding history. A correct diagnosis is essential for optimal perioperative management and treatment of bleeding episodes. PMID:16986130

  2. Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease

    PubMed Central

    Rydz, Natalia; Grabell, Julie; Lillicrap, David; James, Paula D.

    2015-01-01

    In a normal population, VWF plasma levels (VWF:Ag) and VWF activity (VWF:RCo) increase by approximately 0.17 and 0.15 IU/ml per decade, but the influence of age is unknown in patients with type 1 von Willebrand disease (VWD). In a retrospective cohort study, the medical records of 31 type 1 VWD patients over the age of 30, who had been followed for ≥5 years, were reviewed for baseline clinical data and previously performed VWF:Ag, VWF:RCo and factor VIII levels (FVIII:C). VWF multimer analysis was normal in 27/31 cases performed. Mean bleeding score was 9.4 (range 2-21). Mean age at diagnosis was 33 (range 16-60 years), and duration of follow-up ranged from 5-26 years (mean 11 years). Patients had 2-10 time points of VWD testing (mean of 5.2). The mean VWF:Ag, VWF:RCo and FVIII:C at time of diagnosis were 0.44 IU/ml 0.34 IU/ml and 0.75 IU/ml. At last follow-up, the mean VWF:Ag, VWF:RCo and FVIII:C were significantly increased to 0.71 IU/L, 0.56 IU/ml and 0.90 IU/ml (p=<0.001, <0.001, and 0.0081, respectively). 18/31 patients had VWF:Ag, VWF:RCo and FVIII:C levels that increased into the normal range. The rate of change in VWF:Ag and VWF:RCo was 0.30 IU/ml (0.214-0.386, CI 95%, p<0.0001) and 0.20 IU/ml per year (0.126-0.274, CI 95%, p=0.0001). Patients with type 1 VWD experience age-related increases to VWF:Ag and VWF:RCo which can result in normalization of VWF levels. Further studies are required to determine if the bleeding phenotype resolves with the increases in VWF:Ag and VWF:RCo levels. PMID:25756206

  3. [Von Willebrand factor and ADAMTS13 balancing primary haemostasis].

    PubMed

    Schneppenheim, R; Budde, U

    2011-11-01

    Von Willebrand factor (VWF) is an adhesive, multi-functional huge multimerized protein with multiple domains harboring binding sites for collagen, platelet glycoprotein receptors and coagulation factor VIII (FVIII). The functional domains enable VWF to bind to the injured vessel wall, to recruit platelets to the site of injury by adhesion and aggregation and to bind and protect FVIII, an important cofactor of the coagulation cascade. VWF function in primary haemostasis is located in particular in the arterial and micro-circulation. This environment is exposed to high shear forces with hydrodynamic shear rates ranging over several orders of magnitude from 10⁻¹ to 10⁵ s-1 and requires particular mechanisms to enable platelet adhesion and aggregation under these variable conditions. The respective VWF function is strictly correlating with its multimer size. Lack or reduction of large VWF multimers is seen in patients with von Willebrand disease (VWD) type 2A which correlates with reduction of both VWF:platelet GPIb-binding and VWF:collagen binding and a bleeding phenotype. To prevent unlimited platelet adhesion and aggregation which is the cause of the microangiopathic disorder thrombotic thrombocytopenic purpura (TTP), VWF function is regulated by its specific protease ADAMTS13. Whereas a particular susceptibility of VWF to ADAMTS13 proteolysis is the cause of a frequent VWD type 2A phenotype, lack or dysfunction of ADAMTS13, either acquired by ADAMTS13 antibodies or by inherited ADAMTS13 deficiency (Upshaw-Schulman Syndrome), causes TTP. Therefore VWD and TTP represent the opposite manifestations of VWF related disorders, tightly linked to each other. PMID:21792464

  4. Systemic lupus erythematosus complicated by acquired von Willebrand's syndrome.

    PubMed

    Hong, Sc; Lee, Jh; Chi, Hs; Lee, Ck; Nah, Ss; Kim, Yg; Oh, Js; Moon, Hb; Yoo, B

    2008-09-01

    Haematological abnormalities are common in systemic lupus erythematosus (SLE). In some cases of acquired von Willebrand syndrome (AvWS), von Willebrand disease (vWD) is associated with autoimmune or lymphoproliferative disorders. In this study, we describe a 36-year-old woman with SLE and AvWS. The patient was referred to our hospital because of easy bruisability and recurrent vaginal bleeding. She had no history of bleeding tendency and no family history of bleeding diathesis, but she had a history of recurrent arthralgia, photosensitivity and sicca symptoms. Tests for antinuclear, anti-double stranded DNA, anticardiolipin and anti-beta2-glycoprotein I antibodies were all positive. Analysis of haemostatic parameters showed complete absence of von Willebrand factor ristocetin cofactor (vWF:Rco), von Willebrand antigen (vWF:Ag) and ristocetin-induced platelet aggregation (RIPA). Electrophoretic analysis of plasma showed a complete absence of high-molecular weight vWF multimer. The presence of antibody to vWF was detected by enzyme linked immunosorbent assay (ELISA). Treatment with corticosteroids improved SLE symptoms and corrected bleeding diasthesis. Also, the multimeric patterns of vWF became normalised and anti-vWF antibody disappeared. These findings indicated that this patient had SLE associated with AvWS, which was ameliorated by corticosteroid treatment. PMID:18755868

  5. Pathophysiology of acquired von Willebrand disease: a concise review.

    PubMed

    Shetty, Shrimati; Kasatkar, Priyanka; Ghosh, Kanjaksha

    2011-08-01

    Acquired von Willebrand disease (AVWD) is a rare, underdiagnosed hemorrhagic disorder, which is similar to congenital VWD with regard to the clinical and laboratory parameters; however, it is found in individuals with no positive family history and has no genetic basis. The etiology is varied, the commonest being hematoproliferative disorders and cardiovascular disorders. Other disorders associated with AVWD are autoimmune disorders such as systematic lupus erythematosus, hypothyroidism, and neoplasia, or it may also be drug induced. In quite a few cases, the etiology is unknown. The pathogenic mechanisms are different in different underlying disorders or they may be overlapping among these disorders. Some of the proposed mechanisms include the development of autoantibodies, selective absorption of high molecular weight von Willebrand factor (VWF) multimers, non-selective absorption of VWF, mechanical destruction of VWF under high shear stress, and increased proteolysis. This report presents a concise review of the pathophysiological mechanisms of AVWD in these various underlying conditions. PMID:21535159

  6. The diagnosis and management of von Willebrand disease in Canada.

    PubMed

    James, Paula D; Lillicrap, David P

    2011-07-01

    In Canada, care for individuals with inherited bleeding disorders, including Von Willebrand disease, is provided by 26 tertiary care multidisciplinary Inherited Bleeding Disorders clinics geographically spread across the country. The Association of Hemophilia Clinic Directors of Canada, the Canadian Association of Nurses in Hemophilia Care, the Canadian Physiotherapists in Hemophilia Care, the Canadian Social Workers in Hemophilia Care, and the Canadian Hemophilia Society all collaborate to provide optimal management for patients with inherited bleeding disorders. The standards of care for these patients were explicitly laid out in a 2007 document published by the Canadian Hemophilia Standards Group (with representation from all of the groups just mentioned) entitled Canadian Comprehensive Care Standards for Hemophilia and Other Inherited Bleeding Disorders. Separate Canadian guidelines for the management of patients with Hemophilia and Von Willebrand disease also exist, focused on diagnosis, comprehensive care, assessment, and treatment. PMID:22102195

  7. ABO blood group and von Willebrand factor: biological implications.

    PubMed

    Franchini, Massimo; Crestani, Silvia; Frattini, Francesco; Sissa, Cinzia; Bonfanti, Carlo

    2014-09-01

    ABO blood group antigens are complex carbohydrate molecules expressed on the surface of red blood cells and a variety of human cells and tissues. It is well known that ABO blood type exerts a profound influence on hemostasis, being a major determinant of von Willebrand factor (VWF), and consequently factor VIII, plasma levels. In this review, we will focus on the molecular mechanisms underlying the interaction between ABO blood group and VWF in normal and pathological conditions. PMID:24945431

  8. How I treat the acquired von Willebrand syndrome.

    PubMed

    Tiede, Andreas; Rand, Jacob H; Budde, Ulrich; Ganser, Arnold; Federici, Augusto B

    2011-06-23

    The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders. VWF abnormalities in these disorders can result from (1) antibody-mediated clearance or functional interference, (2) adsorption to surfaces of transformed cells or platelets, or (3) increased shear stress and subsequent proteolysis. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AVWS. Furthermore, there are no evidence-based guidelines for management. Treatments of the underlying medical condition, including chemo/radiotherapy, surgery, or immunosuppressants can result in remission of AVWS, but is not always feasible and successful. Because of the heterogeneous mechanisms of AVWS, more than one therapeutic approach is often required to treat acute bleeds and for prophylaxis during invasive procedures; the treatment options include, but are not limited to, desmopressin, VWF-containing concentrates, intravenous immunoglobulin, plasmapheresis or recombinant factor VIIa. Here, we review the management of AVWS with an overview on the currently available evidence and additional considerations for typical treatment situations. PMID:21540459

  9. Association of acquired von Willebrand syndrome with AL amyloidosis.

    PubMed

    Kos, Cynthia A; Ward, Jennifer E; Malek, Karim; Sanchorawala, Vaishali; Wright, Daniel G; O'Hara, Carl; Connors, Lawreen; Skinner, Martha; Seldin, David C

    2007-05-01

    Acquired loss of functional von Willebrand factor (VWF) has been termed the acquired von Willebrand syndrome (AVWS). AVWS is a rare adult-onset bleeding diathesis that is clinically similar to congenital von Willebrand disease (VWD), and occurs with a variety of autoimmune, lymphoproliferative, or myeloproliferative disorders. We have identified four patients with AVWS in association with immunoglobulin light chain (AL) amyloidosis. These patients, lacking any pre-existing or family history of abnormal bleeding, developed cutaneous, mucosal, or gastrointestinal bleeding in the course of their disease without deficiency of clotting factor X or other factors; the activated partial thromboplastin time (aPTT) was prolonged in three out of the four cases. Despite normal VWF antigen levels, VWF ristocetin cofactor activity (VWF:RCo) was low. Electrophoresis patterns of high molecular weight (HMW) VWF multimers were abnormal in two of the four cases. Two of the patients were treated with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) and achieved hematologic remission. In these two patients, the bleeding diathesis improved and the coagulation parameters normalized, confirming a causal relationship between the plasma cell dyscrasia and the AVWS. AVWS should be considered in AL amyloidosis patients with hemorrhagic diatheses and normal clotting factor levels. PMID:17205535

  10. Acquired Von Willebrand's Syndrome in Systemic Lupus Erythematosus

    PubMed Central

    Strakhan, Marianna; Gralla, Richard J.; Reed, Louis J.

    2014-01-01

    Acquired von Willebrand syndrome (AVWS) is an uncommon, underdiagnosed, and heterogeneous disease which is increasingly recognized as a cause of bleeding diatheses. Systemic lupus erythematosus (SLE) is an infrequent cause of AVWS. Herein, we report a case of AVWS diagnosed during the initial presentation of SLE in a previously healthy young man with no family history of bleeding diathesis who presented with worsening epistaxis, gastrointestinal bleeding, and anasarca. He was found to have severe anemia and prolonged activated partial thromboplastin time (aPTT) with severely decreased levels of von Willebrand factor (VWF) measurements in addition to markedly decreased factor VIII levels. Further evaluation revealed nephrotic syndrome and interstitial lung disease due to SLE. He initially received combination therapy with intravenous immunoglobulin (IVIG) and von Willebrand factor/factor VIII concentrates without significant improvement. Treatment with steroids, cyclophosphamide, and rituximab was followed by clinical improvement evidenced by cessation of bleeding. The short follow-up did not allow us to definitely prove the therapeutic effect of immunosuppressive treatment on AVWS in SLE patients. This case adds to the literature supporting the relationship between AVWS and SLE and highlights the importance of combination therapy in the treatment of severe AVWS as well as the role of IVIG, cyclophosphamide, and rituximab in AVWS associated with SLE. PMID:25544909

  11. Defective dimerization of von Willebrand factor subunits due to a Cys-> Arg mutation in type IID von Willebrand disease.

    PubMed Central

    Schneppenheim, R; Brassard, J; Krey, S; Budde, U; Kunicki, T J; Holmberg, L; Ware, J; Ruggeri, Z M

    1996-01-01

    The same heterozygous T -> C transition at nt 8567 of the von Willebrand factor (vWF) transcript was found in two unrelated patients with type III) von Willebrand disease, with no other apparent abnormality. In one family, both alleles were normal in the parents and one sister; thus, the mutation originated de novo in the proposita. The second patient also had asymptomatic parents who, however, were not available for study. The structural consequences of the identified mutation, resulting in the CyS2010 -> Arg substitution, were evaluated by expression of the vWF carboxyl-terminal domain containing residues 1366-2050. Insect cells infected with recombinant baculovirus expressing normal vWF sequence secreted a disulfide linked dimeric molecule with an apparent molecular mass of 150 kDa before reduction, yielding a single band of 80 kDa after disulfide bond reduction. In contrast, cells expressing the mutant fragment secreted a monomeric molecule of apparent molecular mass of 80 kDa, which remained unchanged after reduction. We conclude that CyS2010 is essential for normal dimerization of vWF subunits through disulfide bonding of carboxyl-terminal domains and that a heterozygous mutation in the corresponding codon is responsible for defective multimer formation in type III) von Willebrand disease. Images Fig. 1 Fig. 2 Fig. 4 PMID:8622978

  12. Acquired von Willebrand syndrome--report of 10 cases and review of the literature.

    PubMed

    Nitu-Whalley, I C; Lee, C A

    1999-09-01

    Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with clinical and laboratory features closely resembling hereditary von Willebrand disease (vWD), arising in previously haemostatically normal individuals. We present a retrospective review of 10 cases with AvWS diagnosed over 17 years. The severity of the bleeding tendency varied from mild to severe forms. Multimers electrophoresis showed that 8/10 patients had a normal pattern similar to type 1 vWD, 1/10 had a type 2A vWD pattern (with absence of high and intermediate molecular weight multimers) and 1/10 had a type 3 vWD pattern. An inhibitor screen was performed in 6/10 patients and autoantibodies against von Willebrand factor were found in only two cases. The underlying cause/associated conditions were identified in 8/10 patients. Treatment of the bleeding diathesis was successfully achieved with desmopressin or clotting factor concentrates. Resolution of underlying hypothyroidism (in two cases) and multiple myeloma (in one case) led to normalization of the coagulation parameters. The report on this cohort of 10 patients with AvWS illustrates the complexity of AvWS and its multifactorial aetiology. A brief review of the recent literature on AvWS is also presented, with emphasis on the current opinions in pathogenesis and treatment. Acquired von Willebrand syndrome (AvWS) is an acquired bleeding disorder, characterized by a phenotype similar to the inherited von Willebrand disease (vWD), with a prolonged bleeding time and low plasma levels of factor VIII - von Willebrand factor (vWF) measurements. It occurs in patients with no family history of vWD, who present with recent onset of bleeding symptoms. AvWS appears to be associated mainly with lymphoproliferative disorders, immunological conditions and neoplasia. AvWS is a rare condition and it is difficult to conduct prospective studies, therefore it is important to document the experience with such cases. The aim of this paper is first, to

  13. Von Willebrand factor regulates complement on endothelial cells.

    PubMed

    Noone, Damien G; Riedl, Magdalena; Pluthero, Fred G; Bowman, Mackenzie L; Liszewski, M Kathryn; Lu, Lily; Quan, Yi; Balgobin, Steve; Schneppenheim, Reinhard; Schneppenheim, Sonja; Budde, Ulrich; James, Paula; Atkinson, John P; Palaniyar, Nades; Kahr, Walter H A; Licht, Christoph

    2016-07-01

    Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have traditionally been considered separate entities. Defects in the regulation of the complement alternative pathway occur in atypical hemolytic uremic syndrome, and defects in the cleavage of von Willebrand factor (VWF)-multimers arise in thrombotic thrombocytopenic purpura. However, recent studies suggest that both entities are related as defects in the disease-causing pathways overlap or show functional interactions. Here we investigate the possible functional link of VWF-multimers and the complement system on endothelial cells. Blood outgrowth endothelial cells (BOECs) were obtained from 3 healthy individuals and 2 patients with Type 3 von Willebrand disease lacking VWF. Cells were exposed to a standardized complement challenge via the combination of classical and alternative pathway activation and 50% normal human serum resulting in complement fixation to the endothelial surface. Under these conditions we found the expected release of VWF-multimers causing platelet adhesion onto BOECs from healthy individuals. Importantly, in BOECs derived from patients with von Willebrand disease complement C3c deposition and cytotoxicity were more pronounced than on BOECs derived from normal individuals. This is of particular importance as primary glomerular endothelial cells display a heterogeneous expression pattern of VWF with overall reduced VWF abundance. Thus, our results support a mechanistic link between VWF-multimers and the complement system. However, our findings also identify VWF as a new complement regulator on vascular endothelial cells and suggest that VWF has a protective effect on endothelial cells and complement-mediated injury. PMID:27236750

  14. Orthopaedic surgery in patients with von Willebrand disease.

    PubMed

    Siboni, S M; Biguzzi, E; Solimeno, L P; Pasta, G; Mistretta, C; Mannucci, P M; Peyvandi, F

    2014-01-01

    Patients with von Willebrand disease (VWD) may need orthopaedic surgery because of disabling chronic arthropathy due to recurrent joint bleeding. They may also require this surgery independently of their haemostasis disorder. Knowledge regarding the management of orthopaedic surgery in VWD is limited. Description of management of orthopaedic surgery in patients with VWD, based upon retrospective data collection and analysis of 32 orthopaedic procedures carried out over a period of 33 years in 23 patients was the aim of this study. Of 32 procedures, six were minor (three hand surgery, one foot surgery, two others) and 26 were major (seven joint replacements, nine arthroscopic procedures, two foot surgery, eight others). Twenty-two procedures were performed using replacement therapy with plasma-derived concentrates containing both factor VIII (FVIII) and von Willebrand factor (VWF). Two procedures in patients with acquired von Willebrand syndrome (AWVS) were performed using FVIII-VWF concentrates associated with intravenous immunoglobulins, or desmopressin plus tranexamic acid. Seven procedures were performed using desmopressin alone and one using intravenous immunoglobulins in AVWS. Bleeding complications occurred in seven procedures (22%). In one patient, an anti-VWF antibody was diagnosed after surgery. Anticoagulant prophylaxis of venous thromboembolism was implemented in four cases only and in two instances there was excessive bleeding. In conclusion, control of surgical haemostasis was achieved in most patients with VWD undergoing orthopaedic surgery. The control of haemostasis combined with an adequate surgical technique and early post-operative rehabilitation are warranted for the successful performance of orthopaedic surgery in VWD, which requires the involvement of specialized haemophilia centres. PMID:23992395

  15. Diagnosis and treatment of acquired von Willebrand syndrome.

    PubMed

    Tiede, Andreas

    2012-12-01

    Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that is characterized by structural or functional alterations in von Willebrand factor (VWF) caused by a range of lymphoproliferative, myeloproliferative, cardiovascular, autoimmune, and other disorders. The pathogenic mechanisms responsible for the VWF abnormalities depend on the underlying condition, but include clearance due to binding of paraproteins, inhibition of VWF, adsorption to the surface of platelets, increased fluid shear stress, and resultant proteolysis or, more rarely, decreased synthesis. The diagnosis and treatment of AVWS are complicated by the need for multiple laboratory tests and the management of bleeding risk in a typically elderly population with serious underlying conditions that predispose towards thrombosis. Recently developed diagnostic algorithms, based on standard laboratory assays, may assist clinicians with the diagnostic workup and help differentiate between AVWS and von Willebrand disease (VWD) types 1 and 2. AVWS should be considered in all patients with new-onset bleeding whenever laboratory findings suggest VWD, particularly in the presence of an AVWS-associated disorder. AVWS testing is also recommended prior to surgery or an intervention with a high risk of bleeding in any individual with an AVWS-associated disorder. Treatment of the underlying condition using immunosuppressants, surgery, or chemotherapy, can lead to remission of AVWS in some individuals and should always be considered. Strategies to prevent and/or treat bleeding episodes should also be in place, including the use of VWF-containing factor VIII concentrates, desmopressin and tranexamic acid. Treatment success will depend largely on the underlying pathogenesis of the disorder. PMID:23439003

  16. Mutations in the D1 domain of von Willebrand factor impair their propeptide-dependent multimerization, intracellular trafficking and secretion.

    PubMed

    Yin, Jie; Ma, Zhenni; Su, Jian; Wang, Jiong-Wei; Zhao, Xiaojuan; Ling, Jing; Bai, Xia; Ouyang, Wanyan; Wang, Zhaoyue; Yu, Ziqiang; Ruan, Changgeng

    2015-01-01

    We identified three novel mutations (p.Gly39Arg, p.Lys157Glu, p.Cys379Gly) and one previously known mutation (p.Asp141Asn) in the von Willebrand factor propeptide from three von Willebrand disease patients. All four mutations impaired multimerization of von Willebrand factor, due to reduced oxidoreductase activity of isomeric propeptide. These mutations resulted in the endothelial reticulum retention and impaired basal and stimulated secretions of von Willebrand factor. Our results support that the mutations in the D1 domain lead to defective multimerization, intracellular trafficking, and secretion of von Willebrand factor and result in bleeding of patients. PMID:26088471

  17. von Willebrand factor, Jedi knight of the bloodstream.

    PubMed

    Springer, Timothy A

    2014-08-28

    When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use "the Force" to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended thread-like in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables postsecretion regulation of VWF length. Mutations in VWF in von Willebrand disease contribute to and are illuminated by VWF biology. I attempt to integrate classic studies on the physiology of hemostatic plug formation into modern molecular understanding, and point out what remains to be learned. PMID:24928861

  18. Prophylaxis in von Willebrand Disease: Coming of Age?

    PubMed

    Saccullo, Giorgia; Makris, Mike

    2016-07-01

    Although in most cases von Willebrand disease (VWD) is a mild disorder, a subgroup of patients experience frequent bleeding. In contrast to severe hemophilia in which prophylaxis is the accepted standard of care, this is less frequently used in VWD. Most type 1 VWD patients can be adequately managed with episodic desmopressin and tranexamic acid. In patients with more severe disease, especially those with type 3 VWD, joint bleeds, epistaxis, menorrhagia, and gastrointestinal bleeding are problematic and usually require treatment with von Willebrand factor/factor VIII (VWF/FVIII) concentrate. While in the past these patients were managed with on-demand VWF/FVIII concentrate, several recent reports have demonstrated the value of prophylactic treatment. Despite some uncertainties about the economic impact of treatment of severe VWD, prophylaxis with VWF concentrate should now be considered as the standard of care for the more severe end of the spectrum of affected individuals. The recent introduction of recombinant VWF concentrate is likely to improve the acceptability of prophylaxis in VWD. PMID:27253087

  19. von Willebrand factor, Jedi knight of the bloodstream

    PubMed Central

    2014-01-01

    When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use “the Force” to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended thread-like in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables postsecretion regulation of VWF length. Mutations in VWF in von Willebrand disease contribute to and are illuminated by VWF biology. I attempt to integrate classic studies on the physiology of hemostatic plug formation into modern molecular understanding, and point out what remains to be learned. PMID:24928861

  20. Acquired von Willebrand syndrome associated with left ventricular assist device.

    PubMed

    Nascimbene, Angelo; Neelamegham, Sriram; Frazier, O H; Moake, Joel L; Dong, Jing-Fei

    2016-06-23

    Left ventricular assist devices (LVAD) provide cardiac support for patients with end-stage heart disease as either bridge or destination therapy, and have significantly improved the survival of these patients. Whereas earlier models were designed to mimic the human heart by producing a pulsatile flow in parallel with the patient's heart, newer devices, which are smaller and more durable, provide continuous blood flow along an axial path using an internal rotor in the blood. However, device-related hemostatic complications remain common and have negatively affected patients' recovery and quality of life. In most patients, the von Willebrand factor (VWF) rapidly loses large multimers and binds poorly to platelets and subendothelial collagen upon LVAD implantation, leading to the term acquired von Willebrand syndrome (AVWS). These changes in VWF structure and adhesive activity recover quickly upon LVAD explantation and are not observed in patients with heart transplant. The VWF defects are believed to be caused by excessive cleavage of large VWF multimers by the metalloprotease ADAMTS-13 in an LVAD-driven circulation. However, evidence that this mechanism could be the primary cause for the loss of large VWF multimers and LVAD-associated bleeding remains circumstantial. This review discusses changes in VWF reactivity found in patients on LVAD support. It specifically focuses on impacts of LVAD-related mechanical stress on VWF structural stability and adhesive reactivity in exploring multiple causes of AVWS and LVAD-associated hemostatic complications. PMID:27143258

  1. Massive postoperative intramuscular bleeding in acquired von Willebrand's disease.

    PubMed

    Krebs, M; Meyer, B; Quehenberger, P; Turecek, P L; Hejna, M; Sperr, W R; Lechner, K; Pabinger, I

    2002-07-01

    We describe a case of acquired von Willebrand's disease (vWD) associated with monoclonal gammopathy with undetermined significance (MGUS) in a 54-year-old man who was admitted with hemarthrosis and extensive thigh muscle hematoma following arthroscopic surgery and postoperative prophylaxis with low molecular weight heparin. Coagulation tests were compatible with acquired vWD: prolonged activated partial thromboplastin time (aPTT) (56.1 s), decreased levels of factor VIII coagulant activity (23%), low concentrations of von Willebrand's factor (vWF) antigen (13%), and undetectable ristocetin cofactor activity (<10%). Infusion of a vWF-containing factor VIII concentrate failed to normalize the plasma levels of vWF-related parameters. Only additional intravenous administration of immunoglobulins led to a transient normalization of ristocetin cofactor activity, vWF antigen, and factor VIII coagulant activity. While the spontaneous bleeding tendency in this case was mild, surgery and administration of prophylactic doses of low molecular weight heparin led to life-threatening bleeding. PMID:12185511

  2. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy

    PubMed Central

    2013-01-01

    von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety. PMID:24065240

  3. von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII

    PubMed Central

    Sorvillo, Nicoletta; Hartholt, Robin B.; Bloem, Esther; Sedek, Magdalena; Brinke, Anja ten; van der Zwaan, Carmen; van Alphen, Floris P.; Meijer, Alexander B.; Voorberg, Jan

    2016-01-01

    It has been proposed that von Willebrand factor might affect factor VIII immunogenicity by reducing factor VIII uptake by antigen presenting cells. Here we investigate the interaction of recombinant von Willebrand factor with immature monocyte-derived dendritic cells using flow cytometry and confocal microscopy. Surprisingly, von Willebrand factor was not internalized by immature dendritic cells, but remained bound to the cell surface. As von Willebrand factor reduces the uptake of factor VIII, we investigated the repertoire of factor VIII presented peptides when in complex with von Willebrand factor. Interestingly, factor VIII-derived peptides were still abundantly presented on major histocompatibility complex class II molecules, even though a reduction of factor VIII uptake by immature dendritic cells was observed. Inspection of peptide profiles from 5 different donors showed that different core factor VIII peptide sequences were presented upon incubation with factor VIII/von Willebrand factor complex when compared to factor VIII alone. No von Willebrand factor peptides were detected when immature dendritic cells were pulsed with different concentrations of von Willebrand factor, confirming lack of von Willebrand factor endocytosis. Several von Willebrand factor derived peptides were recovered when cells were pulsed with von Willebrand factor/factor VIII complex, suggesting that factor VIII promotes endocytosis of small amounts of von Willebrand factor by immature dendritic cells. Taken together, our results establish that von Willebrand factor is poorly internalized by immature dendritic cells. We also show that von Willebrand factor modulates the internalization and presentation of factor VIII-derived peptides on major histocompatibility complex class II. PMID:26635035

  4. Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I

    SciTech Connect

    Zhang, Z.P.; Lindstedt, M.; Falk, G.; Blombaeck, M.; Egberg, N.; Anvret, M. )

    1992-10-01

    von Willebrand disease (vWD) is the most common inherited bleeding disorder in humans. The disease is caused by qualitative and quantitative abnormalities of the von Willebrand factor (vWF). Genomic DNA from 25 patients with vWD type III, the most severe form of the disease, was studied using PCR followed by restriction-enzyme analysis and direct sequencing of the products. Nonsense mutations (CGA[yields]TGA) were detected in exons 28, 32, and 45 by screening of all 11 CGA arginine codons of the vWF gene. Two patients were found to be homozygous and five heterozygous for the mutation. Both parents and some of the relatives of the homozygous patients carry the mutation. These are the first reported examples of homozygous point mutations associated with the severe form of vWD. In the three heterozygous probands, one of the parents carried the mutation and had vWD type I. Family studies including parents and family members with or without vWD type I indicted that these three heterozygous patients are likely to be compound heterozygous. Twenty-one individuals from these seven families with vWD type I found to be heterozygous for the mutation. 21 refs., 5 figs., 4 tabs.

  5. Diagnosis and management of von Willebrand disease in The Netherlands.

    PubMed

    de Wee, Eva M; Leebeek, Frank W G; Eikenboom, Jeroen C J

    2011-07-01

    In the Netherlands, specialized care for patients with a bleeding disorder, including hemophilia, von Willebrand disease (VWD), and allied disorders, is concentrated in 13 Hemophilia Treatment Centers. The Dutch Hemophilia Treaters Society, the Dutch Hemophilia Nurses' Society, and the Netherlands Hemophilia Patients Society collaborate to optimize management of patients with a bleeding disorder. A recently updated consensus guideline of hemophilia and allied bleeding disorders provide guidance on the current optimal diagnostic strategy and treatment of VWD. Genetic testing is not routinely performed in the Netherlands. Desmopressin (DDAVP) is the choice of treatment in VWD patients responsive to DDAVP, as determined by a test infusion. Coagulation factor concentrates are used in nonresponsive individuals, in case of a contraindication for DDAVP, or in type 2B and type 3 VWD. These concentrates are available for all patients in the Netherlands; however, these may only be administered in a Hemophilia Treatment Center or under the care of a Hemophilia Treatment Center. Recently a study on moderate and severe VWD (the Willebrand in Netherlands study) was initiated to obtain more insight on VWD diagnosis, treatment, and the burden of the disease. PMID:22102190

  6. Evidence that the primary binding site of von Willebrand factor that mediates platelet adhesion on subendothelium is not collagen.

    PubMed Central

    de Groot, P G; Ottenhof-Rovers, M; van Mourik, J A; Sixma, J J

    1988-01-01

    We have studied the binding of von Willebrand factor to extracellular matrices of endothelial cells and to the vessel wall of human umbilical arteries in relation to its function in supporting platelet adhesion. CLB-RAg 201, an MAb against von Willebrand factor, completely inhibits the binding of von Willebrand factor to collagen type I and type III. CLB-RAg 201 does not inhibit the binding of 125I-von Willebrand factor to extracellular matrices of endothelial cells, to smooth muscle cells, or to the subendothelium. CLB-RAg 201 partly inhibits platelet adhesion to these surfaces, but this directly affects the interaction between von Willebrand factor and platelets and is not due to inhibition of binding of von Willebrand factor to these surfaces. Another MAb, CLB-RAg 38, does not inhibit the binding of von Willebrand factor to collagen. CLB-RAg 38 completely inhibits the binding of von Willebrand factor to extracellular matrices. CLB-RAg 38 inhibits platelet adhesion to cellular matrices completely insofar as it is dependent on plasma von Willebrand factor. CLB-RAg 38 does not inhibit the total binding of von Willebrand factor to subendothelium, as there are too many different binding sites, but it completely inhibits the functional binding sites for von Willebrand factor that support platelet adhesion. The epitopes for CLB-RAg 38 and 201 on the von Willebrand factor molecule are located on different fragments of the molecule. These results indicate that von Willebrand factor binds to subendothelium and matrices of cultured cells by a mechanism that is different from that by which it binds to collagen. Images PMID:2839553

  7. ADAMTS13 and von Willebrand Factor in Thrombotic Thrombocytopenic Purpura

    PubMed Central

    Zheng, X. Long

    2015-01-01

    Pathogenesis of thrombotic thrombocytopenic purpura (TTP) was a mystery for over half a century until the discovery of ADAMTS13. ADAMTS13 is primarily synthesized in the liver, and its main function is to cleave von Willebrand factor (VWF) anchored on the endothelial surface, in circulation, and at the sites of vascular injury. Deficiency of plasma ADAMTS13 activity (<10%) resulting from mutations of the ADAMTS13 gene or autoantibodies against ADAMTS13 causes hereditary or acquired (idiopathic) TTP. ADAMTS13 activity is usually normal or modestly reduced (>20%) in other forms of thrombotic microangiopathy secondary to hematopoietic progenitor cell transplantation, infection, and disseminated malignancy or in hemolytic uremic syndrome. Plasma infusion or exchange remains the initial treatment of choice to date, but novel therapeutics such as recombinant ADAMTS13 and gene therapy are under development. Moreover, ADAMTS13 deficiency has been shown to be a risk factor for the development of myocardial infarction, stroke, cerebral malaria, and preeclampsia. PMID:25587650

  8. Diagnosis and therapeutic management in a patient with type 2B-like acquired von Willebrand syndrome.

    PubMed

    Karger, Ralf; Weippert-Kretschmer, Monika; Budde, Ulrich; Kretschmer, Volker

    2011-03-01

    Acquired von Willebrand syndrome (AVWS) usually mimics von Willebrand disease (VWD) type 1 or 2A. However, in rare cases, the characteristics of other VWD types can predominate in AVWS that might require careful consideration of differential treatment options. The diagnosis and the treatment of a case of type 2B-like AVWS are discussed. Diagnosis of AVWS was ascertained by determining ristocetin cofactor activity, ristocetin-induced platelet aggregation, von Willebrand factor antigen, collagen binding and characterization of von Willebrand factor (VWF) multimers. Inhibitor presence was sought through mixing experiments, the Bethesda method, and calculation of the in-vivo recovery and plasma half-life of VWF after administration of factor VIII/VWF concentrate. Mutations in the A1 domain of VWF were ruled out by sequencing of exon 28 of the VWF gene. A 34-year-old male patient, putatively diagnosed with type 2B VWD, and undergoing laparoscopic cholecystectomy, did not respond adequately to perioperative hemostatic treatment with desmopressin and high doses of factor VIII/VWF concentrate, requiring the administration of recombinant activated factor VII. Further diagnostic workup revealed AVWS mimicking type 2B VWD, most likely owing to an autoantibody developed in the course of underlying monoclonal gammopathy of undetermined significance. The presence of AVWS should be considered before a diagnosis of type 2B VWD is made, especially in patients with a history atypical for inherited disease. PMID:21178586

  9. SUSCEPTIBILITY TO ATHEROSCLEROSIS IN AORTAS AND CORONARY ARTERIES OF SWINE WITH VON WILLEBRAND'S DISEASE

    EPA Science Inventory

    The development of coronary and aortic atherosclerosis was determined after balloon catheter injury of coronary arteries and administration of an atherogenic diet in normal pigs and pigs that were homozygous and heterozygous for von Willebrand's disease. Coronary atherosclerosis ...

  10. The effects of epinephrine infusion in patients with von Willebrand's disease.

    PubMed Central

    Rickles, F R; Hoyer, L W; Rick, M E; Ahr, D J

    1976-01-01

    Epinephrine infusion causes variable increases in the components of the Factor VIII (antihemophilic factor) complex in patients with von Willebrand's disease. The increase in antihemophilic factor procoagulant activity was greater than that of Factor VIII-related antigen and von Willebrand factor activity in two patients with von Willebrand's disease. Similar increases in the three individual factors were demonstrated in two other patients. A 4-10-fold increase in Factor VIII-related properties was identified in each of these individuals after infusion. One patient has been studied with very severe von Willebrand's disease; none of the Factor VIII-related properties increased despite two infusions of epinephrine. Bleeding times were normalized or remained normal in the two patients whose von Willebrand factor activity was greater than 25 U/100 ml. It remained prolonged in those three patients whose von Willebrand factor activity levels remained below that concentration. The increase in procoagulant activity was transient in all patients and t 1/2 values were estimated to be between 0.8 and 3.4 h. PMID:1084352

  11. Acquired von Willebrand syndrome with a type 2B phenotype: diagnostic and therapeutic dilemmas.

    PubMed

    Scepansky, Ellen; Othman, Maha; Smith, Hedy

    2014-01-01

    In this report, we provide evidence of an acquired von Willebrand syndrome (AVWS) with a type 2B phenotype rather than the expected type 1 or 2A. The patient was referred prior to surgical removal of a fibrous mass within the maxillary sinus. His first bleeding 7 years earlier following a retinal tear had been complicated by monocular blindness. Several mucocutanous bleedings followed. Hematological investigations revealed von Willebrand factor (VWF):Ag 91 IU/ml, factor VIII 86 IU/ml, VWF:RCo 34 IU/ml and profound thrombocytopenia with platelet clumping. VWF multimer analysis showed a loss of high-molecular-weight multimers and his plasma aggregated normal platelets under low ristocetin concentration, consistent with type 2B von Willebrand disease (VWD). Sequencing of VWF exon 28 and of the platelet GP1BA gene to investigate the possibility of platelet-type VWD failed to reveal mutations. Serum protein electrophoresis showed a monoclonal IgG protein and led to the diagnosis of monoclonal gammopathy of unknown significance (MGUS), raising suspicion of an AVWS. Over 2 years, he experienced severe gingival bleedings and traumatic intracerebral hemorrhage. Following debridement of the sinus mass, the patient required 20 units of packed red blood cells, despite high-dose Humate-P, continuous Amicar and twice-daily platelet transfusions. Bleeding finally ceased following infusion of activated factor VIIa. A history of prior uncomplicated vasectomy and tendon laceration, no family history of bleeding, the inability to identify a causative mutation in either exon 28 VWF or platelet GP1BA and the MGUS led to diagnosis of AVWS with a type 2B phenotype. This case highlights the difficulties in assigning a diagnosis and the management of bleeding in a patient with an atypical presentation of AVWS. PMID:24296552

  12. Evaluation of a rapid von Willebrand factor activity latex immuno assay for monitoring of patients with von Willebrand disease (VWD) receiving DDAVP or VWF replacement therapy.

    PubMed

    Vinayagam, S; Simons, L R; Chowdary, P; Thurlow, P; Brooks, S V; Riddell, A F

    2014-07-01

    Haemostatic management of surgery in patients with von Willebrand disease (VWD) includes DDAVP or von Willebrand factor (VWF)-containing concentrates. Although the recommendations are for monitoring by VWF activity assays, it is quite common for clinicians to use factor VIII due usually to longer turnaround times required for VWF ristocetin cofactor assay (VWF:RCo) measurements. The aim of this study was to evaluate use of the rapid HaemosIL VWF activity (VWF:Act) latex immuno assay (LIA) on an automated coagulometer (ACL TOP(™) 700; Instrumentation Laboratory, Bedford, MA, USA) compared to platelet-based VWF:RCo assays in this setting. One hundred and sixty-seven plasma samples from 42 patients [Type 1 (n = 22), Type 2A (n = 2), Type 2B (n = 3), Type 2M (n = 10), Type 3 (n = 3)] and acquired von Willebrand syndrome (n = 2) with VWD treated with DDAVP or VWF-containing concentrates were included in the study. Method comparison and method bias were evaluated by Bland-Altman analysis (BA) and Passing and Bablok regression modelling respectively. BA of baseline samples (n = 39) showed a mean difference of -3.0 (±1.96 SD -25.2 to +19.4). Post (treatment) samples (n = 120) were separated into two groups. Group 1 contained samples with VWF:RCo levels 10 to ≤175 IU dL(-1) (n = 97) and group 2, samples with VWF:RCo levels >175 IU dL(-1) (n = 23). BA of group 1 postsamples showed a mean difference of +3.4 (±1.96 SD -44.6 to +51.5), and the BA of Group 2 samples was -23.9 (±1.96 SD -136.1 to +88.3). In conclusion, use of HaemosIL VWF:Act LIA test on an automated coagulometer is a reproducible and rapid assay that can be used as an alternative test for monitoring VWF replacement therapy, facilitating dose adjustments on a real-time basis. PMID:24758424

  13. Acquired von Willebrand syndrome: data from an international registry.

    PubMed

    Federici, A B; Rand, J H; Bucciarelli, P; Budde, U; van Genderen, P J; Mohri, H; Meyer, D; Rodeghiero, F; Sadler, J E

    2000-08-01

    The acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with laboratory findings similar to those of congenital von Willebrand disease (vWD). Despite the numerous cases reported in the literature until 1999 (n = 266), large studies on AvWS are not available. Moreover, diagnosis of AvWS has been difficult and treatment empirical. These considerations prompted us to organize an international registry. A questionnaire, devised to collect specific information on AvWS, was sent to all the members of the International Society on Thrombosis and Haemostasis (ISTH), who were invited to respond if they had diagnosed cases with the AvWS cases. 156 members answered the questionnaire and 54 of them sent information on 211 AvWS cases from 50 centers. Data were compared with those already published in the literature and 25 cases already described or not correctly diagnosed were excluded. The 186 AvWS cases that qualified for the registry were associated with lymphoproliferative (48%) and myeloproliferative disorders (15%), neoplasia (5%), immunological (2%), cardiovascular (21%) and miscellaneous disorders (9%). Ristocetin cofactor activity (vWF:RCo) or collagen binding activity (vWF:CBA) were usually low in AvWS (median values 20 U/dL, range 3-150), while factor VIII coagulant activity was sometimes normal (median 25 U/dL, range 3-191). FVIII/vWF inhibiting activities were present in only a minority of cases (16%). Bleeding episodes in AvWS were mostly of mucocutaneous type (68%) and were managed by DDAVP (32%), FVIII/vWF concentrates (37%), intravenous immunoglobulins (33%), plasmapheresis (19%), corticosteroids (19%) and immunosuppressive or chemotherapic agents (35%). Based upon the data of this international registry, it appears that AvWS is especially frequent in lympho- or myeloproliferative and cardiovascular diseases. Therefore, AvWS should be suspected and searched with the appropriate laboratory tests especially when excessive bleeding occurs in

  14. Epidemiology, diagnosis, and management of von Willebrand disease in India.

    PubMed

    Ghosh, Kanjaksha; Shetty, Shrimati

    2011-07-01

    Von Willebrand disease (VWD) in all developing countries including India is considered a rare coagulation disorder, contrary to many reports from Western countries. Prevalence data based on hospital referrals identifies type 3 VWD as the most common subtype followed by type 1 and type 2. Approximately 60 to 70% cases of type 3 VWD are reportedly born of consanguineous marriages. The discriminatory diagnostic tests mainly include assays for factor (F)VIII:C and ristocetin-induced platelet agglutination and Von Willebrand factor (VWF) antigen either by immunoelectrophoresis or by enzyme-linked immunosorbent assay. VWD-type assisting tests like VWF collagen binding, VWF ristocetin cofactor assay, VWF-FVIII binding assay, and multimer analysis are occasionally used but not routinely applied in many laboratories. Among women, menorrhagia is an important presenting manifestation. Except for a handful of centers mainly in metropolitan cities, most laboratories in the remote parts of the country have no facilities for VWD-related investigations, resulting in occasional misdiagnoses of VWD as hemophilia A. Genetic diagnosis is being offered in two or three centers using the indirect linkage method in type 3 VWD, and efforts are continuing to implementing a direct mutation detection technique for routine practice in a few laboratories. Depending on the subtype or the severity of VWD, desmopressin, cryoprecipitate, fresh-frozen plasma, and factor VIII/VWF concentrates are used for management. Antifibrinolytic agents like epsilon-aminocaproic acid and tranexamic acid are widely used as an adjuvant therapy. In women with menorrhagia, oral contraceptives as a supplementary treatment are also being widely advocated to reduce bleeding. Products like danazol, ethenyl estradiol, thalidomide, and atorvastatin have been used in individual patients; acquired VWD associated with hypothyroidism has been managed successfully with thyroid hormone treatment. Both minor and major surgical

  15. Angiodysplasia as a cause of recurrent bleeding from the small bowel in patients with von Willebrand disease. Report of 4 patients.

    PubMed

    Prochorec-Sobieszek, Monika; Windyga, Jerzy; Maryniak, Renata K; Misiak, Andrzej; Szczepanik, Andrzej

    2004-01-01

    Angiodysplasia, characterized by the presence of malformed vessels in the submucosa of the gastrointestinal tract, may be a cause of recurrent bleeding. Bleeding angiodysplasia can be associated with von Willebrand disease (vWD) and this coincidence is probably the consequence of the lack of high molecular weight molecules of von Willebrand factor in the plasma. We report four patients with unexplained repeated massive intestinal bleeding, recurrent melena and iron deficiency anemia, which required numerous blood transfusions. All patients were adults (average age 68 years). Three patients have congenital von Willebrand disease (type 1, 2A and 3) and one idiopathic acquired von Willenbrand syndrome. Correct diagnosis was made 2-5 years after the onset of the symptoms and was confirmed by histopathological examination of surgically resected small bowel, where vascular lesions were located. Elderly patients with recurrent gastrointestinal bleeding and unexplained iron deficiency anemia should be diagnosed for angiodysplasia and vWD. PMID:15757205

  16. Allosteric activation of ADAMTS13 by von Willebrand factor

    PubMed Central

    Muia, Joshua; Zhu, Jian; Gupta, Garima; Haberichter, Sandra L.; Friedman, Kenneth D.; Feys, Hendrik B.; Deforche, Louis; Vanhoorelbeke, Karen; Westfield, Lisa A.; Roth, Robyn; Tolia, Niraj Harish; Heuser, John E.

    2014-01-01

    The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) within endovascular platelet aggregates, and ADAMTS13 deficiency causes fatal microvascular thrombosis. The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains of ADAMTS13 recognize a cryptic site in VWF that is exposed by tensile force. Another seven T and two complement C1r/C1s, sea urchin epidermal growth factor, and bone morphogenetic protein (CUB) domains of uncertain function are C-terminal to the MDTCS domains. We find that the distal T8-CUB2 domains markedly inhibit substrate cleavage, and binding of VWF or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. Small angle X-ray scattering data indicate that distal T-CUB domains interact with proximal MDTCS domains. Thus, ADAMTS13 is regulated by substrate-induced allosteric activation, which may optimize VWF cleavage under fluid shear stress in vivo. Distal domains of other ADAMTS proteases may have similar allosteric properties. PMID:25512528

  17. Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence

    SciTech Connect

    Eikenboom, J.C.; Brieet, E.; Reitsma, P.H.; Vink, T.; Sixma, J.J.

    1994-03-15

    The authors have analyzed a type IIB and a type I von Willebrand disease family for the presence of mutations in the region coding for the glycoprotein Ib binding domain of the von Willebrand factor. Since this sequence is also present in the highly homologous von Willebrand factor pseudogene, the authors have studied genomic DNA as well as cDNA, which was produced from RNA isolated from endothelial cells or platelets. In both families, they have detected multiple consecutive nucleotide substitutions in the 5{prime} end of exon 28 that result in a sequence identical to the von Willebrand factor pseudogene. These substitutions were also found in cDNA, which proves that they are present in the active gene. The occurrence of multiple adjacent substitutions that exactly reflect a part of the sequence of the von Willebrand factor pseudogene is difficult to reconcile with sequential single mutational events. They therefore hypothesize that each of these multiple substitutions arose from one recombinational event between gene and pseudogene. 34 refs., 4 figs., 2 tabs.

  18. A novel ELISA-based diagnosis of acquired von Willebrand disease with increased VWF proteolysis.

    PubMed

    Rauch, Antoine; Caron, Claudine; Vincent, Flavien; Jeanpierre, Emmanuelle; Ternisien, Catherine; Boisseau, Pierre; Zawadzki, Christophe; Fressinaud, Edith; Borel-Derlon, Annie; Hermoire, Sylvie; Paris, Camille; Lavenu-Bombled, Cécile; Veyradier, Agnès; Ung, Alexandre; Vincentelli, André; van Belle, Eric; Lenting, Peter J; Goudemand, Jenny; Susen, Sophie

    2016-05-01

    Von Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speed-dependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWD-patients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWF-proteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis. PMID:26791163

  19. [Acquired von Willebrand's disease in the course of severe primary hypothyroidism in a patient with autoimmune polyglandular syndrome type 3].

    PubMed

    Lubińska, Monika; Swiatkowska-Stodulska, Renata; Kazimierska, Ewa; Sworczak, Krzysztof

    2008-01-01

    The case of a 20-year old female, who had been followed because of von Willebrand disease (vWD) was presented in this paper . She had a past history of menorrhagia and bleeding after dental procedures and the activity of von Willebrand factor (vWF) was decreased. Because of suggestive clinical features, the workup for hypothyroidism was performed and the patient was found to have severe hypothyroidism due to Hashimoto thyroiditis. After the institution of replacement therapy with levothyroxine, von Willebrand factor activity returned to normal range and symptoms of von Willebrand disease disappeared. Based on these findings, the diagnosis of acquired von Willebrand syndrome (AvWS) due to hypothyroidism was made. The development of myasthenia led to the final diagnosis of autoimmune polyglandular syndrome type 3 (APS) with myasthenia gravis and vitiligo. PMID:18335399

  20. Human von Willebrand factor gene and pseudogene: Structural analysis and differentiation by polymerase chain reaction

    SciTech Connect

    Mancuso, D.J.; Tuley, E.A.; Westfield, L.A.; Lester-Mancuso, T.L.; Sorace, J.M.; Sadler, J.E. ); Le Beau, M.M. )

    1991-01-01

    Structural analysis of the von Willebrand factor gene located on chromosome 12 is complicated by the presence of a partial unprocessed pseudogene on chromosome 22q11-13. The structures of the von Willebrand factor pseudogene and corresponding segment of the gene were determined, and methods were developed for the rapid differentiation of von Willebrand factor gene and pseudogene sequences. The pseudogene is 21-29 kilobases in length and corresponds to 12 exons (exons 23-34) of the von Willebrand factor gene. Approximately 21 kilobases of the gene and pseudogene were sequenced, including the 5{prime} boundary of the pseudogene. The 3{prime} boundary of the pseudogene lies within an 8-kb region corresponding to intron 34 of the gene. The presence of splice site and nonsense mutations suggests that the pseudogene cannot yield functional transcripts. The pseudogene has diverged {approximately}3.1{percent} in nucleotide sequence from the gene. This suggests a recent evolutionary origin {approximately}19-29 million years ago, near the time of divergence of humans and apes from monkeys. Several repetitive sequences were identified, including 4 Alu, one Line-1, and several short simple sequence repeats. Several of these simple repeats differ in length between the gene and pseudogene and provide useful markers for distinguishing these loci. Sequence differences between the gene and pseudogene were exploited to design oligonucleotide primers for use in the polymerase chain reaction to selectivity amplify sequences corresponding to exons 23-34 from either the von Willebrand factor gene or the pseudogene. This method is useful for the analysis of gene defects in patients with von Willebrand disease, without interference from homologous sequences in the pseudogene.

  1. Evaluation of von Willebrand factor in COPD patients*

    PubMed Central

    Bártholo, Thiago Prudente; da Costa, Cláudia Henrique; Rufino, Rogério

    2014-01-01

    OBJECTIVE: To compare the absolute serum von Willebrand factor (vWF) levels and relative serum vWF activity in patients with clinically stable COPD, smokers without airway obstruction, and healthy never-smokers. METHODS: The study included 57 subjects, in three groups: COPD (n = 36); smoker (n = 12); and control (n = 9). During the selection phase, all participants underwent chest X-rays, spirometry, and blood testing. Absolute serum vWF levels and relative serum vWF activity were obtained by turbidimetry and ELISA, respectively. The modified Medical Research Council scale (cut-off score = 2) was used in order to classify COPD patients as symptomatic or mildly symptomatic/asymptomatic. RESULTS: Absolute vWF levels were significantly lower in the control group than in the smoker and COPD groups: 989 ± 436 pg/mL vs. 2,220 ± 746 pg/mL (p < 0.001) and 1,865 ± 592 pg/mL (p < 0.01). Relative serum vWF activity was significantly higher in the COPD group than in the smoker group (136.7 ± 46.0% vs. 92.8 ± 34.0%; p < 0.05), as well as being significantly higher in the symptomatic COPD subgroup than in the mildly symptomatic/asymptomatic COPD subgroup (154 ± 48% vs. 119 ± 8%; p < 0.05). In all three groups, there was a negative correlation between FEV1 (% of predicted) and relative serum vWF activity (r2 = −0.13; p = 0.009). CONCLUSIONS: Our results suggest that increases in vWF levels and activity contribute to the persistence of systemic inflammation, as well as increasing cardiovascular risk, in COPD patients. PMID:25210959

  2. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.

    PubMed

    Abdelmagid, Nada; Bereczky-Veress, Biborka; Atanur, Santosh; Musilová, Alena; Zídek, Václav; Saba, Laura; Warnecke, Andreas; Khademi, Mohsen; Studahl, Marie; Aurelius, Elisabeth; Hjalmarsson, Anders; Garcia-Diaz, Ana; Denis, Cécile V; Bergström, Tomas; Sköldenberg, Birgit; Kockum, Ingrid; Aitman, Timothy; Hübner, Norbert; Olsson, Tomas; Pravenec, Michal; Diez, Margarita

    2016-01-01

    Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89-174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE. PMID:27224245

  3. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis

    PubMed Central

    Atanur, Santosh; Musilová, Alena; Zídek, Václav; Saba, Laura; Warnecke, Andreas; Khademi, Mohsen; Studahl, Marie; Aurelius, Elisabeth; Hjalmarsson, Anders; Garcia-Diaz, Ana; Denis, Cécile V.; Bergström, Tomas; Sköldenberg, Birgit; Kockum, Ingrid; Aitman, Timothy; Hübner, Norbert; Olsson, Tomas; Pravenec, Michal; Diez, Margarita

    2016-01-01

    Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines—generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89–174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11–2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE. PMID:27224245

  4. Acquired von Willebrand's disease associated with gastrointestinal angiodysplasia: a case report.

    PubMed

    Gupta, P K; Kannan, M; Chatterjee, T; Dixit, A; Mahapatra, M; Choudhry, V P; Saxena, R

    2006-07-01

    Acquired von Willebrand syndrome (AVWS) is a rare and probably underestimated bleeding disorder which mimics most of the clinical symptoms and laboratory features of hereditary von Willebrand disease (VWD) in patients devoid of both personal and family history of bleeding diathesis. In this study, we present a case of 55 yrs male patient, presented with gastrointestinal bleeds since three years, diagnosed to have AVWS with inhibitors. From this study it is concluded that AVWS is rare and it is important to diagnose this bleeding disorder so that appropriate treatment with plasmapheresis and IV:Ig can effectively correct the haemostatic defect and manage severe bleeding in these patients. PMID:16834752

  5. Two novel real-time PCR methods for genotyping the von Willebrand disease type I mutation in Doberman Pinscher dogs.

    PubMed

    Gentilini, Fabio; Turba, Maria E

    2013-08-01

    Two single tube real-time PCR methods were designed to genotype the mutation responsible for von Willebrand disease type I (von Willebrand factor c.7437G>A) in Doberman Pinscher dogs: (1) the Divergent PCR assay, which is a modification of the bi-directional PCR amplification of a specific allele (BI-PASA) technique, and (2) a minor groove binder (MGB) real-time PCR assay using fluorescently labelled probes. There was complete agreement between the genotypes determined using the two real-time PCR methods and the results of sequencing of PCR products generated by conventional PCR from genomic DNA purified from the blood of 27 Doberman Pinscher dogs. The Divergent PCR assay yielded reliable results with ≥ 6.4 ng genomic DNA per reaction and the MGB real-time PCR assay yielded reliable results with ≥ 150 pg genomic DNA per reaction. Both real-time PCR methods are suitable for routine genetic testing for the von Willebrand disease type I mutation using blood samples. PMID:23911791

  6. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm.

    PubMed

    Batlle, Javier; Pérez-Rodríguez, Almudena; Corrales, Irene; López-Fernández, Maria Fernanda; Rodríguez-Trillo, Ángela; Lourés, Esther; Cid, Ana Rosa; Bonanad, Santiago; Cabrera, Noelia; Moret, Andrés; Parra, Rafael; Mingot-Castellano, María Eva; Balda, Ignacia; Altisent, Carmen; Pérez-Montes, Rocío; Fisac, Rosa María; Iruín, Gemma; Herrero, Sonia; Soto, Inmaculada; de Rueda, Beatriz; Jiménez-Yuste, Victor; Alonso, Nieves; Vilariño, Dolores; Arija, Olga; Campos, Rosa; Paloma, María José; Bermejo, Nuria; Toll, Teresa; Mateo, José; Arribalzaga, Karmele; Marco, Pascual; Palomo, Ángeles; Sarmiento, Lizheidy; Iñigo, Belén; Nieto, María del Mar; Vidal, Rosa; Martínez, María Paz; Aguinaco, Reyes; César, Jesús María; Ferreiro, María; García-Frade, Javier; Rodríguez-Huerta, Ana María; Cuesta, Jorge; Rodríguez-González, Ramón; García-Candel, Faustino; Cornudella, Rosa; Aguilar, Carlos; Borràs, Nina; Vidal, Francisco

    2016-01-01

    The diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/genotypic association was estimated in 96.5% of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis. PMID:26245874

  7. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A

    PubMed Central

    Castaman, Giancarlo; Linari, Silvia

    2016-01-01

    Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI. PMID:27445481

  8. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A.

    PubMed

    Castaman, Giancarlo; Linari, Silvia

    2016-01-01

    Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI. PMID:27445481

  9. Pharmacokinetic studies with FVIII/von Willebrand factor concentrate can be a diagnostic tool to distinguish between subgroups of patients with acquired von Willebrand syndrome.

    PubMed

    Luboshitz, J; Lubetsky, A; Schliamser, L; Kotler, A; Tamarin, I; Inbal, A

    2001-05-01

    Acquired von Willebrand syndrome (AVWS) has been associated mainly with monoclonal gammopathy of uncertain significance (MGUS), clonal lymphoproliferative or myeloproliferative disorders and autoimmunity. In the present work we studied 6 patients with AVWS: four with MGUS IgG (lambda or kappa), one with small lymphocytic lymphoma and one with agnogenic myeloid metaplasia (AMM). All the patients underwent a pharmacokinetic analysis at presentation in order to study potential differences in recovery, clearance (CL) or terminal half-life (THL) following administration of von Willebrand factor (VWF) concentrate. In all the patients with AVWS an increase in clearance and a decrease in THL was observed as compared to these parameters in patients with hereditary type 3 von Willebrand disease (VWD). No difference in recovery was observed among the groups. The increase in clearance and the decrease in THL were significantly more pronounced in the group of MGUS patients (57.93 +/- 25.6 ml/h/kg, and 1.39 +/- 0.5 h, respectively) as compared to these parameters in the AMM (8.06 ml/h/kg, and 6.96 h, respectively) or the lymphoma (4.76 ml/h/kg, and 6.76 h. respectively) patients (p = 0.03 for clearance and 0.001 for THL). These data indicate that the pharmacokinetic analysis can be a useful tool to distinguish between MGUS-related and other causes of AVWS, and to plan an appropriate treatment accordingly. PMID:11372672

  10. Cancers in Patients with von Willebrand Disease: A Survey from the Italian Association of Haemophilia Centres.

    PubMed

    Franchini, Massimo; Di Perna, Caterina; Santoro, Cristina; Castaman, Giancarlo; Siboni, Simona Maria; Zanon, Ezio; Linari, Silvia; Gresele, Paolo; Pasca, Samantha; Coppola, Antonio; Santoro, Rita; Napolitano, Mariasanta; Ranalli, Paola; Tagliaferri, Annarita

    2016-02-01

    Besides its essential role in hemostasis, there is growing evidence that von Willebrand factor (VWF) has an additional antitumor effect. To elucidate the clinical significance of this biological activity we conducted a retrospective study on cancers among Italian patients with von Willebrand disease (VWD) on behalf of the Italian Association of Haemophilia Centres (AICE). A questionnaire to collect demographic, clinical, and treatment data of VWD patients with cancer was sent to all the 54 Italian Haemophilia Treatment Centres (HTCs) members of AICE. Overall, 18 HTCs (33%) provided information on 92 VWD patients (61 alive and 31 deceased) with 106 cancers collected during the period 1981 to 2014. Of them, 19 (18%) were hematological cancers and 87 (82%) were solid cancers. A total of 61% of patients had type 1, 36% type 2 (12% type 2A, 14% type 2B, 9% type 2M, and 1% type 2N), and 3% type 3 VWD: this distribution was significantly different from that observed in the whole VWD population (79% type 1, 16% type 2 [8% type 2A, 4% type 2B, 2% type 2M, 2% type 2N], and 5% type 3; type 2 vs. non-type 2: p < 0.001). Overall, VWD patients with cancer underwent 52 invasive and 72 surgical procedures, were treated with VWF/factor VIII (FVIII) concentrates in 77 cases, with desmopressin (DDAVP) alone in 24 cases and with DDAVP and VWF/FVIII concentrates in 7 cases. Hemorrhagic complications were observed only rarely (2% of invasive procedures and radiotherapy and 6% of surgical interventions). The data collected by this survey document that a substantial number of cancers are recorded among VWD patients and that these patients are safely managed by HTC physicians through a multidisciplinary approach. PMID:26595151

  11. Fatal Intramyocardial Hemorrhage After Pericardiotomy in a Patient With von Willebrand Disease.

    PubMed

    Singh, Karen E; Hirsch, Benjamin; Colquhoun, Douglas; Durieux, Marcel

    2016-09-01

    Patients with large pericardial effusions and possible tamponade undergoing general anesthesia for pericardial drainage are generally thought to be at a highest risk of cardiovascular collapse before drainage of the effusion. Here, we report a case of extensive and fatal intramyocardial hemorrhage after drainage of a pericardial effusion in a patient with von Willebrand disease. PMID:27580407

  12. von Willebrand factor antigen as a therapeutic target of portal hypertension in cirrhosis

    PubMed Central

    Kalambokis, Georgios N; Baltayiannis, Gerasimos; Christodoulou, Dimitrios

    2016-01-01

    Increased thrombotic potential within the liver sinusoids due to local endothelial production of von Willebrand factor antigen macromolecules could represent an additional therapeutic target of portal hypertension in patients with cirrhosis. In this case, anti-inflammatory and antithrombotic drugs could modulate portal pressure by preventing the formation of intrahepatic platelet-induced microthrombi. PMID:27217711

  13. The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease.

    PubMed

    Makris, M; Federici, A B; Mannucci, P M; Bolton-Maggs, P H B; Yee, T T; Abshire, T; Berntorp, E

    2015-05-01

    Recurrent gastrointestinal bleeding is one of the most challenging complications encountered in the management of patients with von Willebrand disease (VWD). The commonest cause is angiodysplasia, but often no cause is identified due to the difficulty in making the diagnosis. The optimal treatment to prevent recurrences remains unknown. We performed a retrospective study of VWD patients with occult or angiodysplastic bleeding within the setting of the von Willebrand Disease Prophylaxis Network (VWD PN) to describe diagnostic and treatment strategies. Centres participating in the VWD PN recruited subjects under their care with a history of congenital VWD and gastrointestinal (GI) bleeding due to angiodysplasia, or cases in which the cause was not identified despite investigation. Patients with acquired von Willebrand syndrome or those for whom the GI bleeding was due to another cause were excluded. Forty-eight patients from 18 centres in 10 countries were recruited. Seven individuals had a family history of GI bleeding and all VWD types except 2N were represented. Angiodysplasia was confirmed in 38%, with video capsule endoscopy and GI tract endoscopies being the most common methods of making the diagnosis. Recurrent GI bleeding in VWD is associated with significant morbidity and required hospital admission on up to 30 occasions. Patients were treated with multiple pharmacological agents with prophylactic von Willebrand factor concentrate being the most efficient in preventing recurrence of the GI bleeding. The diagnosis and treatment of recurrent GI bleeding in congenital VWD remains challenging and is associated with significant morbidity. Prophylactic treatment with von Willebrand factor concentrate was the most effective method of preventing recurrent bleeding but its efficacy remains to be confirmed in a prospective study. PMID:25381842

  14. Up to date concepts about Von Willebrand disease and the diagnose of this hemostatic disorder

    PubMed Central

    Buga-Corbu, I; Arion, C

    2014-01-01

    Abstract The authors review the current data in literature regarding the recent knowledge about hemostase, coagulation and clinical and laboratory diagnostic algorithms of hemostatic disorders. They also present the pathological classification of bleeding disorders - the basis to clinical approach of these diseases. Abbreviations: AD=autosomal dominant; Ag=antigen; DNA=deoxyribonucleic acid; ADAMTS13=serum metalloproteinase; AR=autosomal recessive; Arg=arginine; RNA=ribonucleic acid; VWD=von Willebrand disease; Cys=cysteine; C1—C9=factors of the seric complement; ELISA=enzyme linked immuno assay; FI---FXIII=plasmatic factors of coagulation; Glu=glutamines; Pg=platelet glycoprotein; HMW=high molecular weight; IL=interleukin; SLE=systemic lupus erythematosus; Met=methionine; PFA=automated study test of platelets aggregation; RCo=ristocetin cofactor; RI PA=ristocetin induced platelet aggregation; Tyr=tyrosine; VWF= von Willebrand factor PMID:25408749

  15. Current controversies in the diagnosis and management of von Willebrand disease

    PubMed Central

    2015-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the world. The spectrum of VWD spans quantitative and qualitative deficiencies of von Willebrand factor (VWF), a platelet adhesive protein. It manifests primarily as mucocutaneous bleeding, but severely affected patients may suffer soft tissue bleeding and hemarthroses. There is disagreement in the multiple guidelines published regarding diagnosis, especially of type 1 VWD, which also remains the most opaque with respect to molecular characterization. Treatment with desmopressin (DDAVP) is most effective in type 1 VWD, but regimens are not standardized. It is not clear which type 2 VWD patients with qualitative deficiencies can be treated with DDAVP and which ones should receive VWF concentrates. No guidelines stipulate which patients might benefit from prophylactic VWF infusions and how they should be dosed. These are some current controversies in VWD that are discussed in this review. PMID:26288715

  16. Acquired von Willebrand disease and multiple myeloma: a case report of a breast cancer survivor.

    PubMed

    Jin, Ning; Salahuddin, Farah F; Nesbitt, John A

    2014-12-01

    Acquired von Willebrand disease (aVWD) is rare disease and is associated with a variety of underlying diseases. We report a case of aVWD in the setting of multiple myeloma. The patient was a 63-year-old female with breast cancer in remission who was admitted for symptomatic anemia. She was diagnosed with multiple myeloma. She also had subcutaneous bleeding before admission. Laboratory studies revealed isolated prolongation of the activated partial thromboplastin time, which corrected in a mixing study. Her factor VIII activity, von Willebrand factor (VWF) Ag, and VWF activity were low. VWF multimer study confirmed the patient had aVWD. The treatment of aVWD is discussed in this article, including the treatment of underlying diseases, and acute management in emergent situations. An intriguing question in this case is whether the patient's multiple myeloma is a chemotherapy-induced hematological malignancy or a second primary malignancy. PMID:24911454

  17. Use of recombinant factor VIIa in inherited and acquired von Willebrand disease.

    PubMed

    Sucker, Christoph; Scharf, Rüdiger E; Zotz, Rainer B

    2009-02-01

    Recombinant factor VIIa (rFVIIa) is increasingly used outside the labeled indications for the treatment of life-threatening bleeding episodes after failure of respective standard therapy. In this article, the authors focus on the use of the agent in patients with inherited or acquired von Willebrand disease (vWD). Although the current experience is sparse, published cases indicate the high efficacy of rFVIIa for the treatment of patients refractory to conventional treatment. The agent may be used in patients with congenital vWD complicated by alloantibodies directed against substituted von Willebrand factor or in the presence of concomitant hemostatic defects as well as acquired vWD with hitherto limited therapeutic options. Controlled clinical studies are necessary to define the use of rFVIIa in this clinical setting. PMID:18263636

  18. Von Willebrand disease-associated angiodysplasia: a few answers, still many questions.

    PubMed

    Franchini, Massimo; Mannucci, Pier Mannuccio

    2013-04-01

    The association between angiodysplasia and von Willebrand disease (VWD) has been known for more than 40 years. Bleeding in the gastrointestinal tract associated with angiodysplasia worsens the clinical course of this inherited haemorrhagic disorder and management may become difficult and challenging. Angiodysplasia associated with acquired defects or dysfunctions of von Willebrand factor (VWF) has also been reported in a variety of conditions such as monoclonal gammopathies, Heyde syndrome and in carriers of ventricular assist devices. The most recent advances concerning the mechanistic, clinical and therapeutic aspects of VWD-associated angiodysplasia are summarized in this review, together with the limitations of our knowledge that warrant further research in the frame of international cooperation. PMID:23432086

  19. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin

    SciTech Connect

    Hill-Eubanks, D.C.; Parker, C.G.; Lollar, P. )

    1989-09-01

    Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. The authors isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO{sub 4}/PAGE and N-terminal sequence analysis. Using a plasma-free assay of the ability of activated {sup 125}I-fVIII to function as a cofactor in the activation of factor X by factor IXa, they found that fVIII is activated by the venom enzyme. The venom enzyme-activated fVIII was isolated in stable form by cation-exchange HPLC. von Willebrand factor inhibited venom enzyme-activated fVIII but not thrombin-activated fVIII. These results suggest that the binding of fVIII to von Willebrand factor depends on the presence of an intact light chain and that activated fVIII must dissociate from von Willebrand factor to exert its cofactor effect. Thus, proteolytic activation of fVIII-von Willebrand factor complex appears to be differentially regulated by light-chain cleavage to dissociate the complex and heavy-chain cleavage to activate the cofactor function.

  20. Linkage disequilibrium patterns vary with chromosomal location: A case study from the von Willebrand factor region

    SciTech Connect

    Watkins, W.S.; Zenger, R.; O'Brien, E.; Jorde, L.B. ); Nyman, D. ); Eriksson, A.W. ); Renlund, M.

    1994-08-01

    Linkage disequilibrium analysis has been used as a tool for analyzing marker order and locating disease genes. Under appropriate circumstances, disequilibrium patterns reflect recombination events that have occurred throughput a population's history. As a result, disequilibrium mapping may be useful in genomic regions of <1 cM where the number of informative meioses needed to detect recombinant individuals within pedigrees is exceptionally high. Its utility for refining target areas for candidate disease genes before initiating chromosomal walks and cloning experiments will be enhanced as the relationship between linkage disequilibrium and physical distance is better understood. To address this issue, the authors have characterized linkage disequilibrium in a 144-kb region of the von Willebrand factor gene on chromosome 12. Sixty CEPH and 12 von Willebrand disease families were genotypes for five PCR-based markers, which include two microsatellite repeats and three single-base-pair substitutions. Linkage disequilibrium and physical distance between polymorphisms are highly correlated (r[sub m] = -.76; P<.05) within this region. None of the five markers showed significant disequilibrium with the von Willebrand disease phenotype. The linkage disequilibrium/physical distance relationship was also analyzed as a function of chromosomal location for this and eight previously characterized regions. This analysis revealed a general trend in which linkage disequilibrium dissipates more rapidly with physical distance in telomeric regions than in centromeric regions. This trend is consistent with higher recombination rates near telomeres. 52 refs., 3 figs., 4 tabs.

  1. von Willebrand disease, pregnancy and neuraxial anesthesia: a multi-disciplinary approach for successful regional anesthesia.

    PubMed

    Kailash, F; Wilkerson, D

    2009-05-01

    Fearing the devastating neurological complications in a parturient with the von Willebrand disease secondary to paucity of studies defining the guidelines to assess the risk of bleeding complications, anesthesiologists are often reluctant to administer neuroaxial anesthesia. We present a case report of a parturient with type I von Willebrand disease who presented for induction of labor at 39 weeks of gestation. After consultation with the hematologist well ahead of the conception, appropriate laboratory workup including clotting factor levels including FVIII, vWF:RcoF, vWF:Ag on different occasions peripartum, and provision of adequate prophylactic medical treatment, she underwent Cesarean section under epidural anesthesia without neurological or bleeding complications. von Willebrand disease is the most common inherited bleeding disorder that may result in various bleeding complications in a parturient as a result of hemostatic challenges during pregnancy. Yet the recommendations are based on anecdotal observations of the authors of small case series and surveys. Our case report emphasizes the importance of advanced planning, careful patient assessment, and multi-disciplinary team approach for the successful regional anesthesia as suggested by the guidelines based on clinical experiences. PMID:19475813

  2. Acquired von Willebrand syndrome associated with hypothyroidism: a mild bleeding disorder to be further investigated.

    PubMed

    Federici, Augusto B

    2011-02-01

    Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). Unlike VWD, AVWS usually occurs in individuals with no personal or family history of bleeding. The prevalence of AVWS in the general population is unknown because data from large prospective studies of this syndrome are not available. Although AVWS is more frequently associated with lympho-myeloproliferative and cardiovascular disorders, it can also occur in solid tumors and in immunological and other miscellaneous conditions. Among these miscellaneous conditions, hypothyroidism has been associated with AVWS type 1 with a frequency of ~2 to 5%. In the 47 cases reported in the literature, the low VWF is apparently due to a reduction in its synthesis and/or secretion. Diagnosis of AVWS is based on assays measuring the level and activity of von Willebrand factor (VWF). These tend to be low, whereas factor VIII (FVIII) coagulant activity can be normal. In patients with AVWS associated with hypothyroidism, mucocutaneous bleeding episodes are the most frequent and can be managed with local therapy and/or systemic administrations of antifibrinolytic agents and desmopressin. VWF/FVIII concentrates have been used in only a few patients. The use of thyroid hormones can reverse this abnormality. PMID:21305800

  3. Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin

    SciTech Connect

    Zhang, Z.P.; Blomback, M.; Egberg, N.; Falk, G.; Anvret, M. )

    1994-05-01

    Twenty-four patients with von Willebrand disease type III were screened for mutations in the von Willebrand factor (VWF) gene using the PCR technique, followed by direct sequencing. More than 250 kb of genomic DNA were sequenced, including the promoter and coding regions (52 exons) of the VWF gene from 24 patients. In addition to the previously reported mutations of a single cytosine deletion in exon 18 and the nonsense mutations in exons 28, 32, and 45, nine new mutations were detected: two nonsense mutations in exons 15 and 16, one allele with a thymidine insertion in exon 14, one allele with a cytosine insertion in exon 28, one 20-bp deletion in exon 15, one mutation in the donor splice site of exon 43, and three missense mutations in exons 28, 49, and 51. Forty-two mutant chromosomes were identified (42/48); 11 probands are homozygous for the mutations, and 8 are compound heterozygous. In addition, a new subfamily of the Alu sequence in the promoter region and 10 new polymorphisms were identified. 15 refs., 3 figs., 3 tabs.

  4. Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor

    SciTech Connect

    Ware, J.; Dent, J.A.; Azuma, Hiroyuki; Sugimoto, Mitsuhiko; Kyrle, P.A.; Yoshioka, Akira; Ruggeri, Z.M. )

    1991-04-01

    von Willebrand factor (vWF) supports platelet adhesion on thrombogenic surfaces by binding to platelet membrane glycoprotein (GP) Ib in the GP Ib-IX receptor complex. This interaction is physiologically regulated so that it does not occur between circulating vWF and platelets but, rather, only at a site of vascular injury. The abnormal vWF found in type IIB von Willebrand disease, however, has a characteristically increased affinity for GP Ib and binds to circulating platelets. The authors have analyzed the molecular basis of this abnormality by sequence analysis of a type IIB vWF cDNA and have identified a single amino acid change, Trp{sup 550} to Cys{sup 550}, located in the GP IB-binding domain of the molecule comprising residues 449-728. Bacterial expression of recombinant fragments corresponding to this vWF domain yielded molecules that, whether containing a normal Trp{sup 550} or a mutant Cys{sup 550} residue, bound directly to GP Ib in the absence of modulators and with similar affinity. These results identify a region of vWF that, although not thought to be directly involved in binding to GP Ib, may modulate the interaction through conformational changes.

  5. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B.

    PubMed

    Hulstein, Janine J J; de Groot, Philip G; Silence, Karen; Veyradier, Agnès; Fijnheer, Rob; Lenting, Peter J

    2005-11-01

    Von Willebrand factor (VWF) is unable to interact spontaneously with platelets because this interaction requires a conversion of the VWF A1 domain into a glycoprotein Ibalpha (GpIbalpha) binding conformation. Here, we discuss a llama-derived antibody fragment (AU/VWFa-11) that specifically recognizes the GpIbalpha-binding conformation. AU/VWFa-11 is unable to bind VWF in solution, but efficiently interacts with ristocetin- or botrocetin-activated VWF, VWF comprising type 2B mutation R1306Q, or immobilized VWF. These unique properties allowed us to use AU/VWFa-11 for the detection of activated VWF in plasma of patients characterized by spontaneous VWF-platelet interactions: von Willebrand disease (VWD) type 2B and thrombotic thrombocytopenic purpura (TTP). For VWD type 2B, levels of activated VWF were increased 12-fold (P < .001) compared to levels in healthy volunteers. An inverse correlation between activated VWF levels and platelet count was observed (R2 = 0.74; P < .003). With regard to TTP, a 2-fold (P < .001) increase in activated VWF levels was found in plasma of patients with acquired TTP, whereas an 8-fold increase (P < .003) was found in congenital TTP. No overlap in levels of activated VWF could be detected between acquired and congenital TTP, suggesting that AU/VWFa-11 could be used to distinguish between both disorders. Furthermore, it could provide a tool to investigate the role of VWF in the development of thrombocytopenia in various diseases. PMID:16014562

  6. The utility of the PFA-100 in the identification of von Willebrand disease: a concise review.

    PubMed

    Favaloro, Emmanuel J

    2006-07-01

    The PFA-100 (platelet function analyser; Dade-Behring, Marburg, Germany) is a relatively new tool for the investigation of primary hemostasis. Recent studies have shown its utility as a screening tool for investigating various platelet disorders and possible von Willebrand disorder (vWD), both in the initial investigation and in subsequent therapeutic monitoring of desmopressin therapy. This article reviews current findings with respect to the identification of vWD, and highlights both the benefits and the limitations of its clinical utility. In brief, sensitivity to vWD types 2A, 2B, 2M, and 3 is > 98%, but overall sensitivity to vWD (types 1, 2A, 2B, 2M, and 3 combined) is ~85 to 90%. Ultimately, the high sensitivity of the PFA-100 to vWD and its simplicity of use provide its greatest strengths. However, because it is a global test system, and also sensitive to low hematocrit, low platelet counts, and platelet dysfunction (both congenital and acquired; e.g., secondary to medication such as aspirin) it must be recognized that the PFA-100 is neither specific for, nor predictive of, any particular disorder (inclusive of vWD). Nevertheless, used appropriately, the PFA-100 can be considered a worthwhile addition to the hemostasis laboratory involved in the diagnosis or therapeutic monitoring of vWD, and a normal PFA-100 result can be used with some confidence to exclude severe vWD. PMID:16862528

  7. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis

    PubMed Central

    Stockschlaeder, Marcus; Schneppenheim, Reinhard; Budde, Ulrich

    2014-01-01

    Normal hemostasis requires von Willebrand factor (VWF) to support platelet adhesion and aggregation at sites of vascular injury. VWF is a multimeric glycoprotein built from identical subunits that contain binding sites for both platelet glycoprotein receptors and collagen. The adhesive activity of VWF depends on the size of its multimers, which range from 500 to over 10 000 kDa. There is good evidence that the high-molecular-weight multimers (HMWM), which are 5000–10 000 kDa, are the most effective in supporting interaction with collagen and platelet receptors and in facilitating wound healing under conditions of shear stress. Thus, these HMWM of VWF are of particular clinical interest. The unusually large multimers of VWF are, under normal conditions, cleaved by the plasma metalloproteinase ADAMTS13 to smaller, less adhesive multimers. A reduction or lack of HMWM, owing to a multimerization defect of VWF or to an increased susceptibility of VWF for ADAMTS13, leads to a functionally impaired VWF and the particular type 2A of von Willebrand disease. This review considers the biology and function of VWF multimers with a particular focus on the characterization of HMWM – their production, storage, release, degradation, and role in normal physiology. Evidence from basic research and the study of clinical diseases and their management highlight a pivotal role for the HMWM of VWF in hemostasis. PMID:24448155

  8. A novel flow cytometry single tube bead assay for quantitation of von Willebrand factor antigen and collagen-binding.

    PubMed

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

    2012-11-01

    Deficiency of or defects in the plasma protein von Willebrand factor (VWF) lead to bleeding and von Willebrand disease (VWD), which may be congenital or acquired. VWD is considered the most common inherited bleeding disorder and laboratory testing for VWF level and activity is critical for appropriate diagnosis and management. We have designed and established a novel Flow Cytometry (FC) based method for measuring VWF antigen (VWF:Ag) and collagen binding (VWF:CB), together in the same tube and at the same time. The results of the novel FC method have been compared against existing reference methods using a range of normal and pathological material. Methods correlated well (VWF:Ag, r=0.866; VWF:CB, r=0.888) and generally permitted similar discrimination of quantitative versus qualitative VWD types (e.g. type 1 vs type 2A or 2B VWD). The novel procedure is expected to permit future streamlined performance of VWD screening, either using stand-alone FC systems or potentially incorporated into FC-capable automated blood cell and particle counters to allow for improved, automated and faster identification or exclusion of VWD. PMID:23014972

  9. The use of desmopressin in the management of two patients with von Willebrand's disease undergoing periodontal surgery. 2 case reports.

    PubMed

    Petrover, M G; Cohen, C I

    1990-04-01

    Von Willebrand's disease is a genetic bleeding disorder characterized by either a reduced plasma concentration of von Willebrand's factor (vWF) or a qualitative deficiency in that vWF which is produced. Previous therapy consisted of injecting concentrates of vWF manufactured from the pooled plasma of multiple donors. With the increased incidence and risk of serum borne transmission of such diseases as hepatitis and AIDS, the advantages of an alternative mode of therapy was obvious. In the course of using 1-desamino-8-D-arginine (desmopressin or DDAVP, a synthetic analogue of 8-arginine vasopressin, a hormone secreted in the posterior pituitary gland) in the treatment of diabetes insipidus, it was discovered that this drug causes the release of bound vWF into the plasma. The elevation lasts for several hours and is effective in producing hemostasis in some types of mild to moderate von Willebrand's disease. In 1984, desmopressin was approved for this usage in the United States. This paper discusses the use of DDAVP in the management of von Willebrand's disease and present two case reports of patients with von Willebrand's disease and in need of periodontal surgery. PMID:2324924

  10. The Prevalence of von Willebrand Disease and Significance of in Vitro Bleeding Time (PFA-100) in von Willebrand Disease Screening in the İzmir Region

    PubMed Central

    Şap, Fatih; Kavaklı, Tülay; Kavaklı, Kaan; Dizdarer, Ceyhun

    2013-01-01

    Objective: von Willebrand disease (vWD) is the most common hereditary bleeding disorder. The purpose of this investigation was to determine the prevalence of vWD among adolescents in İzmir and to assess the sensitivity and specificity of PFA-100 as a screening method in detecting this disease. Material and Methods: Our study was conducted on adolescents in the city of İzmir between October 2006 and March 2007. A total of approximately 1500 high school students between 14 and 19 years of age were planned to be included in the investigation. Survey forms prepared for assessing hemorrhagic diathesis were completed by 1339 individuals (512 males, 827 females). The necessary laboratory tests were performed after having obtained written informed consent from 40 individuals suspected to have hemorrhagic diathesis. Results: Based on the von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activity (vWF:RCo) levels and bleeding symptoms, vWD type-1 was diagnosed in 14 individuals (4 males, 10 females; prevalence: 1.04%). The most common bleeding symptom in these patients was found to be epistaxis (10/14). Screening with PFA-100 revealed prolongation in both cartridges (Col/ADP and Col/Epi) in 3 of the 14 patients. PFA-100 was determined to exhibit 21.4% sensitivity and 100% specificity in the diagnosis of vWD. Conclusion: The PFA-100 device was found to have high specificity but to have exhibited low sensitivity. Therefore, its utilization as a screening test may be problematic in patients with mild type-1 vWD. Specific tests (vWF:RCo, vWF:Ag) are required for the definite diagnosis of vWD. However, further studies with a large number of patients are needed. Conflict of interest:None declared. PMID:24385752

  11. Evaluation of a von Willebrand factor three test panel and chemiluminescent-based assay system for identification of, and therapy monitoring in, von Willebrand disease.

    PubMed

    Favaloro, Emmanuel J; Mohammed, Soma

    2016-05-01

    von Willebrand disease (VWD) is reportedly the most common bleeding disorder and arises from deficiency and/or defects of von Willebrand factor (VWF). Laboratory diagnosis and typing of VWD has important management implications and requires a wide range of tests, including VWF antigen (VWF:Ag) and various activities, involving differential identification of qualitative vs quantitative VWF defects. We have assessed a new hemostasis instrument, the chemiluminescent assay based ACL AcuStar™, and an associated HemosIL AcuStar three test panel comprising VWF:Ag, VWF ristocetin cofactor (VWF:RCo) and VWF collagen binding (VWF:CB) (Instrumentation Laboratory, Bedford, Ma. USA) for ability to identify VWD, to help provisionally type VWD, and for potential use in therapy monitoring. This test system was compared to previously evaluated and validated test systems including VWF:RCo on CS-5100 and BCS analyzers, the new Siemens INNOVANCE assay (VWF Ac) on CS-5100, and VWF:Ag and VWF:CB assays performed by automated ELISA. We employed a large total sample test set (n=535) comprising plasma and platelet-lysate samples from individuals with and without VWD, some on treatment, normal plasmas, and normal and pathological controls. We also evaluated desmopressin (DDAVP) responsiveness, plus differential sensitivity to reduction in high molecular weight (HMW) VWF. The chemiluminescent test panel (VWF:Ag, VWF:RCo, VWF:CB) showed good comparability to similar assays performed by alternate methods, and broadly similar data for identification of VWD, provisional VWD type identification, DDAVP and VWD therapy, and HMW VWF sensitivity, although some notable differences were evident. The chemiluminescent system showed best low level VWF sensitivity, and lowest inter-assay variability, compared to all other systems. In conclusion, we have validated theACL AcuStar and the chemiluminescent HemosIL AcuStar VWF test panel for use in VWD diagnostics, and have identified some favorable

  12. Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor.

    PubMed Central

    Ware, J; Dent, J A; Azuma, H; Sugimoto, M; Kyrle, P A; Yoshioka, A; Ruggeri, Z M

    1991-01-01

    von Willebrand factor (vWF) supports platelet adhesion on thrombogenic surfaces by binding to platelet membrane glycoprotein (GP) Ib in the GP Ib-IX receptor complex. This interaction is physiologically regulated so that it does not occur between circulating vWF and platelets but, rather, only at a site of vascular injury. The abnormal vWF found in type IIB von Willebrand disease, however, has a characteristically increased affinity for GP Ib and binds to circulating platelets. We have analyzed the molecular basis of this abnormality by sequence analysis of a type IIB vWF cDNA and have identified a single amino acid change, Trp550 to Cys550, located in the GP Ib-binding domain of the molecule comprising residues 449-728. Bacterial expression of recombinant fragments corresponding to this vWF domain yielded molecules that, whether containing a normal Trp550 or a mutant Cys550 residue, bound directly to GP Ib in the absence of modulators and with similar affinity. In contrast, mammalian cell expression of the same segment of sequence yielded molecules that, when containing the normal Trp550, did not bind to GP Ib directly but, like native vWF, bound in the presence of ristocetin. However, molecules containing the point mutation (Cys550) behaved like type IIB vWF--namely, bound to GP Ib even without ristocetin modulation and, in the presence of ristocetin, had 10-fold higher affinity than molecules with normal sequence. These results identify a region of vWF that, although not thought to be directly involved in binding to GP Ib, may modulate the interaction through conformational changes. Images PMID:2011604

  13. Functional domains on von Willebrand factor. Recognition of discrete tryptic fragments by monoclonal antibodies that inhibit interaction of von Willebrand factor with platelets and with collagen.

    PubMed Central

    Sixma, J J; Sakariassen, K S; Stel, H V; Houdijk, W P; In der Maur, D W; Hamer, R J; de Groot, P G; van Mourik, J A

    1984-01-01

    We have identified two functional domains on the von Willebrand factor (VWF) moiety of the Factor VIII-von Willebrand factor complex (FVIII-VWF), one interacting with blood platelets, and one interacting with vessel wall collagens, by means of two monoclonal antibodies directed against the VWF molecule, CLB-RAg 35 and CLB-RAg 201. The monoclonal antibody CLB-RAg 35 inhibited virtually all platelet adherence to artery subendothelium and to purified vessel wall collagen type III, at relatively high wall shear rates. CLB-RAg 35 also inhibited the ristocetin-induced platelet aggregation and the binding of FVIII-VWF to the platelet in the presence of ristocetin but did not affect the binding of FVIII-VWF to collagen. The monoclonal antibody CLB-RAg 201 inhibited the binding of FVIII-VWF to purified vessel wall collagen type I and III and all platelet adherence to collagen type III and the platelet adherence to subendothelium that was mediated by FVIII-VWF in plasma. The two functional domains on FVIII-VWF that were recognized by CLB-RAg 35 and CLB-RAg 201 were identified by means of immunoprecipitation studies of trypsin-digested FVIII-VWF. The domains resided on different polypeptide fragments, with a Mr of 48,000 for the collagen binding domain and a Mr of 116,000 for the platelet binding domain. The 116,000-mol wt fragment consisted of subunits of 52,000/56,000 mol wt and 14,000 mol wt after reduction. The 52,000/56,000-mol wt subunits possessed the epitope for CLB-RAg 35. Images PMID:6332119

  14. Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines.

    PubMed

    Nichols, William L; Rick, Margaret E; Ortel, Thomas L; Montgomery, Robert R; Sadler, J Evan; Yawn, Barbara P; James, Andra H; Hultin, Mae B; Manco-Johnson, Marilyn J; Weinstein, Mark

    2009-06-01

    Von Willebrand factor (VWF) mediates blood platelet adhesion and accumulation at sites of blood vessel injury, and also carries coagulation factor VIII (FVIII) that is important for generating procoagulant activity. Von Willebrand disease (VWD), the most common inherited bleeding disorder, affects males and females, and reflects deficiency or defects of VWF that may also cause decreased FVIII. It may also occur less commonly as an acquired disorder (acquired von Willebrand syndrome). This article briefly summarizes selected features of the March 2008 evidence-based clinical and laboratory diagnostic recommendations from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel for assessment for VWD or other bleeding disorders or risks. Management of VWD is also addressed in the NHLBI guidelines, but is not summarized here. The VWD guidelines are available at the NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd). PMID:19415721

  15. Congenital Type III von Willebrand's disease unmasked by hypothyroidism in a Shetland sheepdog.

    PubMed

    Scuderi, Margaret; Bessey, Lauren; Snead, Elisabeth; Burgess, Hilary; Carr, Anthony

    2015-09-01

    A 7-year-old, spayed female Shetland sheepdog had sudden onset of right-sided epistaxis. Diagnostic tests revealed Type III von Willebrand's disease and primary hypothyroidism leading to an acute hypothyroid crisis and acquired factor VIII (FVIII) deficiency. Levothyroxine therapy normalized the serum thyroxine and FVIII concentrations. The delayed onset of disease and the reversible FVIII deficiency that was corrected with levothyroxine therapy, support a role for hypothyroidism in the pathogenesis of this dog's sudden bleeding tendency as has been seen with hypothyroidism in humans. PMID:26347307

  16. Perils, Problems, and Progress in Laboratory Diagnosis of Von Willebrand Disease

    PubMed Central

    Flood, Veronica H.

    2014-01-01

    Diagnosis of von Willebrand disease (VWD) merits consideration of personal and family history of bleeding symptoms along with confirmatory laboratory testing. Because the latter yields quantifiable results, over-reliance on a laboratory diagnosis may occur. However, existing tests for VWD contain potential sources for error. Both intrinsic and extrinsic factors affecting these assays can contribute to either falsely normal or falsely abnormal results. This article will discuss presently available assays as well as new developments in diagnostic testing. A clear understanding of the limitations of VWD testing is helpful for ensuring the correct diagnosis of affected patients. PMID:24338593

  17. Life-threatening bleeding in a patient with mild hemophilia A and heterozygosity for von Willebrand disease Type 2N.

    PubMed

    Allan, John N; Friedman, Kenneth D; DeSancho, Maria T

    2014-12-01

    Hemophilia A and von Willebrand disease (VWD) are distinct bleeding disorders with a spectrum of clinical phenotypes. They are characterized by mutations in either factor VIII (F8) or von Willebrand factor (VWF) genes, respectively. The pattern of inheritance and appropriate laboratory evaluation differentiates these diseases, and treatment strategies for both are different. Here, we report a male patient with hemophilia A and VWD Type 2 Normandy (N) mutations who presented with life-threatening bleeding. We document his medical history, clinical course, management, and diagnostic work up. PMID:25212677

  18. Towards personalised therapy for von Willebrand disease: a future role for recombinant products.

    PubMed

    Favaloro, Emmanuel J

    2016-05-01

    von Willebrand disease (VWD) is reportedly the most common bleeding disorder and is caused by deficiencies and/or defects in the adhesive plasma protein von Willebrand factor (VWF). Functionally, normal VWF prevents bleeding by promoting both primary and secondary haemostasis. In respect to primary haemostasis, VWF binds to both platelets and sub-endothelial matrix components, especially collagen, to anchor platelets to damaged vascular tissue and promote thrombus formation. VWF also stabilises and protects factor VIII in the circulation, delivering FVIII to the site of injury, which then facilitates secondary haemostasis and fibrin formation/thrombus stabilisation. As a result of this, patients with VWD suffer a bleeding diathesis reflective of a primary defect caused by defective/deficient VWF, which in some patients is compounded by a reduction in FVIII. Management of VWD, therefore, chiefly entails replacement of VWF, and sometimes also FVIII, to protect against bleeding. The current report principally focuses on the future potential for "personalised" management of VWD, given the emerging options in recombinant therapies. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may soon change the way in which VWD is managed. In particular, we can envisage a personalised treatment approach using recombinant VWF, with or without recombinant FVIII, depending on the type of VWD, the extent of deficiencies, and the period and duration of treatment. PMID:27136426

  19. Expression of von Willebrand factor Normandy: An autosomal mutation that mimics hemophilia A

    SciTech Connect

    Tuley, E.A.; Worrall, N.K.; Sadler, J.E. ); Gaucher, C.; Jorieux, S.; Mazurier, C. )

    1991-07-15

    von Willebrand disease Normandy (vWD Normandy) is a recently described phenotype in which a mutant von Willebrand factor (VWF) appears structurally and functionally normal except that is does not bind to blood coagulation factor VIII. This interaction is required for normal survival of factor VIII in the circulation; consequently, vWD Normandy can present as apparent hemophilia A but with autosomal recessive rather than X chromosome-linked inheritance. AvWF missense mutation, Thr{sup 28} {r arrow} Met, was identified in the propositus in or near the factor VIII binding site. The corresponding mutant recombinant vWF(T28M) formed normal multimers and had normal ristocetin cofactor activity. However, vWF(T28M) exhibited the same defect in factor VIII binding as natural vWF Normandy, confirming that this mutation causes the vWD Normandy phenotype. The distinction between hemophilia A and vWD Normandy is clinically important and should be considered in families affected by apparent mild hemophilia A that fail to show strict X chromosome-linked inheritance and, particularly, in potential female carriers with low factor VIII levels attributed to extreme lyonization.

  20. Towards personalised therapy for von Willebrand disease: a future role for recombinant products

    PubMed Central

    Favaloro, Emmanuel J.

    2016-01-01

    von Willebrand disease (VWD) is reportedly the most common bleeding disorder and is caused by deficiencies and/or defects in the adhesive plasma protein von Willebrand factor (VWF). Functionally, normal VWF prevents bleeding by promoting both primary and secondary haemostasis. In respect to primary haemostasis, VWF binds to both platelets and sub-endothelial matrix components, especially collagen, to anchor platelets to damaged vascular tissue and promote thrombus formation. VWF also stabilises and protects factor VIII in the circulation, delivering FVIII to the site of injury, which then facilitates secondary haemostasis and fibrin formation/thrombus stabilisation. As a result of this, patients with VWD suffer a bleeding diathesis reflective of a primary defect caused by defective/deficient VWF, which in some patients is compounded by a reduction in FVIII. Management of VWD, therefore, chiefly entails replacement of VWF, and sometimes also FVIII, to protect against bleeding. The current report principally focuses on the future potential for “personalised” management of VWD, given the emerging options in recombinant therapies. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may soon change the way in which VWD is managed. In particular, we can envisage a personalised treatment approach using recombinant VWF, with or without recombinant FVIII, depending on the type of VWD, the extent of deficiencies, and the period and duration of treatment. PMID:27136426

  1. Misfolding of vWF to pathologically disordered conformations impacts the severity of von Willebrand disease.

    PubMed

    Tischer, Alexander; Madde, Pranathi; Moon-Tasson, Laurie; Auton, Matthew

    2014-09-01

    The primary hemostatic von Willebrand factor (vWF) functions to sequester platelets from rheological blood flow and mediates their adhesion to damaged subendothelium at sites of vascular injury. We have surveyed the effect of 16 disease-causing mutations identified in patients diagnosed with the bleeding diathesis disorder, von Willebrand disease (vWD), on the structure and rheology of vWF A1 domain adhesiveness to the platelet GPIbα receptor. These mutations have a dynamic phenotypical range of bleeding from lack of platelet adhesion to severe thrombocytopenia. Using new rheological tools in combination with classical thermodynamic, biophysical, and spectroscopic metrics, we establish a high propensity of the A1 domain to misfold to pathological molten globule conformations that differentially alter the strength of platelet adhesion under shear flow. Rheodynamic analysis establishes a quantitative rank order between shear-rate-dependent platelet-translocation pause times that linearly correlate with clinically reported measures of patient platelet counts and the severity of thrombocytopenia. These results suggest that specific secondary structure elements remaining in these pathological conformations of the A1 domain regulate GPIbα binding and the strength of vWF-platelet interactions, which affects the vWD functional phenotype and the severity of thrombocytopenia. PMID:25185554

  2. Structural origins of misfolding propensity in the platelet adhesive von Willebrand factor A1 domain.

    PubMed

    Zimmermann, Michael T; Tischer, Alexander; Whitten, Steven T; Auton, Matthew

    2015-07-21

    The von Willebrand factor (VWF) A1 and A3 domains are structurally isomorphic yet exhibit distinct mechanisms of unfolding. The A1 domain, responsible for platelet adhesion to VWF in hemostasis, unfolds through a molten globule intermediate in an apparent three-state mechanism, while A3 unfolds by a classical two-state mechanism. Inspection of the sequences or structures alone does not elucidate the source of this thermodynamic conundrum; however, the three-state character of the A1 domain suggests that it has more than one cooperative substructure yielding two separate unfolding transitions not present in A3. We investigate the extent to which structural elements contributing to intermediate conformations can be identified using a residue-specific implementation of the structure-energy-equivalence-of-domains algorithm (SEED), which parses proteins of known structure into their constituent thermodynamically cooperative components using protein-group-specific, transfer free energies. The structural elements computed to contribute to the non-two-state character coincide with regions where Von Willebrand disease mutations induce misfolded molten globule conformations of the A1 domain. This suggests a mechanism for the regulation of rheological platelet adhesion to A1 based on cooperative flexibility of the α2 and α3 helices flanking the platelet GPIbα receptor binding interface. PMID:26200876

  3. Structural Origins of Misfolding Propensity in the Platelet Adhesive Von Willebrand Factor A1 Domain

    PubMed Central

    Zimmermann, Michael T.; Tischer, Alexander; Whitten, Steven T.; Auton, Matthew

    2015-01-01

    The von Willebrand factor (VWF) A1 and A3 domains are structurally isomorphic yet exhibit distinct mechanisms of unfolding. The A1 domain, responsible for platelet adhesion to VWF in hemostasis, unfolds through a molten globule intermediate in an apparent three-state mechanism, while A3 unfolds by a classical two-state mechanism. Inspection of the sequences or structures alone does not elucidate the source of this thermodynamic conundrum; however, the three-state character of the A1 domain suggests that it has more than one cooperative substructure yielding two separate unfolding transitions not present in A3. We investigate the extent to which structural elements contributing to intermediate conformations can be identified using a residue-specific implementation of the structure-energy-equivalence-of-domains algorithm (SEED), which parses proteins of known structure into their constituent thermodynamically cooperative components using protein-group-specific, transfer free energies. The structural elements computed to contribute to the non-two-state character coincide with regions where Von Willebrand disease mutations induce misfolded molten globule conformations of the A1 domain. This suggests a mechanism for the regulation of rheological platelet adhesion to A1 based on cooperative flexibility of the α2 and α3 helices flanking the platelet GPIbα receptor binding interface. PMID:26200876

  4. Some interactions between human platelets and glass: von Willebrand's disease compared with normal.

    PubMed

    O'Brien, J R; Heywood, J B

    1967-01-01

    If native or heparinized blood is passed slowly through a column of glass beads at room temperature, the number of platelets removed from the initial drop emerging from the column is less than that removed from the final drop. At 4 degrees C. this difference disappears. If the blood is passed rapidly through such columns at room temperature fewer platelets are removed, but the initial-final difference persists. Von Willebrand's platelets are removed normally at slow speeds; at fast speeds abnormally few platelets are removed. Platelets emerging from all such columns are in aggregates. On adding glass beads to normal heparinized plasma, the platelets at once become more rounded and after about 50 seconds' delay they aggregate: the delay and rate of aggregation can be quantitated. Aggregation occurs best at 20 to 30 degrees C. and is not inhibited by the addition of some enzyme inhibitors. In von Willebrand's disease all these glass-induced aggregation phenomena occur normally and aggregation in response to adenosine diphosphate (ADP), serotonin creatinine sulphate (5-HT), adrenaline, collagen, and glass is also normal. PMID:5297360

  5. Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor.

    PubMed

    Tischer, Alexander; Campbell, James C; Machha, Venkata R; Moon-Tasson, Laurie; Benson, Linda M; Sankaran, Banumathi; Kim, Choel; Auton, Matthew

    2016-02-19

    Unusually large von Willebrand factor (VWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease, two rare mutations (G1324A and G1324S) within the platelet GPIbα binding interface of the VWF A1 domain impair the hemostatic function of VWF. We investigate structural and conformational effects of these mutations on the A1 domain's efficacy to bind collagen and adhere platelets under shear flow. These mutations enhance the thermodynamic stability, reduce the rate of unfolding, and enhance the A1 domain's resistance to limited proteolysis. Collagen binding affinity is not significantly affected indicating that the primary stabilizing effect of these mutations is to diminish the platelet binding efficiency under shear flow. The enhanced stability stems from the steric consequences of adding a side chain (G1324A) and additionally a hydrogen bond (G1324S) to His(1322) across the β2-β3 hairpin in the GPIbα binding interface, which restrains the conformational degrees of freedom and the overall flexibility of the native state. These studies reveal a novel rheological strategy in which the incorporation of a single glycine within the GPIbα binding interface of normal VWF enhances the probability of local unfolding that enables the A1 domain to conformationally adapt to shear flow while maintaining its overall native structure. PMID:26677223

  6. Acquired von Willebrand's disease associated with epithelial myoepithelial carcinoma of the parotid salivary gland

    PubMed Central

    Chilvers, Geoffrey Spencer; Porter, Graham

    2014-01-01

    This is the first case report of a patient with acquired von Willebrand's disease (AvWD) secondary to epithelial myoepithelial carcinoma (EMC) of the parotid salivary gland. This patient presented to haematology following an abnormal bleeding episode with von Willebrand factor Ristocetin cofactor (VWF:RCo) <5% and VWF:Ag 13%. He was diagnosed with AvWD. At the same time he was found to have a left parotid lump which was excised following a multidisciplinary team meeting. This was histologically reported as an EMC. Following excision, unusually this patient's AvWD did not resolve. Extensive investigation looking for other causes of the AvWD did not reveal any other potential cause; therefore, due to the similar timing of onset of both pathologies it is felt that the AvWD in this case is secondary to the EMC. This case report highlights the presentation, investigation and management of AvWD and parotid lumps as well as discussing proposed pathophysiological mechanisms for AvWD. PMID:25096657

  7. von Willebrand Factor multimers profiling with a semi-automated system.

    PubMed

    Pasotti, Fabio; Martini, Giuliana; Caimi, Luigi; Ricotta, Doris

    2013-03-01

    Abnormalities in plasma von Willebrand factor (vWF) concentration and function result in von Willebrand disease (vWD). The diagnosis requires a battery of tests such as screening procedures, confirmatory tests, phenotypic characterization, and genotyping. The phenotypic testing (multimer pattern analysis) is important in order to subclassify the hereditary and the acquired forms of vWD. Only few laboratories are skilled to perform this analysis. The extreme range of protein size from 250 kDa monomer to over 20,000 kDa multimers requires a time-consuming procedure (3-4 days) and presents many technical difficulties. To standardize the method and to overcome technical difficulties, we developed a rapid and sensitive semi-automated method to visualize the multimeric structure of vWF. The semi-automated method we present performs the electrophoresis of patient's plasma in 120 min on a precast gel. Gels are suitable for the G26 Interlab instrumentation. After gel blotting, the method allows visualization of the vWF multimer pattern directly on the membrane. We reduced the time required from 72 to 8 h and we propose this test for the first level screening of vWF multimer deficiency. PMID:23334940

  8. Wilate use in 47 children with von Willebrand disease: the North London paediatric haemophilia network experience.

    PubMed

    Khair, K; Batty, P; Riat, R; Bowles, L; Burgess, C; Chen, Y-H; Hart, D; Platton, S; Pasi, J; Liesner, R

    2015-01-01

    Children with von Willebrand disease (VWD) in whom DDAVP is ineffective or contraindicated require treatment with a coagulation factor concentrate containing von Willebrand factor (VWF) and factor VIII (FVIII). The aim of this study was to monitor the safety, efficacy and tolerability of Wilate(®) (a VWF:FVIII concentrate with a 1:1 ratio) used across the North London Paediatric Haemophilia Network since May 2010. In total, 47 children (aged 0.0-17.0 years) with type 1 (n = 28), type 2 (n = 7), type 3 (n = 10) and acquired VWS (n = 2) have been treated for bleeds, surgery and/or prophylaxis using 260 000 IU Wilate(®). Analysis of dose and frequency of treatment show expected responses to treatment with mean doses of 55, 50 and 50 IU kg(-1) for bleeds, surgery and prophylaxis respectively. Most bleeds responded to a single treatment. Surgical procedures were covered with clinician approved dosing schedules with 95% (39/41) reported as having excellent or good efficacy. There was no accumulation of FVIII or VWF and no thromboembolic events. This case series confirms the efficacy, safety and tolerability of Wilate(®) in neonates, children and adolescents when used on-demand, prophylactically and in the surgical setting. PMID:25112927

  9. Conventional Rapid Latex Agglutination in Estimation of von Willebrand Factor: Method Revisited and Potential Clinical Applications

    PubMed Central

    Che Hussin, Che Maraina

    2014-01-01

    Measurement of von Willebrand factor antigen (VWF : Ag) levels is usually performed in a specialised laboratory which limits its application in routine clinical practice. So far, no commercial rapid test kit is available for VWF : Ag estimation. This paper discusses the technical aspect of latex agglutination method which was established to suit the purpose of estimating von Willebrand factor (VWF) levels in the plasma sample. The latex agglutination test can be performed qualitatively and semiquantitatively. Reproducibility, stability, linearity, limit of detection, interference, and method comparison studies were conducted to evaluate the performance of this test. Semiquantitative latex agglutination test was strongly correlated with the reference immunoturbidimetric assay (Spearman's rho = 0.946, P < 0.001, n = 132). A substantial agreement (κ = 0.77) was found between qualitative latex agglutination test and the reference assay. Using the scoring system for the rapid latex test, no agglutination is with 0% VWF : Ag (control negative), 1+ reaction is equivalent to <20% VWF : Ag, and 4+ reaction indicates >150% VWF : Ag (when comparing with immunoturbidimetric assay). The findings from evaluation studies suggest that latex agglutination method is suitable to be used as a rapid test kit for the estimation of VWF : Ag levels in various clinical conditions associated with high levels and low levels of VWF : Ag. PMID:25759835

  10. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo.

    PubMed Central

    Sobel, M; McNeill, P M; Carlson, P L; Kermode, J C; Adelman, B; Conroy, R; Marques, D

    1991-01-01

    The intravenous administration of heparin to patients before open heart surgery reduced ristocetin cofactor activity by 58% (P less than 0.01, t test), and this impairment of von Willebrand factor-dependent platelet function was closely related to plasma heparin levels (r2 = 0.9), but not to plasma von Willebrand factor (vWF) levels. We hypothesized that heparin may inhibit vWF-dependent platelet hemostatic functions by directly binding vWF in solution and interfering with vWF-GpIb binding. Using the in vitro techniques of ristocetin-induced platelet agglutination, fluorescent flow cytometric measurement of vWF-platelet binding, and conventional radioligand binding assays we observed that heparin inhibited both vWF-dependent platelet function and vWF-platelet binding in a parallel and dose-dependent manner. Heparin also inhibited platelet agglutination induced by bovine vWF and inhibited the binding of human asialo-vWF to platelets in ristocetin-free systems. The inhibitory potency of heparin was not dependent upon its affinity for antithrombin III, but was molecular weight dependent: homogeneous preparations of lower molecular weight were less inhibitory. Heparin impairment of vWF function may explain why some hemorrhagic complications of heparin therapy are not predictable based on techniques for monitoring the conventional anticoagulant effects of heparin. PMID:2022745

  11. Molecular study of VWF gene from Mexican Mestizo patients with von Willebrand disease, and the finding of three new mutations.

    PubMed

    Melo-Nava, Brenda M; Benítez, Herminia; Palacios, J Jorge; Nieva, Beatriz; Arenas, Diego; Jaloma-Cruz, A Rebeca; Navarrete, Carmen; Salamanca, Fabio; Peñaloza, Rosenda

    2007-01-01

    To investigate the origin of von Willebrand disease in Mexican Mestizo population, we analyzed exons 18, 19, 20, 28, 45, and 52 of the VWF gene from 34 Mexican Mestizo index cases, 28 of them affected but not related, using DNA amplification by polymerase chain reaction and direct sequencing. We found three novel mutations: E1447Q in one patient with type 1; P2781S in one patient with type 2M; and P812L in another type 1/2N patient. These mutations were not found in 100 normal alleles. Moreover, we found other mutations previously reported in the literature; one of them (G1609R) was the most frequent (6/28) in patients with VWD type 2A. This is the first molecular study in a Mexican group that has a particular mixture of Indigenous, Caucasian, and African genes. PMID:17681836

  12. Diagnosis of congenital von Willebrand disease during a preoperative assessment in a multiple myeloma patient without bleeding history.

    PubMed

    El Ouaaliti, Malika; Li, Rong; Gobin, Delphine; Bron, Dominique; Cantinieaux, Brigitte

    2016-07-01

    We report a rare case of type 2M von Willebrand disease diagnosed in an elderly multiple myeloma patient who had no personal and family bleeding history. This case report emphasis the importance to not systematically exclude a congenital vWD in adult patients when coagulation screening tests indicate toward a vWD. PMID:27386134

  13. Von Willebrand factor in patients on mechanical circulatory support – a double-edged sword between bleeding and thrombosis

    PubMed Central

    Kaczmarski, Jacek; Pacholewicz, Jerzy; Zakliczynski, Michal; Gasior, Mariusz; Zembala, Marian

    2015-01-01

    Mechanical circulatory support (MCS) is an umbrella term describing the various technologies used in both short- and long-term management of patients with either end-stage chronic heart failure (HF) or acute HF. Most often, MCS has emerged as a bridge to transplantation, but more recently it is also used as a destination therapy. Mechanical circulatory support includes left ventricular assist device (LVAD) or bi-ventricular assist device (Bi-VAD). Currently, 2- to 3-year survival in carefully selected patients is much better than with medical therapy. However, MCS therapy is hampered by sometimes life-threatening complications including bleeding and device thrombosis. Von Willebrand factor (vWF) has two major functions in haemostasis. First, it plays a crucial role in platelet-subendothelium adhesion and platelet-platelet interactions (aggregation). Second, it is the carrier of factor VIII (FVIII) in plasma. Von Willebrand factor prolongs FVIII half-time by protecting it from proteolytic degradation. It delivers FVIII to the site of vascular injury thus enhancing haemostatic process. On one hand, high plasma levels of vWF have been associated with an increased risk of thrombosis. On the other, defects or deficiencies of vWF underlie the inherited von Willebrand disease or acquired von Willebrand syndrome. Here we review the pathophysiology of thrombosis and bleeding associated with vWF. PMID:26702279

  14. Comprehensive evaluation of haemostatic function in von Willebrand disease patients using a microchip-based flow chamber system.

    PubMed

    Ogiwara, K; Nogami, K; Hosokawa, K; Ohnishi, T; Matsumoto, T; Shima, M

    2015-01-01

    The diagnosis of von Willebrand disease (VWD) is difficult due to the wide spectrum of clinical phenotypes associated with this disorder. We have analysed and characterized haemostatic function in VWD patients using a microchip-based flow chamber system. Microchips coated with either collagen [platelet (PL)-chip] or collagen/thromboplastin [atherome (AR)-chip] were used to evaluate platelet thrombus formation at 1000 s(-1) and fibrin-rich platelet thrombus formation at 240 s(-1) respectively. Blood samples from an asymptomatic patient with VWD type 1 [von Willebrand factor (VWF): RCo 3.2%; bleeding score (BS 2] displayed normal thrombus formation in both PL- and AR-chips, whereas blood from a symptomatic type 1 patient (VWF: RCo 14%, BS 9) had significantly delayed capillary occlusion. Nearly complete suppression of the flow pressure increase was observed in symptomatic patients with VWD type 2A (BS 13) and 2N (BS 27), whereas no flow pressure was found for the type 3 patient (BS 6). Fibrin-rich platelet thrombus formation was only weakly increased by the in vitro addition of factor VIII (FVIII) to blood samples from the type 3 patient, but was normalized by the addition of VWF/FVIII. The in vivo effects of treatment with desmopressin or VWF/FVIII for the symptomatic patients were analysed using two types of microchips. The PL-chip was highly sensitive for patients' VWF-mediated platelet functions, whereas the AR-chip allowed assessment of overall haemostatic ability, including sensitivity to both VWF and FVIII. The combined analysis with PL- and AR-chips may be potentially useful for the diagnosis of VWD based on clinical phenotypes, and for monitoring drug effects. PMID:25545301

  15. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study.

    PubMed

    Hamilton, Alexander; Ozelo, Margareth; Leggo, Jayne; Notley, Colleen; Brown, Hannah; Frontroth, Juan Pablo; Angelillo-Scherrer, Anne; Baghaei, Fariba; Enayat, Said M; Favaloro, Emmanuel; Lillicrap, David; Othman, Maha

    2011-03-01

    Less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non-previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses. PMID:21301777

  16. New assay for measuring binding of platelet glycoprotein IIb/IIIa to unpurified von Willebrand factor.

    PubMed

    Veyradier, A; Jumilly, A L; Ribba, A S; Obert, B; Houllier, A; Meyer, D; Girma, J P

    1999-07-01

    Among the numerous variants of vWD, no patient with an abnormal vWF binding to GPIIb/IIIa has been described to date. To search for such potential variants, we developed a two-site assay for measuring the binding of purified GPIIb/IIIa to vWF in biological fluids and we used it to study a large series of plasmas from various types of von Willebrand disease (vWD) and recombinant vWF (rvWF). vWF in plasma or rvWF in culture medium was immobilized onto anti-vWF monoclonal antibodies (MoAb)-coated wells of microtiter plates. After incubation with either unlabeled GPIIb/IIIa and a 125I-anti-GPIIb/IIIa MoAb or 125I-GPIIb/IIIa, binding curves and binding isotherms were respectively established. Normal pool plasma and wild-type rvWF were used as reference samples. We tested plasmas from 85 normal subjects, 115 patients with different types of vWD (64 type 1, 2 type 3, 9 type 2A, 4 type 2M, 16 type 2B, 15 type 2N, 3 type IID and 2 acquired forms) and 50 patients with various bleeding disorders. Four mutated rvWF with 2A (Glu875Lys and Pro885Ser) or 2B (Dupl.Met540 and Val551Phe) substitutions and one rvWF mutated in the RGD domain of the C-terminal part of vWF-subunit (Asp1746Gly) were also studied. Among the various samples tested, only rvWF Asp1746Gly had no affinity for GPIIb/IIIa. In contrast, GPIIb/IIIa similarly bound to the other vWF, independently of the proteic environment, the factor VIII level, the degree of multimerization or the mutation of vWF. Our results indicate that subjects with an abnormal vWF binding to GPIIb/IIIa are probably rare and difficult to target for a specific screening. PMID:10456467

  17. Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor

    PubMed Central

    Torisu, Takehiro; Torisu, Kumiko; Lee, In Hye; Liu, Jie; Malide, Daniela; Combs, Christian A.; Wu, Xufeng S.; Rovira, Ilsa I.; Fergusson, Maria M.; Weigert, Roberto; Connelly, Patricia S.; Daniels, Mathew P; Komatsu, Masaaki; Cao, Liu; Finkel, Toren

    2013-01-01

    Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here, we demonstrate that WPBs are in some cases found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy, or knockdown of the essential autophagy genes Atg5 or Atg7, inhibits the in vitro secretion of VWF. Furthermore, while mice with an endothelial specific deletion of Atg7 have normal vessel architecture and capillary density, these animals exhibit impaired epinephrine-stimulated VWF release, reduced levels of high molecular weight VWF multimers and a corresponding elevation of their bleeding times. Endothelial deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events. PMID:24056772

  18. Von Willebrand factor availability in platelet concentrates stored for 5 days.

    PubMed

    Cesar, J M; García-Avello, A; Monteagudo, J; Espinosa, J I; Lodos, J C; Castillo, R; Navarro, J L

    1994-02-01

    Von Willebrand factor (vWF) availability was assessed in platelet concentrates (PCs). After 5 days of storage, 82 +/- 9% of basal levels of ristocetin cofactor activity (vWF:RCo) remained in PCs. vWF antigen (vWF:Ag) increased up to 166 +/- 38% (P < 0.05) in the same period. Autoradiograph pattern of vW:Ag showed an increase in low molecular weight multimers, and fast migrating multimeric forms were visualized by crossed immunoelectrophoresis on day 5. Studies carried out in platelet free plasma stored as PCs showed similar changes in vWF:RCo but increments in vWF:Ag were not detected. These data indicate that PCs maintain vWF:RCo levels of clinical value even after 5 days of storage and suggest that vWF comes out from platelets to plasma during storage. PMID:8141116

  19. Turner syndrome associated with acquired von Willebrand disease, primary biliary cirrhosis, and inflammatory bowel disease.

    PubMed

    Sokol, Lubomir; Stueben, Eugen T; Jaikishen, Jay P; Lamarche, Maximo B

    2002-07-01

    We report a unique case of Turner syndrome associated with acquired von Willebrand disease (AvWD), primary biliary cirrhosis (PBC), and inflammatory bowel disease (IBD). During 7 years of close follow-up, the patient presented with multiple major episodes of upper and lower gastrointestinal bleeding caused by different pathogenic mechanisms, such as IBD, AvWD, gastric varices, and thrombocytopenia. AvWD mimicking familial vWD type III on laboratory testing was most probably triggered by autoimmune mechanism associated with PBC. Therapy of PBC with ursodeoxycholic acid (UDCA) resulted in significant decrease of liver enzymes followed by normalization of vWF and FVIII levels. Portosystemic shunt placement with ligation of gastric varices improved hypersplenism and severe thrombocytopenia and led to clinical stability for more than 24 months. The clinicopathological features of these disorders and of the recurrent bleeding episodes are discussed in the text along with a review of the literature. PMID:12116986

  20. Acquired von Willebrand disease in a patient with monoclonal gammopathy of undetermined significance.

    PubMed

    Huang, Yi-Wu; Saidi, Parvin

    2004-02-01

    We describe a patient with acquired von Willebrand disease (vWD), who had typical presentation and clinical manifestations of acquired vWD, but correct diagnosis was delayed because of lack of awareness and early recognition. The patient was initially seen at a community hospital with persistent nasal mucosal bleeding and was transfused with an excessive amount of cryoprecipitates before appropriate hemostatic evaluation. Hemostasis work-up revealed that he had classic features of acquired vWD. Further extensive evaluation revealed the patient to have monoclonal gammopathy of undetermined significance (MGUS). He was refractory to a high dose of corticosteroids and had a very transient response to desmopressin acetate (less than 4 hours) but responded well to a high dose of intravenous immunoglobulin (IVIG), which lasted at least 3 weeks with each treatment. He remained very responsive to IVIG 2 years later. His underlying MGUS has not progressed during the past 4 years. PMID:14770028

  1. Laboratory tests used to help diagnose von Willebrand disease: an update.

    PubMed

    Favaloro, Emmanuel J; Pasalic, Leonardo; Curnow, Jennifer

    2016-06-01

    von Willebrand disease (VWD) is due to quantitative deficiencies and/or qualitative defects in von Willebrand factor (VWF), and is reportedly the most common inherited bleeding disorder. However, diagnosis of VWD is problematic, and is subject to over-, under-, and misdiagnosis. This is due to many factors, including limitations in current test procedures and an over-reliance on these imperfect test systems for clinical diagnosis. VWF is a complex plasma protein with multiple functions, but essentially acts to assist in the formation of a platelet thrombus to stop blood loss from sites of injury. VWF achieves this by several activities, including binding to platelets [primarily through the glycoprotein Ib (GPIb) receptor], binding to subendothelial matrix components (primarily collagen), and binding to factor VIII (FVIII), thus protecting FVIII from degradation and enabling its delivery to sites of vascular injury. Laboratory assessment of VWD entails performance of a battery of tests, some of which aim to mimic in vivo VWF activity. VWD is classified into six separate types, based on quantitative deficiencies [types 1 (partial deficiency) and 3 (total deficiency)] of VWF, or qualitative defects (type 2 VWD), which comprise four 'subtypes'. The current report briefly overviews the diagnosis of VWD, describing the currently available armamentarium of laboratory tests, as well as emerging options for laboratory-assisted diagnostics. Although some methodologies suffer from significant limitations that challenge the accurate diagnosis of VWD, newer methodologies and specific approaches can improve detection of this common bleeding disorder, and the appropriate characterisation and typing of patients. PMID:27131932

  2. C2362F mutation gives rise to an ADAMTS13-resistant von Willebrand factor.

    PubMed

    Casonato, Alessandra; Pontara, Elena; Battiston, Monica; Morpurgo, Margherita; Cattini, Maria Grazia; Casarin, Elisabetta; Saga, Giorgia; Daidone, Viviana; De Marco, Luigi

    2013-06-01

    von Willebrand factor (VWF) multimers result from proteolysis by the metalloprotease ADAMTS13. Since C2362F-VWF features abnormally large multimers with their triplet oligomer structure replaced by a diffuse smear, we explored the susceptibility of C2362F-VWF to ADAMTS13. VWF-enriched blood samples, obtained by cryoethanol precipitation of plasma from a patient with von Willebrand disease (VWD) homozygous for the C2362F mutation and a normal subject, were submitted to cleavage by recombinant ADAMTS13 under static conditions in the presence of urea. C2362F-VWF proved completely ADAMTS13-resistant in vitro. At any concentration of recombinant ADAMTS13 (from 0.1 µM to 1 µM), there was no evidence of the abnormally large VWF multimers of C2362F-VWF disappearing, nor any increased representation of triplet multimer bands, unlike the situation seen in normal VWF. This is due partly to a defective ADAMTS13 binding to C2362F-VWF under static conditions, as seen in both the patient's and recombinant mutated VWF proteins. These findings were associated with a significantly shorter than normal survival of C2362F-VWF after DDAVP, demonstrating that proteolysis and VWF survival may be independent phenomena. Our findings clearly demonstrate that the loss of cysteine 2362 makes VWF resistant to proteolysis by ADAMTS13, at least partly due to an impaired ADAMTS13 binding to VWF. This suggests that the B2 domain of VWF is involved in modulating ADAMTS13 binding to VWF and the consequent proteolytic process. The C2362F-VWF mutation also enables a new abnormality to be identified in the VWF-ADAMTS13 relationship, i.e. an ADAMTS13-resistant VWF. PMID:23446343

  3. Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias.

    PubMed

    Dicke, Christina; Schneppenheim, Sonja; Holstein, Katharina; Spath, Brigitte; Bokemeyer, Carsten; Dittmer, Rita; Budde, Ulrich; Langer, Florian

    2016-05-01

    Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that may cause life-threatening hemorrhages in patients with plasma cell dyscrasias (PCDs). Early diagnosis and treatment require a thorough understanding of its underlying pathophysiology. Two patients with IgG MGUS presented with dramatically decreased plasma von Willebrand factor (VWF) and a severe type-1 pattern on multimer analysis. A prompt response to intravenous immunoglobulins (IVIG), but not to VWF/FVIII, was consistent with accelerated immunologic clearance of plasma VWF. Another IgG MGUS patient showed a type-2 pattern and a less pronounced response to IVIG, suggesting that additional mechanism(s) contributed to AVWS evolution. In a patient with Waldenström's macroglobulinemia and severe depletion of plasma VWF, multimer analysis indicated association of the IgM paraprotein with VWF before, but not after plasmapheresis, resulting in destruction of the agarose gel and a characteristically distorted band structure of VWF multimers. A type-2 pattern with highly abnormal VWF triplets and laboratory evidence of excessive fibrinolytic activity suggested that plasmin-mediated VWF degradation contributed to AVWS in a patient with multiple myeloma (MM) and AL amyloidosis. Finally, in a patient with IgG MM, maximally prolonged PFA-100® closure times and a specific defect in ristocetin-induced platelet agglutination, both of which resolved after remission induction, indicated interference of the paraprotein with VWF binding to platelet GPIb. Importantly, in none of the six patients, circulating autoantibodies to VWF were detected by a specific in-house ELISA. In summary, when evaluating PCD patients with severe bleeding symptoms, AVWS due to various pathogenic mechanisms should be considered. PMID:27040683

  4. In Vivo Gene Transfer Strategies to Achieve Partial Correction of von Willebrand Disease

    PubMed Central

    Wang, Lan; Rosenberg, Jonathan B.; De, Bishnu P.; Ferris, Barbara; Wang, Rui; Rivella, Stefano; Kaminsky, Stephen M.

    2012-01-01

    Abstract von Willebrand disease (VWD), the most common hereditary coagulation disorder, results from mutations in the 52-exon gene for von Willebrand factor (VWF), which encodes an 8.4-kB cDNA. Studies with VWF cDNA plasmids have demonstrated that in vivo gene transfer to the liver will correct the coagulation dysfunction in VWF−/− mice, but the correction is transient. To develop gene therapy for VWF that would mediate long-term expression of the VWF cDNA in liver, we first evaluated segmental pre-mRNA trans-splicing (SPTS) with two adeno-associated virus (AAV) serotype 8 vectors, each delivering one-half of the VWF cDNA. However, although the two vectors functioned well to generate VWF multimers after infection of cells in vitro, the efficiency of SPTS was insufficient to correct the VWF−/− mouse in vivo. As an alternative, we assessed the ability of a lentiviral vector to transfer the intact murine VWF cDNA in vivo directly to the neonatal liver of VWF−/− mice, using generation of VWF multimers, bleeding time, and bleeding volume as efficacy parameters. The VWF lentivirus generated VWF multimers and partially or completely corrected the coagulation defect on a persistent basis in 33% of the treated VWF-deficient mice. On the basis of the concept that partial persistent correction with gene transfer could be beneficial in VWD patients, these observations suggest that lentiviral delivery of VWF cDNA should be explored as a candidate for gene therapy in patients with a severe form of VWD. PMID:22482515

  5. Effect of levothyroxine administration on hemostatic analytes in Doberman Pinschers with von Willebrand disease.

    PubMed

    Heseltine, Johanna C; Panciera, David L; Troy, Gregory C; Monroe, William E; Brooks, Marjory B; Feldman, Bernard F

    2005-01-01

    Levothyroxine administration has been suggested to be an effective treatment for canine von Willebrand disease (vWd), but evidence supporting this treatment is lacking. Effects of levothyroxine administration were evaluated in 8 euthyroid Doberman Pinschers with plasma von Willebrand factor (vWf) concentrations < 15%, characteristic of type 1 vWd. Levothyroxine (0.04 mg/kg PO q12h) and placebo were administered for 30 days in a 2-period, 2-treatment, double-blinded, crossover design with a 30-day washout period between treatments. Buccal mucosal bleeding time (BMBT), plasma vWf concentration (vWf: Ag), vWf collagen binding activity (vWf:CBA), factor VIII coagulant activity (FVIII:C), and serum concentrations of total thyroxine (T4), free thyroxine (fT4), 3,5,3'-triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured on days 0, 2, and 30 of each treatment period. The 8 dogs (1 male, 7 females) had markedly low plasma vWf:Ag (mean, 8.9%; reference range, 70-180%) and vWf:CBA (mean, 11.1%; reference range, >70%). Response to placebo versus levothyroxine treatment was not significantly different between groups at day 0, 2, or 30 for BMBT, vWf:Ag, vWf:CBA, and FVIII:C. Serum T4, fT4, and T3 concentrations were significantly higher and serum TSH significantly lower in the levothyroxine-treated group than in the placebo group at days 2 and 30. Administration of levothyroxine at 0.04 mg/kg caused laboratory evidence of hyperthyroidism but did not affect plasma FVIII:C and vWf:Ag concentrations or vWf-dependent collagen binding and BMBT. The results of this study failed to identify a direct action of levothyroxine supplementation on plasma vWf concentration or activity in euthyroid Doberman Pinschers with vWd. PMID:16095169

  6. Genetic Heterogeneity in a Large Cohort of Indian Type 3 von Willebrand Disease Patients

    PubMed Central

    Kasatkar, Priyanka; Shetty, Shrimati; Ghosh, Kanjaksha

    2014-01-01

    Background Though von Willebrand disease (VWD) is a common coagulation disorder, due to the complexity of the molecular analysis of von Willebrand factor gene (VWF), not many reports are available from this country. Large size of the gene, heterogeneous nature of mutations and presence of a highly homologous pseudogene region are the major impediments in the genetic diagnosis of VWD. The study is aimed at unravelling the molecular pathology in a large series of VWD patients from India using an effective strategy. Method We evaluated 85 unrelated Indian type 3 VWD families to identify the molecular defects using a combination of techniques i.e. PCR-RFLP, direct DNA sequencing and multiple ligation probe amplification (MLPA). Results Mutations could be characterized in 77 unrelated index cases (ICs). 59 different mutations i.e. nonsense 20 (33.9%), missense 13 (22%), splice site 4 (6.8%), gene conversions 6 (10.2%), insertions 2 (3.4%), duplication 1 (1.7%), small deletions 10 (17%) and large deletions 3 (5.1%) were identified, of which 34 were novel. Two common mutations i.e. p.R1779* and p.L970del were identified in our population with founder effect. Development of alloantibodies to VWF was seen in two patients, one with nonsense mutation (p.R2434*) and the other had a large deletion spanning exons 16–52. Conclusion The molecular pathology of a large cohort of Indian VWD patients could be identified using a combination of techniques. A wide heterogeneity was observed in the nature of mutations in Indian VWD patients. PMID:24675615

  7. Platelet-type von Willebrand disease: a rare, often misdiagnosed and underdiagnosed bleeding disorder.

    PubMed

    Othman, Maha

    2011-07-01

    Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant rare bleeding disorder characterized by hyperresponsive platelets. This inherent platelet function defect is due to a gain-of-function mutation within the GP1BA gene coding for the platelet surface glycoprotein Ib alpha protein, the receptor for the adhesive protein von Willebrand factor (VWF). The defect results in excessive and unnecessary platelet-VWF interaction with subsequent removal of the hemostatically efficient high molecular weight VWF as well as platelets from the circulation, leading to thrombocytopenia and bleeding diathesis. Patients with PT-VWD present with mild to moderate mucocutaneous bleeding, which becomes more pronounced during pregnancy and following aspirin ingestion or drugs that have antiplatelet activity. Laboratory testing shows low VWF:ristocetin cofactor and low or normal VWF:antigen and characteristically an enhanced ristocetin-induced platelet agglutination (RIPA). These laboratory features are also indicators of the closely similar and more common bleeding disorder type 2B VWD. Simplified RIPA mixing assays, cryoprecipitate challenge, and flow cytometry can differentiate between the two disorders. However, the gold standard is to identify mutations within the VWF gene (indicating type 2B VWD) or the platelet GP1BA gene (confirming PT-VWD). Treatment is based on making a correct diagnosis of PT-VWD where platelet concentrates instead of VWF/factor VIII preparations should be administered. A recent fairly large retrospective/prospective registry-based international study showed that PT-VWD is very rare, likely to be misdiagnosed as type 2B VWD or idiopathic thrombocytopenic purpura, and represents 15% of type 2B VWD diagnoses. PMID:22102188

  8. Functional behavior of vessels from pigs with von Willebrand disease. Values of platelet deposition are identical to those obtained on normal vessels

    SciTech Connect

    Badimon, L.; Badimon, J.J.; Turitto, V.T.; Rand, J.; Fuster, V.

    1989-03-01

    Vessels from normal pigs and pigs with severe von Willebrand disease were exposed for up to 30 minutes to both nonanticoagulated and heparinized blood from normal pigs in an ex vivo perfusion system. Shear rates at the vessel surface were varied over a broad physiological range, gamma w = 212 to 3380 sec-1. The deposition of /sup 111/In-labeled platelets was determined by radiometric counting. For all shear rates and exposure times investigated, the levels of platelet deposition on de-endothelialized thoracic aorta of normal and von Willebrand disease pigs were not significantly different. Thus, the functional activity of the vessels correlated with the results obtained previously by immunofluorescence. Namely, the von Willebrand factor protein in the thoracic subendothelium of normal pigs is significantly diminished or absent and is comparable to the levels observed in von Willebrand disease pigs.

  9. Ionizing radiation enhances platelet adhesion to the extracellular matrix of human endothelial cells by an increase in the release of von Willebrand factor

    SciTech Connect

    Verheij, M.; Dewit, L.G.H. ); Boomgaard, M.N.; Brinkman, H.J.M.; Mourik, J.A. van )

    1994-02-01

    The effect of radiation on the secretion of von Willebrand factor by endothelial cells was studied in a three-compartment culture system. The release of von Willebrand factor was significantly increased at 48 h after a single [gamma]-radiation dose of 20 Gy in both the luminal and abluminal direction by 23 (P < 0.05) and 41% (P < 0.02), respectively. To establish whether the enhanced production of von Willebrand factor affected the thrombogenicity of the extracellular matrix, platelet adhesion to the matrix produced by a monolayer of cultured endothelial cells during 48 h after irradiation was analyzed in a perfusion chamber at high shear rate (1300 s[sup [minus]1]). Platelet adhesion was significantly increased by irradiation both in the presence and in the absence of plasmatic von Willebrand factor by 65 (P < 0.05) and 34.5% (P < 0.005), respectively. Incubation of the perfusate with a monoclonal antibody that blocks the binding of von Willebrand factor to platelet GPIb (CLB-RAg 35) resulted in an almost complete inhibition of platelet adhesion. These data indicate that radiation enhances platelet adhesion to the extracellular matrix by an increase in the release of von Willebrand factor by endothelial cells. This event may be important in early radiation-induced vascular pathology. 37 refs., 2 figs., 2 tabs.

  10. Single molecule force spectroscopy data and BD- and MD simulations on the blood protein von Willebrand factor.

    PubMed

    Posch, Sandra; Aponte-Santamaría, Camilo; Schwarzl, Richard; Karner, Andreas; Radtke, Matthias; Gräter, Frauke; Obser, Tobias; König, Gesa; Brehm, Maria A; Gruber, Hermann J; Netz, Roland R; Baldauf, Carsten; Schneppenheim, Reinhard; Tampé, Robert; Hinterdorfer, Peter

    2016-09-01

    We here give information for a deeper understanding of single molecule force spectroscopy (SMFS) data through the example of the blood protein von Willebrand factor (VWF). It is also shown, how fitting of rupture forces versus loading rate profiles in the molecular dynamics (MD) loading-rate range can be used to demonstrate the qualitative agreement between SMFS and MD simulations. The recently developed model by Bullerjahn, Sturm, and Kroy (BSK) was used for this demonstration. Further, Brownian dynamics (BD) simulations, which can be utilized to estimate the lifetimes of intramolecular VWF interactions under physiological shear, are described. For interpretation and discussion of the methods and data presented here, we would like to directly point the reader to the related research paper, "Mutual A domain interactions in the force sensing protein von Willebrand Factor" (Posch et al., 2016) [1]. PMID:27508268

  11. IgG kappa monoclonal gammopathy of undetermined significance presenting as acquired type III Von Willebrand syndrome.

    PubMed

    Howard, Christin R; Lin, Tara L; Cunningham, Mark T; Lipe, Brea C

    2014-09-01

    Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder associated with hematoproliferative disorders, autoimmune conditions, neoplasia and cardiovascular disorders that often present a diagnostic challenge. Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common causes of AVWS that typically presents later in life with mucocutaneous or postsurgical bleeding and multimers consistent with type I or II von Willebrand disease (VWD). Here, we present the case of a patient with a 32-year history of type III VWD that was ultimately found to be AVWS related to an IgG MGUS. In this case report, we highlight the diagnostic challenges of AVWS to ensure proper identification and potentially lifesaving treatment of this rare disorder. PMID:24686099

  12. IgGG Kappa Monoclonal Gammopathy of Undetermined Significance (MGUS) Presenting as Acquired Type III Von Willebrand Syndrome

    PubMed Central

    Howard, C; Lin, T; Cunningham, M; Lipe, B

    2014-01-01

    Acquired von Willebrand Syndrome (AVWS) is a rare bleeding disorder associated with hematoproliferative disorders, autoimmune conditions, neoplasia, and cardiovascular disorders that often presents a diagnostic challenge. Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common causes of AVWS that typically presents later in life with mucocutaneous or postsurgical bleeding and multimers consistent with type I or II von Willebrand Disease (VWD). Here we present the case of a patient with a 32 year history of type III VWD that was ultimately found to be AVWS related to an IgG MGUS. In this case report, we highlight the diagnostic challenges of AVWS to ensure proper identification and potentially lifesaving treatment of this rare disorder. PMID:24686099

  13. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease.

    PubMed

    Cattaneo, M; Federici, A B; Lecchi, A; Agati, B; Lombardi, R; Stabile, F; Bucciarelli, P

    1999-07-01

    We have evaluated platelet function at high shear with the PFA-100 system in different subtypes of von Willebrand disease (vWD), before and after the intravenous infusions of desmopressin or a factor-VIII/von Willebrand factor (vWF) concentrate. Closure times with the PFA-100 system were determined for both the collagen/ADP and the collagen/epinephrine cartridges in 52 patients with vWD (9 type 1 "platelet normal", 5 type 1 "platelet-discordant", 8 type 1 "platelet-low", 6 type 2A, 9 type 2B, 6 type 2M Vicenza. 6 type 3 and 3 acquired vWD) and 40 controls. Measurements were repeated 1 and 4 h after the i.v. infusion of desmopressin (0.3 microg/Kg) in 26 patients with types 1, type 2M Vicenza or type 2A vWD, or of a factorVIII/vWF concentrate (Alphanate HT, 60 U/Kg) in 4 patients with type 3 vWD. At all time points, vWF plasma levels and the bleeding time (Symplate II) were also determined. Baseline closure times were longer in vWD patients than in controls with both the collagen/ADP and the collagen/ epinephrine cartridges. The sensitivity of the PFA-100 system (88% and 87% with the two cartridges) was higher than that of the bleeding time (65%). Treatment with desmopressin normalized the closure times in patients with type 1 "platelet-normal" or type 2M Vicenza vWD, had no significant effects in patients with type 1 "platelet-low", type 1 "platelet-discordant" or type 2A vWD. Infusion of a factorVIII/vWF concentrate in patients with type 3 vWD slightly shortened their prolonged closure times. In general, changes in PFA-100 were paralleled by shortenings of the bleeding times and increases in plasma vWF levels. The PFA-100 test reflects vWF-dependent platelet function under high shear stress and could be useful in the diagnosis and therapeutic monitoring of patients with vWD. PMID:10456451

  14. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches.

    PubMed

    Federici, A B; Stabile, F; Castaman, G; Canciani, M T; Mannucci, P M

    1998-10-15

    Patients with monoclonal gammopathies of uncertain significance (MGUS) may develop an acquired bleeding disorder similar to congenital von Willebrand disease, called acquired von Willebrand syndrome (AvWS). In these patients, measures to improve hemostasis are required to prevent or treat bleeding episodes. We diagnosed 10 patients with MGUS and AvWS: 8 had IgGkappa (3) or lambda (5) MGUS and 2 IgM-kappa MGUS. Three therapeutic approaches were compared in them: (1) desmopressin (DDAVP), (2) factor VIII/von Willebrand factor (FVIII/vWF) concentrate, and (3) high-dose (1 g/kg/d for 2 days) intravenous Ig (IVIg). In patients with IgG-MGUS, DDAVP and FVIII/vWF concentrate increased factor VIII and von Willebrand factor in plasma, but only transiently. IVIg determined a more sustained improvement of the laboratory abnormalities and prevented bleeding during surgery (short-term therapy). In addition to the standard 2-day infusion protocol, a long-term IVIg therapy was performed in 2 patients with IgG-MGUS: repeated (every 21 days) single infusions of IVIg did improve laboratory abnormalities and stopped chronic gastrointestinal bleeding. On the other hand, IVIg failed to correct laboratories abnormalities in patients with IgM-MGUS. These comparative data obtained in a relative large and homogeneous group of patients with AvWS and MGUS confirm that DDAVP and FVIII/vWF concentrates improve the bleeding time (BT) and FVIII/vWF measurements only transiently, whereas IVIg provides a sustained treatment of AvWS associated with IgG-MGUS, but not with IgM-MGUS. PMID:9763553

  15. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor.

    PubMed Central

    Dent, J A; Berkowitz, S D; Ware, J; Kasper, C K; Ruggeri, Z M

    1990-01-01

    Proteolytic cleavage of the von Willebrand factor subunit may be important for processing and/or function of the molecule and is altered in certain subtypes of von Willebrand disease. It results in the generation of two main fragments with apparent molecular masses of 140 kDa and 176 kDa from the 225-kDa subunit. We have now obtained chemical evidence to locate the protease-sensitive bond between residues Tyr-842 and Met-843, a site that appears to reflect the specificity of calcium-dependent neutral proteases (calpains). Antibodies were raised against four synthetic peptides that represented sequences immediately preceding or following or including the cleavage site. One antibody (against the fragment from Ala-837 through Asp-851) reacted only with the intact subunit, and its epitope included the cleavage site. All others reacted specifically with either the 140-kDa or the 176-kDa fragment, demonstrating their origin from a single cleavage. In samples of purified von Willebrand factor from four of five patients with type IIA von Willebrand disease, the anti-peptide antibodies showed markedly decreased reactivity with either the 140-kDa or the 176-kDa fragment, suggesting the existence of distinct molecular abnormalities clustered around the cleavage site. Thus, in the majority of type IIA patients, a common pathogenetic mechanism may lead to the disappearance of the larger multimers as a consequence of structural changes that may expose a sensitive bond to the action of specific proteases. These studies demonstrate the use of anti-peptide antibodies directed at a relevant structural domain for the immunochemical differentiation of normal and mutant molecules. Images PMID:2385594

  16. Changes in thermodynamic stability of von Willebrand factor differentially affect the force-dependent binding to platelet GPIbalpha.

    PubMed

    Auton, Matthew; Sedlák, Erik; Marek, Jozef; Wu, Tao; Zhu, Cheng; Cruz, Miguel A

    2009-07-22

    In circulation, plasma glycoprotein von Willebrand Factor plays an important role in hemostasis and in pathological thrombosis under hydrodynamic forces. Mutations in the A1 domain of von Willebrand factor cause the hereditary types 2B and 2M von Willebrand disease that either enhance (2B) or inhibit (2M) the interaction of von Willebrand factor with the platelet receptor glycoprotein Ibalpha. To understand how type 2B and 2M mutations cause clinically opposite phenotypes, we use a combination of protein unfolding thermodynamics and atomic force microscopy to assess the effects of two type 2B mutations (R1306Q and I1309V) and a type 2M mutation (G1324S) on the conformational stability of the A1 domain and the single bond dissociation kinetics of the A1-GPIbalpha interaction. At physiological temperature, the type 2B mutations destabilize the structure of the A1 domain and shift the A1-GPIbalpha catch to slip bonding to lower forces. Conversely, the type 2M mutation stabilizes the structure of the A1 domain and shifts the A1-GPIbalpha catch to slip bonding to higher forces. As a function of increasing A1 domain stability, the bond lifetime at low force decreases and the critical force required for maximal bond lifetime increases. Our results are able to distinguish the clinical phenotypes of these naturally occurring mutations from a thermodynamic and biophysical perspective that provides a quantitative description of the allosteric coupling of A1 conformational stability with the force dependent catch to slip bonding between A1 and GPIbalpha. PMID:19619477

  17. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease

    PubMed Central

    Veyradier, Agnès; Boisseau, Pierre; Fressinaud, Edith; Caron, Claudine; Ternisien, Catherine; Giraud, Mathilde; Zawadzki, Christophe; Trossaert, Marc; Itzhar-Baïkian, Nathalie; Dreyfus, Marie; d’Oiron, Roseline; Borel-Derlon, Annie; Susen, Sophie; Bezieau, Stéphane; Denis, Cécile V.; Goudemand, Jenny

    2016-01-01

    Abstract von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50 IU/dL). The French reference center for VWD performed a laboratory phenotypic and genotypic analysis in 1167 VWD patients (670 families) selected by their basic biologic phenotype: type 3, type 2, and type 1 with VWF levels <30 IU/dL. In these patients indeed, to achieve an accurate diagnosis of VWD type and subtype is crucial for the management (treatment and genetic counseling). A phenotype/genotype correlation was present in 99.3% of cases; 323 distinct VWF sequence variations (58% of novel) were identified (missense 67% versus truncating 33%). The distribution of VWD types was: 25% of type 1, 8% of type 3, 66% of type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% of undetermined type. Type 1 VWD was related either to a defective synthesis/secretion or to an accelerated clearance of VWF. In type 3 VWD, bi-allelic mutations of VWF were found in almost all patients. In type 2A, the most frequent mechanism was a hyper-proteolysis of VWF. Type 2B showed 85% of patients with deleterious mutations (distinct from type 2B New York). Type 2M was linked to a defective binding of VWF to platelet glycoprotein Ib or to collagen. Type 2N VWD included almost half type 2N/3. This biologic study emphasizes the complex mechanisms for both quantitative and qualitative VWF defects in VWD. In addition, this study provides a new epidemiologic picture of the most bleeding forms of VWD in which

  18. Acquired von Willebrand syndrome: an underdiagnosed and misdiagnosed bleeding complication in patients with lymphoproliferative and myeloproliferative disorders.

    PubMed

    Federici, Augusto B

    2006-01-01

    Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). Unlike the congenital disease, AVWS usually occurs in individuals with no personal or family history of bleeding. The prevalence of AVWS in the general population is unknown because data from large prospective studies of this syndrome are not available. Although AVWS is particularly frequent in lymphoproliferative or myeloproliferative disorders, it can also be associated with solid tumors, immunologic and cardiovascular disorders, and other miscellaneous conditions. Diagnosis of AVWS is based on assays measuring the activity of von Willebrand factor (VWF). This tends to be abnormally low, but factor VIII (FVIII) coagulant activity can sometimes be normal. FVIII/VWF inhibiting activity is found in only a minority of cases. Bleeding episodes in patients with AVWS are mostly of the mucocutaneous type and can be managed with desmopressin, plasma-derived FVIII/VWF concentrates, and intravenous immunoglobulin (IVIg). Recombinant activated factor VII can be useful in patients unresponsive to standard therapy. An updated version of the International Registry on AVWS, recently available online, will provide more information on this rare, but underdiagnosed and misdiagnosed, disorder. PMID:16427386

  19. Genome-wide association studies identify genetic loci for low von Willebrand factor levels.

    PubMed

    van Loon, Janine; Dehghan, Abbas; Weihong, Tang; Trompet, Stella; McArdle, Wendy L; Asselbergs, Folkert F W; Chen, Ming-Huei; Lopez, Lorna M; Huffman, Jennifer E; Leebeek, Frank W G; Basu, Saonli; Stott, David J; Rumley, Ann; Gansevoort, Ron T; Davies, Gail; Wilson, James J F; Witteman, Jacqueline C M; Cao, Xiting; de Craen, Anton J M; Bakker, Stephan J L; Psaty, Bruce M; Starr, John M; Hofman, Albert; Wouter Jukema, J; Deary, Ian J; Hayward, Caroline; van der Harst, Pim; Lowe, Gordon D O; Folsom, Aaron R; Strachan, David P; Smith, Nicolas; de Maat, Moniek P M; O'Donnell, Christopher

    2016-07-01

    Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10(-8) and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10(-10)), 9q34 (2.4 × 10(-64)), 12p13 (5.3 × 10(-22)), 12q23 (1.2 × 10(-8)) and 13q13 (2.6 × 10(-8)). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels. PMID:26486471

  20. Evaluation of ADAMTS-13 activity in plasma using recombinant von Willebrand Factor A2 domain polypeptide as substrate.

    PubMed

    Cruz, Miguel A; Whitelock, Jody; Dong, Jing-fei

    2003-12-01

    The metalloprotease ADAMTS-13 cleaves von Willebrand factor (VWF), and is absent or severely reduced in the plasma of patients with thrombotic thrombocytopenia purpura (TTP). Under physiologic flowing conditions, the enzyme cleaves endothelial cell-derived ultra-large VWF multimers at the Y842/M843 peptide bond located in the A2 domain, where many mutations associated with Type 2A VWD cluster. These VWF mutants are more susceptible for cleavage activity, decreasing the large VWF multimers in the plasma. The susceptibility of a recombinant VWF-A2 domain to ADAMTS-13 and the potential application in detecting enzyme activity were investigated. In vitro, fluid phase cleavage of VWF by ADAMTS-13 requires denaturing conditions and prolonged incubation in order to estimate enzyme activity. We have measured ADAMTS-13 activity based on enzyme cleavage of a recombinant VWF-A2 domain under non-denaturing conditions. In our assay, enzyme activity was absent in plasma from congenital and acquired TTP patient, and blocked by each EDTA, monoclonal antibody VP-1 (peptide-specific antibody against residues 828-842 of VWF), and an ADAMTS-13 antibody purified from plasma of an acquired TTP patient. This novel recombinant VWF-A2 protein has potential utility as matrix for a rapid clinical measurement of plasma ADAMTS-13 activity. PMID:14652658

  1. Molecular evolution of the nuclear von Willebrand factor gene in mammals and the phylogeny of rodents.

    PubMed

    Huchon, D; Catzeflis, F M; Douzery, E J

    1999-05-01

    Nucleotide sequences of exon 28 of the von Willebrand Factor (vWF) were analyzed for a representative sampling of rodent families and eutherian orders, with one marsupial sequence as outgroup. The aim of this study was to test if inclusion of an increased taxonomic diversity in molecular analyses would shed light on three uncertainties concerning rodent phylogeny: (1) relationships between rodent families, (2) Rodentia monophyly, and (3) the sister group relationship of rodents and lagomorphs. The results did not give evidence of any particular rodent pattern of molecular evolution relative to a general eutherian pattern. Base compositions and rates of evolution of vWF sequences of rodents were in the range of placental variation. The 10 rodent families studied here cluster in five clades: Hystricognathi, Sciuridae and Aplodontidae (Sciuroidea), Muridae, Dipodidae, and Gliridae. Among hystricognaths, the following conclusions are drawn: a single colonization event in South America by Caviomorpha, a paraphyly of Old World and New World porcupines, and an African origin for Old World porcupines. Despite a broader taxonomic sampling diversity, we did not obtain a robust answer to the question of Rodentia monophyly, but in the absence of any other alternative, we cannot reject the hypothesis of a single origin of rodents. Moreover, the phylogenetic position of Lagomorpha remains totally unsettled. PMID:10335651

  2. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress

    PubMed Central

    Reininger, Armin J.; Heijnen, Harry F. G.; Schumann, Hannah; Specht, Hanno M.; Schramm, Wolfgang; Ruggeri, Zaverio M.

    2006-01-01

    We describe here the mechanism of platelet adhesion to immobilized von Willebrand factor (VWF) and subsequent formation of platelet-derived microparticles mediated by glycoprotein Ibα (GPIbα) under high shear stress. As visualized in whole blood perfused in a flow chamber, platelet attachment to VWF involved one or few membrane areas of 0.05 to 0.1 μm2 that formed discrete adhesion points (DAPs) capable of resisting force in excess of 160 pN. Under the influence of hydrodynamic drag, membrane tethers developed between the moving platelet body and DAPs firmly adherent to immobilized VWF. Continued stretching eventually caused the separation of many such tethers, leaving on the surface tube-shaped or spherical microparticles with a diameter as low as 50 to 100 nm. Adhesion receptors (GPIbα, αIIbβ3) and phosphatidylserine were expressed on the surface of these microparticles, which were procoagulant. Shearing platelet-rich plasma at the rate of 10 000 s–1 in a cone-and-plate viscosimeter increased microparticle counts up to 55-fold above baseline. Blocking the GPIb-VWF interaction abolished microparticle generation in both experimental conditions. Thus, a biomechanical process mediated by GPIbα-VWF bonds in rapidly flowing blood may not only initiate platelet arrest onto reactive vascular surfaces but also generate procoagulant microparticles that further enhance thrombus formation. PMID:16449527

  3. Heavy menstrual bleeding and health-associated quality of life in women with von Willebrand's disease

    PubMed Central

    GOVOROV, IGOR; EKELUND, LENA; CHAIRETI, ROZA; ELFVINGE, PETRA; HOLMSTRÖM, MARGARETA; BREMME, KATARINA; MINTS, MIRIAM

    2016-01-01

    Women with the inherited bleeding disorder von Willebrand's disease (VWD) face gender-specific hemostatic challenges during menstruation. Heavy menstrual bleeding (HMB) can negatively affect their overall life activities and the health-associated quality of life. The purpose of the present study was to investigate whether women with VWD experienced HMB and an impaired health-associated quality of life. The study subjects were recruited from the Coagulation Unit of Karolinska University Hospital. Information was retrieved from various self-administered forms and medical records. Of the 30 women (18–52 years) that were included in the present study, 50% suffered from HMB, although the majority received treatment for HMB. In addition, almost all the included women perceived limitations in the overall life activities due to menstruation. The health-associated quality of life for women with HMB was significantly lower (P<0.10) with regards to ‘bodily pain’ compared with Swedish women of the general population. In conclusion, women with VWD experienced reduced health-associated quality of life as a result of HMB. Therefore, preventing limitations in overall life activities and improving their health-associated quality of life thorough counseling on menstrual bleeding is important for women with VWD. PMID:27168829

  4. An explanation for minor multimer species in endothelial cell-synthesized von Willebrand factor.

    PubMed Central

    Lynch, D C; Zimmerman, T S; Ling, E H; Browning, P J

    1986-01-01

    Initial synthesis of von Willebrand factor (vWf) by cultured human endothelial cells proceeds by formation of a dimer of pro-vWf subunits. These subunits are found only within the cell and have an apparent molecular weight of 240,000-260,000, as measured by electrophoresis in sodium dodecyl sulfate-polyacrylamide gels. Posttranslational modifications, including proteolytic cleavage, glycosylation, and sulfation, result in the appearance of two additional vWf subunits. The major one migrates with the subunit of plasma vWf at an apparent molecular weight of 220,000-225,000 and the other migrates more slowly than pro-vWf at an apparent molecular weight of 260,000-275,000. These subunits oligomerize to form a set of vWf multimers, which are subsequently secreted into the culture medium. We isolated individual vWf oligomer species from the agarose gel bands and show that vWf minor, or satellite, species differ from major species in subunit composition. Images PMID:3486890

  5. Single-molecule force measurements of the polymerizing dimeric subunit of von Willebrand factor

    NASA Astrophysics Data System (ADS)

    Wijeratne, Sithara S.; Li, Jingqiang; Yeh, Hui-Chun; Nolasco, Leticia; Zhou, Zhou; Bergeron, Angela; Frey, Eric W.; Moake, Joel L.; Dong, Jing-fei; Kiang, Ching-Hwa

    2016-01-01

    Von Willebrand factor (VWF) multimers are large adhesive proteins that are essential to the initiation of hemostatic plugs at sites of vascular injury. The binding of VWF multimers to platelets, as well as VWF proteolysis, is regulated by shear stresses that alter VWF multimeric conformation. We used single molecule manipulation with atomic force microscopy (AFM) to investigate the effect of high fluid shear stress on soluble dimeric and multimeric forms of VWF. VWF dimers are the smallest unit that polymerizes to construct large VWF multimers. The resistance to mechanical unfolding with or without exposure to shear stress was used to evaluate VWF conformational forms. Our data indicate that, unlike recombinant VWF multimers (RVWF), recombinant dimeric VWF (RDVWF) unfolding force is not altered by high shear stress (100 dynes/cm2 for 3 min at 37°C ). We conclude that under the shear conditions used (100 dynes/cm2 for 3 min at 37°C ) , VWF dimers do not self-associate into a conformation analogous to that attained by sheared large VWF multimers.

  6. Flow and delta-P dictate where thrombin, fibrin, and von Willebrand Factor will be found.

    PubMed

    Diamond, Scott L

    2016-05-01

    Hemostasis occurs in two different topological scenarios: complete severing of a vessel or disruption of the vessel wall. Either to meet the daily rigors of active life or during an acute trauma, hemostasis involves the regulated and self-limiting production of thrombin to stop bleeding. In contrast, arterial and venous thrombosis typically involves the unregulated, intraluminal growth of a clot, in the absence of bleeding. For either hemostasis or thrombosis, the presence of flow and pressure gradients (delta-P, ΔP) dictates when and where thrombin and fibrin are located and in what quantity. For hemostatic clots, fibrin formation helped limit clot growth. We found that γ'-fibrinogen had a role in limiting clot growth via anti-thrombin activity at venous, but not arterial conditions. For hemophilic blood, severe factor deficiency (<1% healthy) led to a defect in both platelet and fibrin deposition under flow. However, moderate deficiency, which is associated with a less severe bleeding phenotype, had normalized platelet function but still lacked fibrin production. We conclude signaling levels of thrombin can be generated during moderate hemophilia to sufficiently activate platelets to achieve primary hemostasis, even if fibrin formation remains defective. Finally, as a clot grows, shear stresses can become sufficiently extreme in diseased arteries to drive von Willebrand Factor self-association into massive fibers, potentially the final burst of clot growth towards full thrombotic occlusion. PMID:27207416

  7. Force sensing by the vascular protein von Willebrand factor is tuned by a strong intermonomer interaction.

    PubMed

    Müller, Jochen P; Mielke, Salomé; Löf, Achim; Obser, Tobias; Beer, Christof; Bruetzel, Linda K; Pippig, Diana A; Vanderlinden, Willem; Lipfert, Jan; Schneppenheim, Reinhard; Benoit, Martin

    2016-02-01

    The large plasma glycoprotein von Willebrand factor (VWF) senses hydrodynamic forces in the bloodstream and responds to elevated forces with abrupt elongation, thereby increasing its adhesiveness to platelets and collagen. Remarkably, forces on VWF are elevated at sites of vascular injury, where VWF's hemostatic potential is important to mediate platelet aggregation and to recruit platelets to the subendothelial layer. Adversely, elevated forces in stenosed vessels lead to an increased risk of VWF-mediated thrombosis. To dissect the remarkable force-sensing ability of VWF, we have performed atomic force microscopy (AFM)-based single-molecule force measurements on dimers, the smallest repeating subunits of VWF multimers. We have identified a strong intermonomer interaction that involves the D4 domain and critically depends on the presence of divalent ions, consistent with results from small-angle X-ray scattering (SAXS). Dissociation of this strong interaction occurred at forces above [Formula: see text]50 pN and provided [Formula: see text]80 nm of additional length to the elongation of dimers. Corroborated by the static conformation of VWF, visualized by AFM imaging, we estimate that in VWF multimers approximately one-half of the constituent dimers are firmly closed via the strong intermonomer interaction. As firmly closed dimers markedly shorten VWF's effective length contributing to force sensing, they can be expected to tune VWF's sensitivity to hydrodynamic flow in the blood and to thereby significantly affect VWF's function in hemostasis and thrombosis. PMID:26787887

  8. Von Willebrand factor is reversibly decreased during torpor in 13-lined ground squirrels.

    PubMed

    Cooper, Scott; Sell, Shawn; Nelson, Luke; Hawes, Jennifer; Benrud, Jacob A; Kohlnhofer, Bridget M; Burmeister, Bradley R; Flood, Veronica H

    2016-01-01

    During torpor in a hibernating mammal, decreased blood flow increases the risk of blood clots such as deep vein thrombi (DVT). In other animal models platelets, neutrophils, monocytes and von Willebrand factor (VWF) have been found in DVT. Previous research has shown that hibernating mammals decrease their levels of platelets and clotting factors VIII (FVIII) and IX (FIX), increasing both bleeding time and activated partial thromboplastin time. In this study, FVIII, FIX and VWF activities and mRNA levels were measured in torpid and non-hibernating ground squirrels (Ictidomys tridecemlineatus). Here, we show that VWF high molecular weight multimers, collagen-binding activity, lung mRNA and promoter activity decrease during torpor. The VWF multimers reappear in plasma within 2 h of arousal in the spring. Similarly, FIX activity and liver mRNA both dropped threefold during torpor. In contrast, FVIII liver mRNA levels increased twofold while its activity dropped threefold, consistent with a post-transcriptional decrease in FVIII stability in the plasma due to decreased VWF levels. Finally, both neutrophils and monocytes are decreased eightfold during torpor which could slow the formation of DVT. In addition to providing insight in how blood clotting can be regulated to allow mammals to survive in extreme environments, hibernating ground squirrels provide an interesting model for studying. PMID:26481634

  9. [Stable expression and characterization of the von Willebrand factor cleaving protease].

    PubMed

    Ma, Zhenni; Dong, Ningzheng; Zhang, Jingyu; Su, Jian; Wang, Anyou; Ruan, Changgeng

    2010-02-01

    This study was to acquire recombinant protein of von Willebrand factor cleaving protease (ADAMTS13, a disintegrin and metalloprotease with a thromboSpondin type 1 motifs 13), for further studies on its biological function in thrombosis and hemostasis. We transfected the Hela cells with the plasmid pSecTag-ADAMTS13 by lipofectamine. A positive cell cloning was selected by hygromycin-B. The recombinant protein was purified with Ni-NTA agarose column by gradient imidazole. The purity and immune activity of purified products were identified with SDS-PAGE and Western blotting respectively. We also measured the enzymatic activity of recombinant protein (rADAMTS13) by GST-His two-site ELISA assay. The results showed that we successfully constructed Hela cells ADAMTS2-4 which expressed high level of rADAMTS13. We received about 5.8 mg recombinant protein in culture supernantants per liter purified with Ni-NTA column. The protein formed a main lane at the position of 190 kDa with SDS-PAGE and reacted with polyclonal antibody against ADAMTS13 by Western blotting. The amount of rADAMTS13 activity was 6.4 U/mL, according to the normal plasma defined as 1 U/mL. In conclusion, rADAMTS13 protein had high purity, immune activity and good enzymatic activity, which could establish the experimental foundation for further research on biological function and mechanism of this unique metalloprotease. PMID:20432945

  10. Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von Willebrand's disease.

    PubMed

    Gomez García, E B; Ruitenberg, A; Madretsma, G S; Hintzen, R Q

    2003-03-01

    A middle-aged woman was admitted to the hospital after being found unconscious at home. A brain CT scan excluded an intracranial bleed or other focal abnormality. Laboratory analysis showed hyponatraemia (sodium: 121 mmol L(-1)) and a low plasma osmolality, with normal sodium excretion and urine osmolality. A diagnosis of hyponatraemic coma was made. The patient was treated with water restriction; 24 h later the sodium was 135 mmol L(-1) and the patient was neurologically fully recovered. The patient, who suffered from von Willebrand's disease, had received desmopressin and ibuprofen for analgesia 2 days before after a dental intervention. She had received desmopressin several times in the past without any complications. A few patients treated with desmopressin for coagulation abnormalities have been reported to develop water intoxication and severe hyponatraemia resulting in seizures and coma. By inhibiting prostaglandin synthesis, non-steroid anti-inflammatory agents (NSAIDs) potentiate the effect of water reabsorption in the renal tubules of vasopressin, therefore enhancing water retention. Desmopressin and NSAIDs should not be used in combination in patients with bleeding disorders, but it is often followed in clinical practice. In addition, this is probably not an unusual situation in patients treated with desmopressin for other 'non-haemorrhagic' indications. This report emphasizes the need for practitioners to be aware of this rare but severe complication. PMID:12614377

  11. Complex regional pain syndrome in a young athlete with von Willebrand disease.

    PubMed

    Khadavi, Michael J; Alm, John C; Emerson, Jane-Anne

    2014-06-01

    A 17-year-old female with type 1 Von Willebrand Disease (vWD) developed left medial calf pain while running track. Over the next 6 months, orthopedic surgery, sports medicine, vascular surgery, and neurology treated her under various working diagnoses; however, the pain, allodynia, coldness, and pale skin color worsened. She was admitted to a tertiary pediatric hospital for intractable pain where PM&R diagnosed her with complex regional pain syndrome (CRPS) type 1, began gabapentin, and initiated an aggressive inpatient rehabilitation program. During her 3 weeks of inpatient rehabilitation, passive range of motion of knee extension improved from 40° from extension to full extension, and ankle dorsiflexion improved from 15° from neutral to a consistent range of motion beyond neutral. Additional outcome measures were distance of ambulation and assistive device usage; from admission to inpatient rehabilitation to 2 months postdischarge, her weight-bearing tolerance progressed from nonweight-bearing to partial weight-bearing, and ambulation improved from 20 feet with a three-point crutch gait to unlimited distances with a four-point crutch gait. This is the first known case of a bleeding disorder as the likely underlying microvascular pathology associated with CRPS, a theory exposed in 2010. PMID:24666636

  12. von Willebrand Factor and Oxidative Stress Parameters in Acute Coronary Syndromes

    PubMed Central

    Koprivica, Zoran; Djordjevic, Dusica; Vuletic, Milena; Zivkovic, Vladimir; Barudzic, Nevena; Andjelkovic, Nebojsa; Djuric, Dragan; Iric-Cupic, Violeta; Krkeljic, Jelena; Jakovljevic, Vladimir

    2011-01-01

    Considering the role of von Willebrand factor (vWf) in hemostasis, and the role of oxidative stress in the development of endothelial dysfunction and atherosclerotic disease, the aim of our study was to investigate the relationship between vWf, parameters of oxidative stress and different types of acute coronary syndromes (ACS). Levels of vWf activity (vWfAct), vWf antigen (vWfAg), nitric oxide (estimated through nitrites–NO2 −), superoxide anion radical (O2 −), hydrogen peroxide (H2O2), index of lipid peroxidation (estimated through thiobarbituric acid reactive substances–TBARS), superoxide dismutase (SOD) and catalase (CAT) activity of 115 patients were compared with those of 40 healthy controls. ACS patients had significantly higher vWfAct and vWfAg levels, as well as TBARS levels, while their levels of NO2 −, H2O2, SOD and CAT activities were lower than controls'. vWfAg showed high specificity and sensitivity as a test to reveal healthy or diseased subjects. Multivariant logistic regression marked only vWfAg and TBARS as parameters that were under independent effect of ACS type. The results of our study support the implementation of vWf in clinical rutine and into therapeutic targets, and suggest that ACS patients are in need of antioxidant supplementation to improve their impaired antioxidant defence. PMID:21904649

  13. An explanation for minor multimer species in endothelial cell-synthesized von Willebrand factor.

    PubMed

    Lynch, D C; Zimmerman, T S; Ling, E H; Browning, P J

    1986-06-01

    Initial synthesis of von Willebrand factor (vWf) by cultured human endothelial cells proceeds by formation of a dimer of pro-vWf subunits. These subunits are found only within the cell and have an apparent molecular weight of 240,000-260,000, as measured by electrophoresis in sodium dodecyl sulfate-polyacrylamide gels. Posttranslational modifications, including proteolytic cleavage, glycosylation, and sulfation, result in the appearance of two additional vWf subunits. The major one migrates with the subunit of plasma vWf at an apparent molecular weight of 220,000-225,000 and the other migrates more slowly than pro-vWf at an apparent molecular weight of 260,000-275,000. These subunits oligomerize to form a set of vWf multimers, which are subsequently secreted into the culture medium. We isolated individual vWf oligomer species from the agarose gel bands and show that vWf minor, or satellite, species differ from major species in subunit composition. PMID:3486890

  14. Force sensing by the vascular protein von Willebrand factor is tuned by a strong intermonomer interaction

    PubMed Central

    Müller, Jochen P.; Mielke, Salomé; Löf, Achim; Obser, Tobias; Beer, Christof; Bruetzel, Linda K.; Pippig, Diana A.; Vanderlinden, Willem; Lipfert, Jan; Schneppenheim, Reinhard; Benoit, Martin

    2016-01-01

    The large plasma glycoprotein von Willebrand factor (VWF) senses hydrodynamic forces in the bloodstream and responds to elevated forces with abrupt elongation, thereby increasing its adhesiveness to platelets and collagen. Remarkably, forces on VWF are elevated at sites of vascular injury, where VWF’s hemostatic potential is important to mediate platelet aggregation and to recruit platelets to the subendothelial layer. Adversely, elevated forces in stenosed vessels lead to an increased risk of VWF-mediated thrombosis. To dissect the remarkable force-sensing ability of VWF, we have performed atomic force microscopy (AFM)-based single-molecule force measurements on dimers, the smallest repeating subunits of VWF multimers. We have identified a strong intermonomer interaction that involves the D4 domain and critically depends on the presence of divalent ions, consistent with results from small-angle X-ray scattering (SAXS). Dissociation of this strong interaction occurred at forces above ∼50 pN and provided ∼80 nm of additional length to the elongation of dimers. Corroborated by the static conformation of VWF, visualized by AFM imaging, we estimate that in VWF multimers approximately one-half of the constituent dimers are firmly closed via the strong intermonomer interaction. As firmly closed dimers markedly shorten VWF’s effective length contributing to force sensing, they can be expected to tune VWF’s sensitivity to hydrodynamic flow in the blood and to thereby significantly affect VWF’s function in hemostasis and thrombosis. PMID:26787887

  15. P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface.

    PubMed

    Padilla, Arnoldo; Moake, Joel L; Bernardo, Aubrey; Ball, Chalmette; Wang, Yongtao; Arya, Maneesh; Nolasco, Leticia; Turner, Nancy; Berndt, Michael C; Anvari, Bahman; López, José A; Dong, Jing-Fei

    2004-03-15

    von Willebrand factor (VWF) released from endothelium is ultralarge (UL) and hyperreactive. If released directly into plasma, it can spontaneously aggregate platelets, resulting in systemic thrombosis. This disastrous consequence is prevented by the ADAMTS13 (ADisintegrin and Metalloprotease with ThromboSpondin motif) cleavage of ULVWF into smaller, less active forms. We previously showed that ULVWF, on release, forms extremely long stringlike structures. ADAMTS13 cleaves these strings under flow significantly faster than it does under static conditions. As ULVWF tethering to endothelium is important for its rapid proteolysis, we investigated 2 molecules for their potential to anchor the ULVWF strings: P-selectin and integrin alpha v beta 3. We demonstrated that P-selectin anchors ULVWF to endothelium by several means. First, Chinese hamster ovary (CHO) cells expressing P-selectin specifically adhered to immobilized ULVWF and ULVWF-coated beads to immobilized P-selectin. Second, an anti-VWF antibody coimmunoprecipitates P-selectin from the histamine-activated endothelial cells. Third, P-selectin antibody or soluble P-selectin, but not a alpha v beta 3 antibody, RGDS peptide, or heparin, blocked the formation of ULVWF strings. Fourth, P-selectin expression was in clusters predominantly along the ULVWF strings. Finally, the strength of the minimal ULVWF-P-selectin bond was measured to be 7.2 pN. We, therefore, conclude that P-selectin may anchor ULVWF strings to endothelial cells and facilitate their cleavage by ADAMTS13. PMID:14630802

  16. Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease

    PubMed Central

    DiStefano, Youmna E.; Lazar, Michael D.

    2015-01-01

    Peripheral nerve blockade (PNB) is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR). Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD). Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year-old female undergoing TKR. A Humate-P intravenous infusion was started and the patient was positioned supinely. Using sterile technique with ultrasound guidance, a Contiplex 18 Gauge Tuohy needle was advanced in plane through the fascia iliaca towards the femoral nerve. A nerve catheter was threaded through the needle and secured without complications. Postoperatively, a levobupivacaine femoral catheter infusion was maintained, and twice daily Humate-P intravenous infusions were administered for 48 hours; enoxaparin thromboprophylaxis was initiated thereafter. The patient was discharged uneventfully on postoperative day 4. Given documentation of delayed, unheralded bleeding from PNB in coagulopathic patients, we recommend individualized PNB in vWD patients. Multidisciplinary team involvement is required to guide factor supplementation and thromboprophylaxis, as is close follow-up to elicit signs of bleeding throughout the delayed postoperative period. PMID:26113995

  17. Mapping the interaction between factor VIII and von Willebrand factor by electron microscopy and mass spectrometry

    PubMed Central

    Chiu, Po-Lin; Bou-Assaf, George M.; Chhabra, Ekta Seth; Chambers, Melissa G.; Peters, Robert T.; Kulman, John D.

    2015-01-01

    Association with the D′D3 domain of von Willebrand factor (VWF) stabilizes factor VIII (FVIII) in the circulation and maintains it at a level sufficient to prevent spontaneous bleeding. We used negative-stain electron microscopy (EM) to visualize complexes of FVIII with dimeric and monomeric forms of the D′D3 domain. The EM averages show that FVIII interacts with the D′D3 domain primarily through its C1 domain, with the C2 domain providing a secondary attachment site. Hydrogen-deuterium exchange mass spectrometry corroborated the importance of the C1 domain in D′D3 binding and implicates additional surface regions on FVIII in the interaction. Together, our results establish that the C1 domain is the major binding site on FVIII for VWF, reiterate the importance of the a3 acidic peptide in VWF binding, and suggest that the A3 and C2 domains play ancillary roles in this interaction. PMID:26065652

  18. von Willebrand Factor Propeptide: A Potential Disease Biomarker Not Affected by ABO Blood Groups

    PubMed Central

    Marianor, Mahat; Zaidah, Abdullah Wan; Maraina, CH Che

    2015-01-01

    Epidemiological studies have shown that vascular-related disorders are associated with high von Willebrand factor antigen (VWF:Ag) and VWF propeptide (VWFpp). VWFpp is secreted together with VWF:Ag upon endothelial cell activation, hence it could be a potential biomarker. This study was conducted to compare between VWF:Ag and VWFpp levels among 30 healthy individuals and 42 patients with high levels of VWF:Ag in different medical conditions and ABO blood groups. VWFpp levels were strongly correlated with VWF:Ag. VWF:Ag and VWFpp levels were significantly increased in patients compared to healthy individuals. VWFpp is not affected by ABO blood group in both healthy individual and patient groups unlike VWF:Ag. As expected, this study showed that VWFpp levels increased in parallel with VWF:Ag levels in patients with diseases associated with endothelial activation. VWFpp though nonspecific is a potential biomarker reflecting underlying pathophysiological changes in various medical conditions with an additional advantage of not being influenced by ABO blood groups. PMID:26339184

  19. The use of desmopressin in von Willebrand disease: the experience of the first 30 years (1977-2007).

    PubMed

    Federici, A B

    2008-01-01

    The aim of the treatment for von Willebrand disease (VWD) is to correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion as a result of reduced and/or dysfunctional von Willebrand factor (VWF) and the abnormal coagulation expressed by low levels of factor VIII (FVIII). Correction of both deficiencies can be achieved by administering the synthetic peptide desmopressin (DDAVP) or, in cases unresponsive to this agent, the plasma concentrates containing VWF and FVIII (VWF/FVIII). DDAVP is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments, but the drug can be clinically useful also in other VWD types, including acquired von Willebrand syndrome (AVWS). A test dose of DDAVP at the time of diagnosis is recommended to establish the individual patterns of biological response and to predict clinical efficacy during bleeding and surgery. DDAVP is not effective in VWD type 3 and in severe forms of VWD 1 and 2. It can induce transient thrombocytopenia in patients with VWD type 2B. The results of several retrospective studies on the use of DDAVP in VWD management have been reported by many authors in different countries for the last 30 years. However, despite the widespread use of DDAVP in the treatment of VWD, there are only a few prospective clinical trials in a large number of cases on DDAVP efficacy and safety aimed at determining benefits and limits of this therapeutic approach. An investigator-driven observational prospective study on clinical efficacy of DDAVP in 200 patients with VWD types 1 and 2 has been recently organized: the effectiveness and safety of DDAVP will be evaluated prospectively for 24 months during bleeding episodes and minor or major surgeries in the VWD patients who were exposed to an infusion trial at enrollment. PMID:18173689

  20. Atypical variant of acquired von Willebrand syndrome in Wilms tumor: is hyaluronic acid secreted by nephroblastoma cells the cause?

    PubMed

    Michiels, J; Schroyens, W; Berneman, Z; van der Planken, M

    2001-04-01

    Acquired von Willebrand syndrome (AvWS) has been reported in eight children with Wilms tumor (nephroblastoma in four boys and four girls) at a mean age of 3.3 years (range, 0.33-9 years). Only three of eight patients with AvWS in Wilms tumor presented with mild mucocutaneous bleeding symptoms. The AvWS in seven children with Wilms tumor featured either undetectable or very low von Willebrand factor antigen (vWF.Ag) levels (mean, 3%) and decreased values for vWF ristocetin cofactor (RCF) activity (mean, 20%) and factor VIII coagulant (VIIIc) activity (mean, 16%). The response to 1-desamino-8-arginine vasopressin (DDAVP) was good in two and poor in one patient. Multimeric analysis of the vWF showed a normal pattern of type I von Willebrand disease (vWD) in three patients and an absence of multimers consistent with type III vWD in two patients. The higher functional levels, as compared with antigen levels, with increased ratios for factor VIIIc/vWFAg (mean, 5.3) and vWF.RCF/vWF.Ag (mean, 6.6) in seven patients with Wilms tumor are unexplained physiologically and are not consistent with type I vWF deficiency. The absence of vWD in the patient's family, and the return of factor VIII-vWF parameters to normal after chemotherapy or surgical removal of the Wilms tumor, support the diagnosis of AvWS causally related to the Wilms tumor. The causative agent is thought to be hyaluronic acid secreted by nephroblastoma cells of the Wilms tumor. Prospective studies to determine the nature of AvWS in children with Wilms tumor are warranted. PMID:11292185

  1. Comparison of PFA-100 testing and bleeding time for detecting platelet hypofunction and von Willebrand disease in clinical practice.

    PubMed

    Posan, Emoke; McBane, Robert D; Grill, Diane E; Motsko, Cheri L; Nichols, William L

    2003-09-01

    The PFA-100 instrument (Platelet Function Analyzer, Dade Behring) has been reported to be superior to the bleeding time (BT) as a screening test of primary hemostasis. However evaluation of this device has been principally limited to selected populations. The study's aim was to determine testing performance in clinical practice, by comparing the PFA-100 to the BT for the identification of von Willebrand disease (VWD) and intrinsic platelet hypofunction. From 1998-2000, PFA-100 closure time (CT) for epinephrinecollagen (EPI) and ADP-collagen (ADP) cartridges and modified Ivy BTs were performed on outpatients referred for testing for suspected or known hemorrhagic diathesis (n = 346). Evaluation included assays of von Willebrand factor and platelet aggregometry in addition to platelet flow cytometry and electron microscopy when indicated. The normal distribution of PFA-100 CTs was determined using blood samples from 61 normal donors studied on 155 occasions. Results show that thirty-four patients met the diagnostic criteria for VWD and 31 patients were diagnosed with congenital or acquired intrinsic platelet hypofunction. The sensitivity of the PFA-100 for identification of VWD was significantly better (p < 0.01) than the BT with similar specificity. In contrast, the PFA-100 was comparable, but not superior to the BT for detecting platelet hypofunction. We conclude that the PFA-100 performance compares favorably to the BT for the identification of intrinsic platelet hypofunction in clinical practice with superior sensitivity for detecting VWD. Therefore, the PFA-100 could replace the BT for purposes of screening for VWD and intrinsic platelet hypofunction. When clinical suspicion is strong, testing should be supplemented with assays of von Willebrand factor and platelet aggregometry. PMID:12958618

  2. pH-Dependent Interactions in Dimers Govern the Mechanics and Structure of von Willebrand Factor.

    PubMed

    Müller, Jochen P; Löf, Achim; Mielke, Salomé; Obser, Tobias; Bruetzel, Linda K; Vanderlinden, Willem; Lipfert, Jan; Schneppenheim, Reinhard; Benoit, Martin

    2016-07-26

    Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that is activated for hemostasis by increased hydrodynamic forces at sites of vascular injury. Here, we present data from atomic force microscopy-based single-molecule force measurements, atomic force microscopy imaging, and small-angle x-ray scattering to show that the structure and mechanics of VWF are governed by multiple pH-dependent interactions with opposite trends within dimeric subunits. In particular, the recently discovered strong intermonomer interaction, which induces a firmly closed conformation of dimers and crucially involves the D4 domain, was observed with highest frequency at pH 7.4, but was essentially absent at pH values below 6.8. However, below pH 6.8, the ratio of compact dimers increased with decreasing pH, in line with a previous transmission electron microscopy study. These findings indicated that the compactness of dimers at pH values below 6.8 is promoted by other interactions that possess low mechanical resistance compared with the strong intermonomer interaction. By investigating deletion constructs, we found that compactness under acidic conditions is primarily mediated by the D4 domain, i.e., remarkably by the same domain that also mediates the strong intermonomer interaction. As our data suggest that VWF has the highest mechanical resistance at physiological pH, local deviations from physiological pH (e.g., at sites of vascular injury) may represent a means to enhance VWF's hemostatic activity where needed. PMID:27463134

  3. Preclinical Models for Translational Investigations of Left Ventricular Assist Device-Associated von Willebrand Factor Degradation.

    PubMed

    Restle, David J; Zhang, David M; Hung, George; Howard, Jessica L; Kallel, Faouzi; Acker, Michael A; Atluri, Pavan; Bartoli, Carlo R

    2015-07-01

    Evidence suggests a major role for von Willebrand factor (vWF) in left ventricular assist device (LVAD)-associated bleeding. However, the mechanisms of vWF degradation during LVAD support are not well understood. We developed: (i) a simple and inexpensive vortexer model; and (ii) a translational LVAD mock circulatory loop to perform preclinical investigations of LVAD-associated vWF degradation. Whole blood was obtained from LVAD patients (n = 8) and normal humans (n = 15). Experimental groups included: (i) blood from continuous-flow LVAD patients (baseline vs. post-LVAD, n = 8); (ii) blood from normal humans (baseline vs. 4 h in vitro laboratory vortexer, ∼ 2400 rpm, shear stress ∼175 dyne/cm(2) , n = 8); and (iii) blood from normal humans (baseline vs. 12 h HeartMate II mock circulatory loop, 10 000 rpm, n = 7). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblotting. Blood from LVAD patients, blood exposed to in vitro supraphysiologic shear stress, and blood circulated through an LVAD mock circulatory loop demonstrated a similar profile of decreased large vWF multimers and increased vWF degradation fragments. A laboratory vortexer and an LVAD mock circulatory loop reproduced the pathologic degradation of vWF that occurs during LVAD support. Both models are appropriate for preclinical studies of LVAD-associated vWF degradation. PMID:25810063

  4. Thrombin-dependent Incorporation of von Willebrand Factor into a Fibrin Network*

    PubMed Central

    Miszta, Adam; Pelkmans, Leonie; Lindhout, Theo; Krishnamoorthy, Ganeshram; de Groot, Philip G.; Hemker, Coenraad H.; Heemskerk, Johan W. M.; Kelchtermans, Hilde; de Laat, Bas

    2014-01-01

    Attachment of platelets from the circulation onto a growing thrombus is a process involving multiple platelet receptors, endothelial matrix components, and coagulation factors. It has been indicated previously that during a transglutaminase reaction activated factor XIII (FXIIIa) covalently cross-links von Willebrand factor (VWF) to polymerizing fibrin. Bound VWF further recruits and activates platelets via interactions with the platelet receptor complex glycoprotein Ib (GPIb). In the present study we found proof for binding of VWF to a fibrin monomer layer during the process of fibrinogen-to-fibrin conversion in the presence of thrombin, arvin, or a snake venom from Crotalus atrox. Using a domain deletion mutant we demonstrated the involvement of the C domains of VWF in this binding. Substantial binding of VWF to fibrin monomers persisted in the presence of the FXIIIa inhibitor K9-DON, illustrating that cross-linking via factor XIII is not essential for this phenomenon and suggesting the identification of a second mechanism through which VWF multimers incorporate into a fibrin network. Under high shear conditions, platelets were shown to adhere to fibrin only if VWF had been incorporated. In conclusion, our experiments show that the C domains of VWF and the E domain of fibrin monomers are involved in the incorporation of VWF during the polymerization of fibrin and that this incorporation fosters binding and activation of platelets. Fibrin thus is not an inert end product but partakes in further thrombus growth. Our findings help to elucidate the mechanism of thrombus growth and platelet adhesion under conditions of arterial shear rate. PMID:25381443

  5. Chitosan scaffold enhances growth factor release in wound healing in von Willebrand disease

    PubMed Central

    Periayah, Mercy Halleluyah; Halim, Ahmad Sukari; Saad, Arman Zaharil Mat; Yaacob, Nik Soriani; Hussein, Abdul Rahim; Karim, Faraizah Abdul; Rashid, Ahmad Hazri Abdul; Ujang, Zanariah

    2015-01-01

    Chitosan-derived biomaterials have been reported to adhere when in contact with blood by encouraging platelets to adhere, activate and aggregate at the sites of vascular injury, thus enhanced wound healing capacity. This study investigated platelet morphology changes and the expression level of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor-AB (PDGF-AB) in the adherence of two different types of chitosans in von Willebrand disease (vWD): N,O-carboxymethylchitosan (NO-CMC) and oligo-chitosan (O-C). Fourteen vWD voluntary subjects were recruited, and they provided written informed consent. Scanning electron microscopy and enzyme-linked immunosorbent assay test procedures were employed to achieve the objective of the study. The results suggest that the O-C group showed dramatic changes in the platelet’s behaviors. Platelets extended filopodia and generated lamellipodia, leading to the formation of grape-like shaped aggregation. The platelet aggregation occurred depending on the severity of vWD. O-C was bound to platelets on approximately 90% of the surface membrane in vWD type 1; there was 70% and 50% coverage in vWD type II and III, respectively. The O-C chitosan group showed an elevated expression level of TGF-β1 and PDGF-AB. This finding suggests that O-C stimulates these mediators from the activated platelets to the early stage of restoring the damaged cells and tissues. This study demonstrated that the greater expression level of O-C assists in mediating the cytokine complex networks of TGF-β1 and PDGF-AB and induces platelet activities towards wound healing in vWD. With a better understanding of chitosan’s mechanisms of action, researchers are able to accurately develop novel therapies to prevent hemorrhage. PMID:26629055

  6. Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5

    PubMed Central

    Pegon, Julie N.; Kurdi, Mohamad; Casari, Caterina; Odouard, Soline; Denis, Cécile V.; Christophe, Olivier D.; Lenting, Peter J.

    2012-01-01

    Background Factor VIII (FVIII) and von Willebrand factor (VWF) circulate in plasma in a tight non-covalent complex, being critical to hemostasis. Although structurally unrelated, both share the presence of sialylated glycan-structures, making them potential ligands for sialic-acid-binding-immunoglobulin-like-lectins (Siglecs). Design and Methods We explored the potential interaction between FVIII/VWF and Siglec-5, a receptor expressed in macrophages using various experimental approaches, including binding experiments with purified proteins and cell-binding studies with Siglec-5 expressing cells. Finally, Siglec-5 was overexpressed in mice via hydrodynamic gene transfer. Results In different systems using purified proteins, saturable, dose-dependent and reversible interactions between a soluble Siglec-5 fragment and both hemostatic proteins were found. Sialidase treatment of VWF resulted in a complete lack of Siglec-5 binding. In contrast, sialidase treatment left interactions between FVIII and Siglec-5 unaffected. FVIII and VWF also bound to cellsurface exposed Siglec-5, as was visualized by classical immunostaining as well as by Duolinkproximity ligation assays. Co-localization of FVIII and VWF with early endosomal markers further suggested that binding to Siglec-5 is followed by endocytosis of the proteins. Finally, overexpression of human Siglec-5 in murine hepatocytes following hydrodynamic gene transfer resulted in a significant decrease in plasma levels of FVIII and VWF in these mice. Conclusions Our data indicate that FVIII and VWF may act as a ligand for Siglec-5, and that Siglec-5 may contribute to the regulation of plasma levels of the FVIII/VWF complex. PMID:22733016

  7. Force-Sensitive Autoinhibition of the von Willebrand Factor Is Mediated by Interdomain Interactions

    PubMed Central

    Aponte-Santamaría, Camilo; Huck, Volker; Posch, Sandra; Bronowska, Agnieszka K.; Grässle, Sandra; Brehm, Maria A.; Obser, Tobias; Schneppenheim, Reinhard; Hinterdorfer, Peter; Schneider, Stefan W.; Baldauf, Carsten; Gräter, Frauke

    2015-01-01

    Von Willebrand factor (VWF) plays a central role in hemostasis. Triggered by shear-stress, it adheres to platelets at sites of vascular injury. Inactivation of VWF has been associated to the shielding of its adhesion sites and proteolytic cleavage. However, the molecular nature of this shielding and its coupling to cleavage under shear-forces in flowing blood remain unknown. In this study, we describe, to our knowledge, a new force-sensory mechanism for VWF-platelet binding, which addresses these questions, based on a combination of molecular dynamics (MD) simulations, atomic force microscopy (AFM), and microfluidic experiments. Our MD simulations demonstrate that the VWF A2 domain targets a specific region at the VWF A1 domain, corresponding to the binding site of the platelet glycoprotein Ibα (GPIbα) receptor, thereby causing its blockage. This implies autoinhibition of the VWF for the binding of platelets mediated by the A1-A2 protein-protein interaction. During force-probe MD simulations, a stretching force dissociated the A1A2 complex, thereby unblocking the GPIbα binding site. Dissociation was found to be coupled to the unfolding of the A2 domain, with dissociation predominantly occurring before exposure of the cleavage site in A2, an observation that is supported by our AFM experiments. This suggests that the A2 domain prevents platelet binding in a force-dependent manner, ensuring that VWF initiates hemostasis before inactivation by proteolytic cleavage. Microfluidic experiments with an A2-deletion VWF mutant resulted in increased platelet binding, corroborating the key autoinhibitory role of the A2 domain within VWF multimers. Overall, autoinhibition of VWF mediated by force-dependent interdomain interactions offers the molecular basis for the shear-sensitive growth of VWF-platelet aggregates, and might be similarly involved in shear-induced VWF self-aggregation and other force-sensing functions in hemostasis. PMID:25954888

  8. Circulating but not immobilized N-deglycosylated von Willebrand factor increases platelet adhesion under flow conditions

    PubMed Central

    Fallah, M. A.; Huck, V.; Niemeyer, V.; Desch, A.; Angerer, J. I.; McKinnon, T. A. J.; Wixforth, A.; Schneider, S. W.; Schneider, M. F.

    2013-01-01

    The role of von Willebrand factor (VWF) as a shear stress activated platelet adhesive has been related to a coiled-elongated shape conformation. The forces dominating this transition have been suggested to be controlled by the proteins polymeric architecture. However, the fact that 20% of VWF molecular weight originates from glycan moieties has so far been neglected in these calculations. In this study, we present a systematic experimental investigation on the role of N-glycosylation for VWF mediated platelet adhesion under flow. A microfluidic flow chamber with a stenotic compartment that allows one to mimic various physiological flow conditions was designed for the efficient analysis of the adhesion spectrum. Surprisingly, we found an increase in platelet adhesion with elevated shear rate, both qualitatively and quantitatively fully conserved when N-deglycosylated VWF (N-deg-VWF) instead of VWF was immobilized in the microfluidic channel. This has been demonstrated consistently over four orders of magnitude in shear rate. In contrast, when N-deg-VWF was added to the supernatant, an increase in adhesion rate by a factor of two was detected compared to the addition of wild-type VWF. It appears that once immobilized, the role of glycans is at least modified if not—as found here for the case of adhesion—negated. These findings strengthen the physical impact of the circulating polymer on shear dependent platelet adhesion events. At present, there is no theoretical explanation for an increase in platelet adhesion to VWF in the absence of its N-glycans. However, our data indicate that the effective solubility of the protein and hence its shape or conformation may be altered by the degree of glycosylation and is therefore a good candidate for modifying the forces required to uncoil this biopolymer. PMID:24404057

  9. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura.

    PubMed

    Furlan, M; Robles, R; Solenthaler, M; Wassmer, M; Sandoz, P; Lämmle, B

    1997-05-01

    In patients with thrombotic thrombocytopenic purpura (TTP), excessive intravascular platelet aggregation has been associated with appearance in plasma of unusually large von Willebrand factor (vWF) multimers. These extremely adhesive vWF multimers may arise due to deficiency of a "depolymerase" cleaving vWF to smaller molecular forms, either by reducing the interdimeric disulfide bridges or by proteolytic degradation. We studied the activity of a recently described vWF-cleaving protease in four patients with chronic relapsing TTP. Diluted plasma samples of TTP patients were incubated with purified normal human vWF in the presence of a serine protease inhibitor, at low ionic strength, and in the presence of urea and barium ions. The extent of vWF degradation was assayed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. Four patients, that included two brothers, with chronic relapsing TTP displayed either substantially reduced levels or a complete absence of vWF-cleaving protease activity. In none of these patient plasmas was an inhibitor of or an antibody against the vWF-cleaving protease established. Our data suggest that the unusually large vWF multimers found in TTP patients may be caused by deficient vWF-cleaving protease activity. Deficiency of this protease may be inherited in an autosomal recessive manner and seems to predispose to chronic relapsing TTP. The assay of the vWF-cleaving protease activity may be used as a sensitive diagnostic tool for identification of subjects with a latent TTP tendency. PMID:9129011

  10. Disulfide Bond Reduction of Von Willebrand Factor by ADAMTS-13†

    PubMed Central

    Yeh, Hui-Chun; Zhou, Zhou; Choi, Hiuwan; Tekeoglu, Senem; May, William; Wang, Christina; Turner, Nancy; Scheiflinger, Friedrich; Moake, Joel L.; Dong, Jing-fei

    2010-01-01

    Summary Background von Willebrand factor (VWF) released from endothelial cells is rich in ultra-large (UL) multimers that are intrinsically active in binding platelets, whereas plasma-type VWF multimers require shear stress to be activated. This functional difference may be attributed to thiols exposed on the surface of plasma-type VWF multimers, but not on ULVWF multimers. Shear stress induces the exposed thiols to form disulfide bonds between laterally apposed plasma-type VWF multimers, leading to enhanced VWF binding to platelets. Objectives We tested a hypothesis that ADAMTS-13 has a disulfide bond-reducing activity that regulates shear-induced thiol-disulfide exchange of VWF. Methods Thiol blocking agents and active thiol bead capturing were used to identify and locate this activity; along with truncated ADAMTS-13 mutants. Results ADAMTS-13 contains a disulfide-bond–reducing activity that primarily targets disulfide bonds in plasma-type VWF multimers induced by high shear stress or formed with thiol beads, but not on disulfide bonds in native multimeric structures. Cysteine thiols targeted by this activity are in the VWF C-domain and are known to participate in shear-induced thiol-disulfide exchange. ADAMTS-13 contains cysteine thiols that remain exposed after being subjected to hydrodynamic forces. Blocking these active thiols eliminates this reducing activity and moderately decreases ADAMTS-13 activity in cleaving ULVWF strings anchored to endothelial cells under flow conditions, but not under static conditions. The activity is located in the C-terminal region of ADAMTS-13. Conclusions This novel disulfide-bond-reducing activity of ADAMTS-13 may prevent covalent lateral association and increased platelet adherence of plasma-type VWF multimers induced by high fluid shear stress. PMID:20946172

  11. von Willebrand factor multimerization and the polarity of secretory pathways in endothelial cells.

    PubMed

    Lopes da Silva, Mafalda; Cutler, Daniel F

    2016-07-14

    The von Willebrand factor (VWF) synthesized and secreted by endothelial cells is central to hemostasis and thrombosis, providing a multifunctional adhesive platform that brings together components needed for these processes. VWF secretion can occur from both apical and basolateral sides of endothelial cells, and from constitutive, basal, and regulated secretory pathways, the latter two via Weibel-Palade bodies (WPB). Although the amount and structure of VWF is crucial to its function, the extent of VWF release, multimerization, and polarity of the 3 secretory pathways have only been addressed separately, and with conflicting results. We set out to clarify these relationships using polarized human umbilical vein endothelial cells (HUVECs) grown on Transwell membranes. We found that regulated secretion of ultra-large (UL)-molecular-weight VWF predominantly occurred apically, consistent with a role in localized platelet capture in the vessel lumen. We found that constitutive secretion of low-molecular-weight (LMW) VWF is targeted basolaterally, toward the subendothelial matrix, using the adaptor protein complex 1 (AP-1), where it may provide the bulk of collagen-bound subendothelial VWF. We also found that basally-secreted VWF is composed of UL-VWF, released continuously from WPBs in the absence of stimuli, and occurs predominantly apically, suggesting this could be the main source of circulating plasma VWF. Together, we provide a unified dataset reporting the amount and multimeric state of VWF secreted from the constitutive, basal, and regulated pathways in polarized HUVECs, and have established a new role for AP-1 in the basolateral constitutive secretion of VWF. PMID:27106123

  12. Differential surface activation of the A1 domain of von Willebrand factor

    PubMed Central

    Tronic, Elaine H.; Yakovenko, Olga; Weidner, Tobias; Baio, Joe E.; Penkala, Rebecca; Castner, David G.; Thomas, Wendy E.

    2016-01-01

    The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibα (GPIbα) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbα-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF-SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID:26968213

  13. Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene

    SciTech Connect

    Pena, S.D.J.; De Souza, K.T. ); De Andrade, M.; Chakraborty, R. )

    1994-01-18

    At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the same alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, the authors observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of cooperative changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes.

  14. Paradoxical Effect of Nonphysiological Shear Stress on Platelets and von Willebrand Factor.

    PubMed

    Chen, Zengsheng; Mondal, Nandan K; Ding, Jun; Koenig, Steven C; Slaughter, Mark S; Wu, Zhongjun J

    2016-07-01

    Blood can become hypercoagulable by shear-induced platelet activation and generation of microparticles. It has been reported that nonphysiological shear stress (NPSS) could induce shedding of platelet receptor glycoprotein (GP) Ibα, which may result in an opposite effect to hemostasis. The aim of this study was to investigate the influence of the NPSS on platelets and von Willebrand factor (vWF). Human blood was exposed to two levels of NPSS (25 Pa, 125 Pa) with an exposure time of 0.5 s, generated by using a novel blood-shearing device. Platelet activation (P-selectin expression, GPIIb/IIIa activation and generation of microparticles) and shedding of three platelet receptors (GPIbα, GPVI, GPIIb/IIIa) in sheared blood were quantified using flow cytometry. Aggregation capacity of sheared blood induced by ristocetin and collagen was evaluated using an aggregometer. Shear-induced vWF damage was characterized with Western blotting. Consistent with the published data, the NPSS caused significantly more platelets to become activated with increasing NPSS level. Meanwhile, the NPSS induced the shedding of platelet receptors. The loss of the platelet receptors increased with increasing NPSS level. The aggregation capacity of sheared blood induced by ristocetin and collagen decreased. There was a loss of high molecular weight multimers (HMWMs) of vWF in sheared blood. These results suggest that the NPSS induced a paradoxical effect. More activated platelets increase the risk of thrombosis, while the reduction in platelet receptors and the loss of HMWM-vWF increased the propensity of bleeding. The finding might provide a new perspective to understand thrombosis and acquired bleeding disorder in patients supported with blood contacting medical devices. PMID:26582038

  15. Differential surface activation of the A1 domain of von Willebrand factor.

    PubMed

    Tronic, Elaine H; Yakovenko, Olga; Weidner, Tobias; Baio, Joe E; Penkala, Rebecca; Castner, David G; Thomas, Wendy E

    2016-06-01

    The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibα (GPIbα) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbα-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF-SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID:26968213

  16. Identification of a Small Molecule That Modulates Platelet Glycoprotein Ib-von Willebrand Factor Interaction*

    PubMed Central

    Broos, Katleen; Trekels, Mieke; Jose, Rani Alphonsa; Demeulemeester, Jonas; Vandenbulcke, Aline; Vandeputte, Nele; Venken, Tom; Egle, Brecht; De Borggraeve, Wim M.; Deckmyn, Hans; De Maeyer, Marc

    2012-01-01

    The von Willebrand factor (VWF) A1-glycoprotein (GP) Ibα interaction is of major importance during thrombosis mainly at sites of high shear stress. Inhibitors of this interaction prevent platelet-dependent thrombus formation in vivo, without major bleeding complications. However, the size and/or protein nature of the inhibitors currently in development limit oral bioavailability and clinical development. We therefore aimed to search for a small molecule protein-protein interaction inhibitor interfering with the VWF-GPIbα binding. After determination of putative small molecule binding pockets on the surface of VWF-A1 and GPIbα using site-finding algorithms and molecular dynamics, high throughput molecular docking was performed on both binding partners. A selection of compounds showing good in silico docking scores into the predicted pockets was retained for testing their in vitro effect on VWF-GPIbα complex formation, by which we identified a compound that surprisingly stimulated the VWF-GPIbα binding in a ristocetin cofactor ELISA and increased platelet adhesion in whole blood to collagen under arterial shear rate but in contrast inhibited ristocetin-induced platelet aggregation. The selected compound adhering to the predicted binding partner GPIbα could be confirmed by saturation transfer difference NMR spectroscopy. We thus clearly identified a small molecule that modulates VWF-GPIbα binding and that will now serve as a starting point for further studies and chemical modifications to fully characterize the interaction and to manipulate specific activity of the compound. PMID:22232560

  17. Decrease in the plasma von Willebrand factor concentration following glucose ingestion: the role of insulin sensitivity.

    PubMed

    von Känel, R; Nelesen, R A; Le, D T; Ziegler, M G; Dimsdale, J E

    2001-12-01

    Elevated plasma von Willebrand factor (vWF) concentration is thought to be associated with increased prevalence of cardiovascular events in the insulin resistance syndrome. We examined the effects of oral glucose challenge and accompanying metabolic and hemodynamic changes on vWF levels with respect to insulin sensitivity. Forty normotensive and hypertensive subjects (mean age +/- SD, 40 +/- 5 years) underwent a standard oral glucose tolerance test (OGTT). Plasma vWF antigen, glucose, insulin, catecholamines, and hemodynamics were measured at rest, and at 30, 60, 90, and 120 minutes after glucose intake. Insulin sensitivity was determined by the insulin sensitivity index (ISI(0,120)). Resting plasma vWF concentration was associated with screening systolic blood pressure (BP) (r =.43, P =.005). There were time effects for all variables of interest. While vWF antigen (P =.044), epinephrine (P =.003), and diastolic BP (P =.001) decreased after glucose challenge, norepinephrine (P =.009), systolic BP (P =.022), and heart rate (P <.001) increased. Decline in vWF (area under the curve) was associated with decrease in epinephrine (r =.46, P =.004) and with screening systolic BP (r =.45, P =.004). However, neither resting plasma vWF levels nor vWF decrease following glucose ingestion were significantly associated with the ISI(0,120.) The plasma vWF concentration decreases following glucose ingestion. While mechanisms underlying this phenomenon may relate to sympathetic nervous system function, they seem not related to insulin sensitivity. Endothelial dysfunction such as caused by hypertension rather than metabolic dysregulation per se may underlie the elevated plasma vWF concentration found with insulin resistance. PMID:11735092

  18. Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis.

    PubMed

    Dmitrieva, Natalia I; Burg, Maurice B

    2014-04-29

    Hypercoagulability increases risk of thrombi that cause cardiovascular events. Here we identify plasma sodium concentration as a factor that modulates blood coagulability by affecting the production of von Willebrand factor (vWF), a key initiator of the clotting cascade. We find that elevation of salt over a range from the lower end of what is normal in blood to the level of severe hypernatremia reversibly increases vWF mRNA in endothelial cells in culture and the rate of vWF secretion from them. The high NaCl increases expression of tonicity-regulated transcription factor NFAT5 and its binding to promoter of vWF gene, suggesting involvement of hypertonic signaling in vWF up-regulation. To elevate NaCl in vivo, we modeled mild dehydration, subjecting mice to water restriction (WR) by feeding them with gel food containing 30% water. Such WR elevates blood sodium from 145.1 ± 0.5 to 150.2 ± 1.3 mmol/L and activates hypertonic signaling, evidenced from increased expression of NFAT5 in tissues. WR increases vWF mRNA in liver and lung and raises vWF protein in blood. Immunostaining of liver revealed increased production of vWF protein by endothelium and increased number of microthrombi inside capillaries. WR also increases blood level of D-dimer, indicative of ongoing coagulation and thrombolysis. Multivariate regression analysis of clinical data from the Atherosclerosis Risk in Communities Study demonstrated that serum sodium significantly contributes to prediction of plasma vWF and risk of stroke. The results indicate that elevation of extracellular sodium within the physiological range raises vWF sufficiently to increase coagulability and risk of thrombosis. PMID:24733925

  19. Biological Variations of Lupus Anticoagulant, Antithrombin, Protein C, Protein S, and von Willebrand Factor Assays.

    PubMed

    Shou, Weiling; Chen, Qian; Wu, Wei; Cui, Wei

    2016-02-01

    The results of lupus anticoagulant (LA), antithrombin (AT), protein C (PC), and protein S (PS) testing, and the values of von Willebrand factor antigen (VWF:Ag) are important in diagnosis and therapeutic monitoring of thrombosis and hemostasis diseases. Till now, no published study has focused on the biological variations in LA testing, and only a few studies have examined the biological variations of AT, PC, PS, and VWF:Ag. With the latest fully automated instruments and improved reagents, the analytical, within-subject, and between-subject biological variations were estimated for these five coagulant parameters in a cohort of 25 apparently healthy subjects. Blood specimens were collected at 8:00 am, 12:00 pm, and 4:00 pm on days 1, 3, and 5. The analytical biological variation (CV(A)) values of all the parameters were less than 3%. The within-subject biological variation (CV(W)) and between-subject biological variation (CV(G)) values of the LA normalized ratio were 4.64 and 6.83%, respectively. No significant differences were observed in the intraday and interday biological variations of LA tests, or in AT, PC, PS, and VWF:Ag values. Additionally, the utility of the conventional population-based reference intervals of the five coagulation parameters was evaluated by the index of individuality, and data on CV(W) and CV(A) were used to calculate the reference change value to identify the significance of changes in serial results from the same individual. PMID:26516946

  20. Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis

    PubMed Central

    Dmitrieva, Natalia I.; Burg, Maurice B.

    2014-01-01

    Hypercoagulability increases risk of thrombi that cause cardiovascular events. Here we identify plasma sodium concentration as a factor that modulates blood coagulability by affecting the production of von Willebrand factor (vWF), a key initiator of the clotting cascade. We find that elevation of salt over a range from the lower end of what is normal in blood to the level of severe hypernatremia reversibly increases vWF mRNA in endothelial cells in culture and the rate of vWF secretion from them. The high NaCl increases expression of tonicity-regulated transcription factor NFAT5 and its binding to promoter of vWF gene, suggesting involvement of hypertonic signaling in vWF up-regulation. To elevate NaCl in vivo, we modeled mild dehydration, subjecting mice to water restriction (WR) by feeding them with gel food containing 30% water. Such WR elevates blood sodium from 145.1 ± 0.5 to 150.2 ± 1.3 mmol/L and activates hypertonic signaling, evidenced from increased expression of NFAT5 in tissues. WR increases vWF mRNA in liver and lung and raises vWF protein in blood. Immunostaining of liver revealed increased production of vWF protein by endothelium and increased number of microthrombi inside capillaries. WR also increases blood level of D-dimer, indicative of ongoing coagulation and thrombolysis. Multivariate regression analysis of clinical data from the Atherosclerosis Risk in Communities Study demonstrated that serum sodium significantly contributes to prediction of plasma vWF and risk of stroke. The results indicate that elevation of extracellular sodium within the physiological range raises vWF sufficiently to increase coagulability and risk of thrombosis. PMID:24733925

  1. Complex Changes in von Willebrand Factor-Associated Parameters Are Acquired during Uncomplicated Pregnancy

    PubMed Central

    Drury-Stewart, Danielle N.; Lannert, Kerry W.; Chung, Dominic W.; Teramura, Gayle T.; Zimring, James C.; Konkle, Barbara A.; Gammill, Hilary S.; Johnsen, Jill M.

    2014-01-01

    Background The coagulation protein von Willebrand Factor (VWF) is known to be elevated in pregnancy. However, the timing and nature of changes in VWF and associated parameters throughout pregnancy are not well understood. Objectives To better understand the changes in VWF provoked by pregnancy, we studied VWF-associated parameters in samples collected over the course of healthy pregnancies. Methods We measured VWF antigen (VWF:Ag), VWF propeptide (VWFpp), Factor VIII (FVIII), and ADAMTS13 activity in samples collected from 46 women during pregnancy and at non-pregnant baseline. We also characterized pregnant vs. non-pregnant VWF multimer structure in 21 pregnancies, and performed isoelectric focusing (IEF) of VWF in two pregnancies which had samples from multiple trimesters. Results VWF:Ag and FVIII levels were significantly increased during pregnancy. ADAMTS13 activity was unchanged. VWFpp levels increased much later in pregnancy than VWF:Ag, resulting in a progressive decrease in VWFpp:Ag ratios. FVIII:VWF ratios also decreased in pregnancy. Most pregnancies exhibited a clear loss of larger VWF multimers and altered VWF triplet structure. Further evidence of acquired VWF qualitative changes in pregnancy was found in progressive, reversible shifts in VWF IEF patterns over gestation. Conclusions These data support a new view of pregnancy in which VWF can acquire qualitative changes associated with advancing gestational age. Modeling supports a scenario in which both increased VWF production and doubling of the VWF half-life would account for the data observed. We propose that gestation induces a prolongation in VWF survival, which likely contributes to increased total VWF levels and altered VWF structure. PMID:25409031

  2. A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria

    PubMed Central

    O’Regan, Niamh; Gegenbauer, Kristina; O’Sullivan, Jamie M.; Maleki, Sanaz; Brophy, Teresa M.; Dalton, Niall; Chion, Alain; Fallon, Padraic G.; Grau, Georges E.; Budde, Ulrich; Smith, Owen P.; Craig, Alister G.; Preston, Roger J. S.

    2016-01-01

    Plasmodium falciparum malaria infection is associated with an early marked increase in plasma von Willebrand factor (VWF) levels, together with a pathological accumulation of hyperreactive ultra-large VWF (UL-VWF) multimers. Given the established critical role of platelets in malaria pathogenesis, these increases in plasma VWF raise the intriguing possibility that VWF may play a direct role in modulating malaria pathogenesis. To address this hypothesis, we used an established murine model of experimental cerebral malaria (ECM), in which wild-type (WT) C57BL/6J mice were infected with Plasmodium berghei ANKA. In keeping with findings in children with P falciparum malaria, acute endothelial cell activation was an early and consistent feature in the murine model of cerebral malaria (CM), resulting in significantly increased plasma VWF levels. Despite the fact that murine plasma ADAMTS13 levels were not significantly reduced, pathological UL-VWF multimers were also observed in murine plasma following P berghei infection. To determine whether VWF plays a role in modulating the pathogenesis of CM in vivo, we further investigated P berghei infection in VWF−/− C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF−/− mice compared with WT controls. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF−/− and WT mice. Interestingly, however, the degree of ECM-associated enhanced blood–brain barrier permeability was significantly attenuated in VWF−/− mice compared with WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance. PMID:26511133

  3. Treatment of Acquired von Willebrand Syndrome and Prevention of Bleeding Postautologous Stem Cell Transplant during Severe Pancytopenia with IVIG

    PubMed Central

    Zoghi, Behyar; Shaughnessy, Paul; Lyons, Roger M.; Helmer, Richard; Bachier, Carlos; LeMaistre, C. Frederick

    2015-01-01

    The use of high dose chemotherapy followed by autologous hematopoietic stem cell transplantation for remission consolidation after initial induction represents standard of care for patients with multiple myeloma. Patients with myeloma and Acquired von Willebrand Syndrome (AVWS) undergoing autologous stem cell transplant (ASCT) are at significant risk of bleeding due to the profound thrombocytopenia, low Factor VIII levels, fever, and toxicities associated with the preparative regimen. We report a patient with AVWS associated with multiple myeloma who underwent autologous stem cell transplants as consolidation after initial induction and again at relapse. He was successfully treated with high dose intravenous immunoglobulin (IVIG) prior to each transplant with rapid resolution of AVWS. PMID:25922770

  4. Severe von Willebrand disease due to a defect at the level of von Willebrand factor mRNA expression: Detection by exonic PCR-restriction fragment length polymorphism analysis

    SciTech Connect

    Nichols, W.C.; Lyons, S.E.; Harrison, J.S.; Cody, R.L.; Ginsburg, D. )

    1991-05-01

    von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, results from abnormalities in the plasma clotting protein von Willebrand factor (vWF). Severe (type III) vWD is autosomal recessive in inheritance and is associated with extremely low or undetectable vWF levels. The authors report a method designed to distinguish mRNA expression from the two vWF alleles by PCR analysis of peripheral blood platelet RNA using DNA sequence polymorphisms located within exons of the vWF gene. This approach was applied to a severe-vWD pedigree in which three of eight siblings are affected and the parents and additional siblings are clinically normal. Each parent was shown to carry a vWF allele that is silent at the mRNA level. Family members inheriting both abnormal alleles are affected with severe vWD, whereas individuals with only one abnormal allele are asymptomatic. Given the frequencies of the two exon polymorphisms reported here, this analysis should be applicable to {approx}70% of type I and type III vWD patients. This comparative DNA and RNA PCR-restriction fragment length polymorphism approach may also prove useful in identifying defects at the level of gene expression associated with other genetic disorders.

  5. A molten globule intermediate of the Von Willebrand Factor A1 domain firmly tethers platelets under shear flow

    PubMed Central

    Tischer, Alexander; Madde, Pranathi; Blancas-Mejia, Luis. M.; Auton, Matthew

    2014-01-01

    Clinical mutations in patients diagnosed with Type 2A von Willebrand disease (vWD) have been identified that break the single disulfide bond linking N- and C-termini in the vWF A1 domain. We have modeled the effect of these mutations on the disulfide-bonded structure of A1 by reducing and carboxy-amidating these cysteines. Solution biophysical studies show that loss of this disulfide bond induces a molten globule conformational state lacking global tertiary structure but retaining residual secondary structure. The conformational dependence of platelet adhesion to these native and molten globule states of A1 is quantitatively compared using real-time high-speed video microscopy analysis of platelet translocation dynamics under shear flow in a parallel plate micro-fluidic flow chamber. While normal platelets translocating on surface-captured native A1 domain retain the catch-bond character of pause times that increase as a function of shear rate at low shear and decrease as a function of shear rate at high shear, platelets that interact with A1 lacking the disulfide bond remain stably attached and do not translocate. Based on these findings, we propose that the shear stress-sensitive regulation of the A1-GPIb interaction is due to folding the tertiary structure of this domain. Removal of the tertiary structure by disrupting the disulfide bond destroys this regulatory mechanism resulting in high-strength interactions between platelets and vWF A1 that are dependent only on residual secondary structure elements present in the molten globule conformation. PMID:24265179

  6. A molten globule intermediate of the von Willebrand factor A1 domain firmly tethers platelets under shear flow.

    PubMed

    Tischer, Alexander; Madde, Pranathi; Blancas-Mejia, Luis M; Auton, Matthew

    2014-05-01

    Clinical mutations in patients diagnosed with Type 2A von Willebrand disease (VWD) have been identified that break the single disulfide bond linking N- and C-termini in the vWF A1 domain. We have modeled the effect of these mutations on the disulfide-bonded structure of A1 by reducing and carboxy-amidating these cysteines. Solution biophysical studies show that loss of this disulfide bond induces a molten globule conformational state lacking global tertiary structure but retaining residual secondary structure. The conformational dependence of platelet adhesion to these native and molten globule states of A1 is quantitatively compared using real-time high-speed video microscopy analysis of platelet translocation dynamics under shear flow in a parallel plate microfluidic flow chamber. While normal platelets translocating on surface-captured native A1 domain retain the catch-bond character of pause times that increase as a function of shear rate at low shear and decrease as a function of shear rate at high shear, platelets that interact with A1 lacking the disulfide bond remain stably attached and do not translocate. Based on these findings, we propose that the shear stress-sensitive regulation of the A1-GPIb interaction is due to folding the tertiary structure of this domain. Removal of the tertiary structure by disrupting the disulfide bond destroys this regulatory mechanism resulting in high-strength interactions between platelets and vWF A1 that are dependent only on residual secondary structure elements present in the molten globule conformation. PMID:24265179

  7. Von Willebrand gene tracking by single-tube automated fluorescent analysis of four short tandem repeat polymorphisms.

    PubMed

    Vidal, Francisco; Julià, Antoni; Altisent, Carme; Puig, Lluís; Gallardo, Doinique

    2005-05-01

    Molecular diagnosis of von Willebrand disease (VWD) has been hampered by the large size and complex genomic characteristics of the gene involved. For this reason, indirect methods using intragenic polymorphic markers described along the von Willebrand factor (VWF) gene are valuable tools for gene monitoring and linkage analysis. Several studies have demonstrated the four commonly utilized short tandem repeats (STRs), three located in intron 40 and one in the promoter region of the VWF gene, to be highly informative for this task. Our objective was t o develop a rapid, automated method to simultaneously analyze these four STRs for VWF gene tracking. Amplification of the four loci is achieved in a single multiplex fluorescent PCR which is then analyzed in the same run by capillary electrophoresis. Data processing with GeneScan and Genotyper software has simplified management and tabulation of the resulting haplotypes. Analysis of the VWF gene in DNA from 102 individuals (204 chromosomes) revealed that the three STRs within intron 40 showed significant linkage disequilibrium against each other but not against the VWP locus. Moreover, the combination of the four markers offers a high heterozygosity rate (>99%) that improves tracing VWF gene inheritance. In conclusion, the automated fluorescent capillary electrophoresis method presented here is an extremely rapid, simple and highly informative technique for association studies between VWD and the VWF gene in addition to genetic counseling and prenatal diagnosis by precise linkage analysis in VWD-affected families. PMID:15886817

  8. Defective von willebrand factor activity detected by the filterometer in three clinical conditions.

    PubMed

    O'Brien, J R; Tsai, H M; Etherington, M D

    2000-11-01

    When exposed to high levels of shear in a filterometer, platelets bind to von Willebrand factor (vWF) via receptors Ib and IIb/IIIa, forming aggregates that block the filteromer. In this study we used the filterometer to explore the mechanisms by which abnormal vWF-platelet interaction might occur. In the first phase of the study, the global vWF-platelet interaction in native blood was investigated. In the second phase, to eliminate the difference that platelets might contribute, samples of platelet-poor plasma from test individuals were added to normal control blood and the mixtures were investigated by the filterometer. The filterometer results were adjusted for the antigen concentrations to obtain vWF potency ratios. Sodium dodecyl sulphate (SDS) agarose gel electrophoresis and SDS-Polyacylamide gel electrophoresis (PAGE) were used to analyze multimeric size and proteolytic profiles of vWF. Pregnancy was associated with high platelet retention, high vWF antigen concentration, normal multimeric size distribution, but decreased vWF potency ratios. The plasma samples of pregnancy contained one 183-kDa fragment not detected in normal plasma. These results suggested that in pregnancy, platelets were highly active. However, presumably due to abnormal proteolytic cleavage, vWF potency was decreased. This decrease in vWF potency might minimize the risk of thrombosis in association with highly active platelets. Renal transplant patients had normal platelet retention but high vWF levels. The plasma vWF contained normal multimers. A decrease in vWF potency, presumably caused by toxic inhibitors in the plasma, was detected. Aortic valve stenosis patients had decreased platelet retention, normal or slightly increased vWF antigen concentration and a decrease in large multimers. As a result, the vWF potency was markedly decreased. However, the results obtained with the filterometer became normal when the studies were repeated 3 months postpartum, when renal function had

  9. Effects of Increased Von Willebrand Factor Levels on Primary Hemostasis in Thrombocytopenic Patients with Liver Cirrhosis

    PubMed Central

    Wannhoff, Andreas; Müller, Oliver J.; Friedrich, Kilian; Rupp, Christian; Klöters-Plachky, Petra; Leopold, Yvonne; Brune, Maik; Senner, Mirja; Weiss, Karl-Heinz; Stremmel, Wolfgang; Schemmer, Peter; Katus, Hugo A.; Gotthardt, Daniel N.

    2014-01-01

    In patients with liver cirrhosis procoagulant and anticoagulant changes occur simultaneously. During primary hemostasis, platelets adhere to subendothelial structures, via von Willebrand factor (vWF). We aimed to investigate the influence of vWF on primary hemostasis in patients with liver cirrhosis. Therefore we assessed in-vitro bleeding time as marker of primary hemostasis in cirrhotic patients, measuring the Platelet Function Analyzer (PFA-100) closure times with collagen and epinephrine (Col-Epi, upper limit of normal ≤165 s) or collagen and ADP (Col-ADP, upper limit of normal ≤118 s). If Col-Epi and Col-ADP were prolonged, the PFA-100 was considered to be pathological. Effects of vWF on primary hemostasis in thrombocytopenic patients were analyzed and plasma vWF levels were modified by adding recombinant vWF or anti-vWF antibody. Of the 72 included cirrhotic patients, 32 (44.4%) showed a pathological result for the PFA-100. They had mean closure times (± SD) of 180±62 s with Col-Epi and 160±70 s with Col-ADP. Multivariate analysis revealed that hematocrit (P = 0.027) and vWF-antigen levels (P = 0.010) are the predictors of a pathological PFA-100 test in cirrhotic patients. In 21.4% of cirrhotic patients with platelet count ≥150/nL and hematocrit ≥27.0%, pathological PFA-100 results were found. In thrombocytopenic (<150/nL) patients with cirrhosis, normal PFA-100 results were associated with higher vWF-antigen levels (462.3±235.9% vs. 338.7±151.6%, P = 0.021). These results were confirmed by multivariate analysis in these patients as well as by adding recombinant vWF or polyclonal anti-vWF antibody that significantly shortened or prolonged closure times, respectively. In conclusion, primary hemostasis is impaired in cirrhotic patients. The effect of reduced platelet count in cirrhotic patients can at least be partly compensated by increased vWF levels. Recombinant vWF could be an alternative to platelet transfusions in the future. PMID

  10. Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis.

    PubMed

    Wannhoff, Andreas; Müller, Oliver J; Friedrich, Kilian; Rupp, Christian; Klöters-Plachky, Petra; Leopold, Yvonne; Brune, Maik; Senner, Mirja; Weiss, Karl-Heinz; Stremmel, Wolfgang; Schemmer, Peter; Katus, Hugo A; Gotthardt, Daniel N

    2014-01-01

    In patients with liver cirrhosis procoagulant and anticoagulant changes occur simultaneously. During primary hemostasis, platelets adhere to subendothelial structures, via von Willebrand factor (vWF). We aimed to investigate the influence of vWF on primary hemostasis in patients with liver cirrhosis. Therefore we assessed in-vitro bleeding time as marker of primary hemostasis in cirrhotic patients, measuring the Platelet Function Analyzer (PFA-100) closure times with collagen and epinephrine (Col-Epi, upper limit of normal ≤ 165 s) or collagen and ADP (Col-ADP, upper limit of normal ≤ 118 s). If Col-Epi and Col-ADP were prolonged, the PFA-100 was considered to be pathological. Effects of vWF on primary hemostasis in thrombocytopenic patients were analyzed and plasma vWF levels were modified by adding recombinant vWF or anti-vWF antibody. Of the 72 included cirrhotic patients, 32 (44.4%) showed a pathological result for the PFA-100. They had mean closure times (± SD) of 180 ± 62 s with Col-Epi and 160 ± 70 s with Col-ADP. Multivariate analysis revealed that hematocrit (P = 0.027) and vWF-antigen levels (P = 0.010) are the predictors of a pathological PFA-100 test in cirrhotic patients. In 21.4% of cirrhotic patients with platelet count ≥ 150/nL and hematocrit ≥ 27.0%, pathological PFA-100 results were found. In thrombocytopenic (< 150/nL) patients with cirrhosis, normal PFA-100 results were associated with higher vWF-antigen levels (462.3 ± 235.9% vs. 338.7 ± 151.6%, P = 0.021). These results were confirmed by multivariate analysis in these patients as well as by adding recombinant vWF or polyclonal anti-vWF antibody that significantly shortened or prolonged closure times, respectively. In conclusion, primary hemostasis is impaired in cirrhotic patients. The effect of reduced platelet count in cirrhotic patients can at least be partly compensated by increased vWF levels. Recombinant vWF could be an alternative to platelet transfusions in the future

  11. Phenotypic and molecular characterisation of type 3 von Willebrand disease in a cohort of Indian patients.

    PubMed

    Ahmad, Firdos; Budde, Ulrich; Jan, Rifat; Oyen, Florian; Kannan, Meganathan; Saxena, Renu; Schneppenheim, Reinhard

    2013-04-01

    Severe type 3 VWD (VWD3) is characterised by complete absence or presence of trace amounts of non-functional von Willebrand factor (VWF). The study was designed to evaluate the VWF mutations in VWD3 patients and characterise the breakpoints of two identified homozygous novel large deletions. Patients were diagnosed by conventional tests and VWF multimer analysis. Mutation screening was performed in 19 VWD3 patients by direct sequencing of VWF including flanking intronic sequence and multiplex ligation-dependent probe amplification (MLPA) analysis. Breakpoint characterisation of two identified novel large deletions was done using walking primers and long spanning PCR. A total of 21 different mutations including 15 (71.4%) novel ones were identified in 17 (89.5%) patients. Of these mutations, five (23.8%) were nonsense (p.R1659*, p.R1779*, p.R1853*, p.Q2470*, p.Q2520*), one was a putative splice site (p.M814I) and seven (33.3%) were deletions (p.L254fs*48, p.C849fs*60, p.L1871fs*6, p.E2720fs*24) including three novel large deletions of exon 14-15, 80,830bp (-41510_657+7928A*del) and 2,231bp [1534-2072T_c.1692G*del(p.512fs*terminus)] respectively. A patient carried gene conversion comprising of pseudogene harbouring mutations. The missense mutations (p.G19R, p.K355R, p.D437Y, p.C633R, p.M771V, p.G2044D, p.C2491R) appear to play a major role and were identified in seven (36.8%) patients. In conclusion, a high frequency of novel mutations suggests the high propensity of VWF for new mutations. Missense and deletion mutations found to be a common cause of VWD3 in cohort of Indian VWD3 patients. Breakpoints characterisation of two large deletions reveals the double strand break and non-homologous recombination as deletions mechanism. PMID:23407766

  12. Ets transcription factors bind and transactivate the core promoter of the von Willebrand factor gene.

    PubMed

    Schwachtgen, J L; Janel, N; Barek, L; Duterque-Coquillaud, M; Ghysdael, J; Meyer, D; Kerbiriou-Nabias, D

    1997-12-18

    von Willebrand factor (vWF) gene expression is restricted to endothelial cells and megakaryocytes. Previous results demonstrated that basal transcription of the human vWF gene is mediated through a promoter located between base pairs -89 and +19 (cap site: +1) which is functional in endothelial and non endothelial cells. Two DNA repeats TTTCCTTT correlating with inverted consensus binding sites for the Ets family of transcription factors are present in the -56/-36 sequence. In order to analyse whether these DNA elements are involved in transcription, human umbilical vein endothelial cells (HUVEC), bovine calf pulmonary endothelial cell line (CPAE), HeLa and COS cells were transfected with constructs containing deletions of the -89/+19 fragment, linked to the chloramphenicol acetyl transferase (CAT) reporter gene. The -60/+19 region exhibits significant promoter activity in HUVEC and CPAE cells only. The -42/+19 fragment is not active. Mutations of the -60/+19 promoter fragment in the 5' (-56/-49) Ets binding site abolish transcription in endothelial cells whereas mutations in the 3' (-43/-36) site does not. The -60/-33 fragment forms three complexes with proteins from HUVEC nuclear extracts in electrophoretic mobility shift assay which are dependent on the presence of the 5' Ets binding site. Binding of recombinant Ets-1 protein to the -60/-33 fragment gives a complex which also depends on the 5' site. The -60/+19 vWF gene core promoter is transactivated in HeLa cells by cotransfecting with Ets-1 or Erg (Ets-related gene) expression plasmids. In contrast to the wild type construct, transcription of the 5' site mutants is not increased by these expressed proteins. The results indicate that the promoter activity of the -60/+19 region of the vWF gene depends on transcription factors of the Ets family of which several members like Ets-1, Ets-2 and Erg are expressed in endothelium. Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 v

  13. Contribution of the collagen binding activity (VWF:CB) in the range of tests for the diagnosis and classification of von Willebrand disease.

    PubMed

    Ferhat-Hamida, Meriem Yasmine; Boukerb, Houda; Hariti, Ghania

    2015-01-01

    Von willebrand disease (VWD) is a common inherited bleeding disorder. The diagnosis may need a large panel of tests that differ in term of sensibility and specificity, and because of the effect of multifactorial modifiers (genetic or environmental); there is difficulty in defining diagnostic limits. We performed a panel of tests on 19 patients suffering from recurrent bleeding, to diagnose and classify VWD subtypes, by introducing the von Willebrand factor (VWF) collagen binding test (VWF:CB), then comparing the results with the activity of VWF risticetin cofactor (VWF:RCo) and multimer pattern. We considered 30% limit rate of VWF, as described by many authors, to make the diagnosis of VWD. The diagnosis of type 1 of VWD has been confirmed in 7patients, subtype 2A in 2 patients, subtype 2M in 2 patients and type 3 in 2 patients. We also defined a new group of 6 patients named "uncertain type 1" that didn't fill into the type 1 diagnostic criterion. The comparison between VWF:CB and VWF:RCo showed good correlation for all types of VWD except for type 2 while comparison between VWF:CB and multimer pattern showed good concordance for all types of VWD diagnosed. In conclusion, VWF:CB can be a good alternative to VWF:RCo for the diagnosis of quantitative deficiencies of VWF. It can also replace the multimer pattern study. However, the introduction of VWF:CB didn't help in the diagnosis of the "uncertain type 1" group of patients and cannot be a replacement for qualitative defect. PMID:26411913

  14. A two-centre comparative evaluation of new automated assays for von Willebrand factor ristocetin cofactor activity and antigen.

    PubMed

    Stufano, F; Lawrie, A S; La Marca, S; Berbenni, C; Baronciani, L; Peyvandi, F

    2014-01-01

    von Willebrand disease (VWD) is caused by a quantitative and/or qualitative deficiency of the von Willebrand factor (VWF). The laboratory diagnosis of VWD is dependent on the measurement of VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo). The aim of this study was to undertake a two-centre evaluation of two new automated VWF:Ag and VWF:RCo assays systems from Instrumentation Laboratory (Bedford, USA). Using the two new analytical systems that operated with different detection principles: immunoturbidimetric (TOP500 analyser) and chemiluminescent (AcuStar analyser), VWF:Ag and VWF:RCo levels were determined in samples from 171 healthy normal subjects, 80 VWD patients (16 type 1, 58 type 2 and 6 type 3) and 7 acquired von Willebrand syndrome patients. With commercial lyophilized normal and pathological plasmas VWF: Ag and VWF:RCo assays performed on both analysers exhibited low levels of inter-assay imprecision (AcuStar: CV% range 3.3-6.9; TOP500: CV% range 2.6-6.3). Samples from normal healthy subjects (range: VWF:Ag 44.6-173.9 IU dL(-1) ; VWF:RCo 43.1-191.5 IU dL(-1)) and patients (range: VWF:Ag <0.3-115.1 IU dL(-1) ; VWF:RCo <0.5-57.2 IU dL(-1)) showed a good correlation between the two VWF:Ag and VWF:RCo methods (rs = 0.92 and 0.82 respectively), with only a few inconsistent cases among the patients' samples evaluated. The chemiluminescent assays had a lower limit of detection for both VWF:Ag and VWF:RCo compared to immunoturbidimetric tests (0.3 IU dL(-1) vs. 2.2 IU dL(-1) and 0.5 IU dL(-1) vs. 4.4 IU dL(-1) respectively). The TOP500 and AcuStar VWF:Ag and VWF:RCo assays were precise and compare well between centres, making these systems suitable for the diagnosis of VWD in non-specialized and reference laboratories. PMID:24028703

  15. Germ-line mosaicism for a valine-to-methionine substitution at residue 553 in the glycoprotein Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand disease

    SciTech Connect

    Murray, E.W.; Giles, A.R.; Lillicrap, D. )

    1992-01-01

    The origin of new single-gene mutations resulting in inherited disease is an issue which may be at least partially resolved by our enhanced ability to detect these changes. In this report the authors describe the identification of a missense mutation at codon 553 (guanine to adenine) in the von Willebrand factor (vWf) gene in affected members of a family with type IIB von Willebrand's disease (vWd). They found no evidence for this substitution in 190 normal vWf genes. The encoded substitution of a methionine for a valine at this residue is nonconservative in nature and has affected a vWf protein region which has been shown to facilitate binding to the platelet receptor glycoprotein Ib. In patients with type IIb vWd this interaction is characteristically increased in affinity. This mutation has also recently been recorded in four other type IIb vWd families. Thus, there is strong circumstantial evidence to incriminate this substitution as the disease causing mutation in this family. As further supporting evidence for this claim, they have shown by vWf polymorphism analysis that the mutation originated in a vWf gene transmitted from a phenotypically normal grandfather. These results confirm (1) that the candidate type IIB vWd mutation in this family occurred at some time during the development of the germ line of the grandfather and presumably was related to a mitotic cell division and (2) that, as a result, he is a low-level germ-line mosaic for the mutation.

  16. Salvage therapy with high dose Intravenous Immunoglobulins in acquired Von Willebrand Syndrome and unresponsive severe intestinal bleeding

    PubMed Central

    2014-01-01

    A 91-year-old woman affected with acquired Von Willebrand (VW) syndrome and intestinal angiodysplasias presented with severe gastrointestinal bleeding (hemoglobin 5 g/dl). Despite replacement therapy with VW factor/factor VIII concentrate qid, bleeding did not stop (eleven packed red blood cell units were transfused over three days). High circulating levels of anti-VW factor immunoglobulin M were documented immunoenzimatically. Heart ultrasound showed abnormalities of the mitral and aortic valves with severe flow alterations. When intravenous immunoglobulins were added to therapy, prompt clinical and laboratory responses occurred: complete cessation of bleeding, raise in hemoglobin, VW factor antigen, VW ristocetin cofactor and factor VIII levels as well as progressive reduction of the anti-VWF autoantibody levels. PMID:24926417

  17. Cerebral venous thrombosis associated with thyrotoxicosis, the use of desmopressin and elevated factor VIII/von Willebrand factor.

    PubMed

    Waheed, Waqar; Aljerdi, Salman; Decker, Barbara; Cushman, Mary; Hamill, Robert W

    2016-01-01

    Cerebral venous thrombosis (CVT) is an uncommon disorder associated with diverse processes. We report a patient who, while receiving desmopressin and contraceptive pills (OCP), developed straight sinus thrombosis. Clinical assessment and laboratory investigations revealed untreated hyperthyroidism and a hypercoagulable state, characterised by high levels of von Willebrand factor, factor VIII coagulant activity and IgM cardiolipin antibody. The clinical picture improved with anticoagulation, treatment of hyperthyroidism and discontinuation of OCP and desmopressin. To the best of our knowledge, the association between the use of oral desmopressin and CVT has not been described. The multiple risk factors present in our case were probably additive in increasing the risk of CVT. Although this case represents a rare occurrence, practitioners should be alerted to the possible associations of desmopressin, oral contraceptives and Graves' disease with venous thrombosis. PMID:27503942

  18. 150-kD von Willebrand factor binding protein extracted from human vascular subendothelium is type VI collagen.

    PubMed Central

    Rand, J H; Patel, N D; Schwartz, E; Zhou, S L; Potter, B J

    1991-01-01

    We have previously shown that von Willebrand factor (vWF), a glycoprotein which plays a critical role in the adhesion of platelets to injured blood vessels, is present within vascular subendothelium. We investigated the identity of the subendothelial binding site(s) for vWF by examining vWF binding to subendothelial constituents and solubilized a 150-kD protein with SDS-urea that bound vWF. This protein had an amino-acid composition similar to that of the type VI collagen alpha-1/alpha-2 chains, was recognized by specific polyclonal antibodies against type VI collagen, and had a similar acidic isoelectric point. Furthermore, we found that purified type VI collagen also bound vWF. Thus, we have identified the extracted 150-kD protein as type VI collagen. This protein may play a significant role in the binding of vWF to vascular subendothelium in vivo. Images PMID:2056120

  19. Internal tension in a collapsed polymer under shear flow and the connection to enzymatic cleavage of von Willebrand factor.

    PubMed

    Radtke, Matthias; Lippok, Svenja; Rädler, Joachim O; Netz, Roland R

    2016-03-01

    By means of Brownian hydrodynamics simulations we show that the tension distribution along the contour of a single collapsed polymer in shear flow is inhomogeneous and above a threshold shear rate exhibits a double-peak structure when hydrodynamic interactions are taken into account. We argue that the tension maxima close to the termini of the polymer chain reflect the presence of polymeric protrusions. We establish the connection to shear-induced globule unfolding and determine the scaling behavior of the maximal tensile forces and the average protrusion length as a function of shear rate, globule size, and cohesive strength. A quasi-equilibrium theory is employed in order to describe the simulation results. Our results are used to explain experimental data for the shear-sensitive enzymatic degradation of von Willebrand factor. PMID:26993993

  20. A genetically-engineered von Willebrand disease type 2B mouse model displays defects in hemostasis and inflammation

    PubMed Central

    Adam, Frédéric; Casari, Caterina; Prévost, Nicolas; Kauskot, Alexandre; Loubière, Cécile; Legendre, Paulette; Repérant, Christelle; Baruch, Dominique; Rosa, Jean-Philippe; Bryckaert, Marijke; de Groot, Philip G.; Christophe, Olivier D.; Lenting, Peter J.; Denis, Cécile V.

    2016-01-01

    von Willebrand disease (VWD)-type 2B is characterized by gain-of-function mutations in the von Willebrand factor (VWF) A1-domain, leading to increased affinity for its platelet-receptor, glycoprotein Ibα. We engineered the first knock-in (KI) murine model for VWD-type 2B by introducing the p.V1316M mutation in murine VWF. Homozygous KI-mice replicated human VWD-type 2B with macrothrombocytopenia (platelet counts reduced by 55%, platelet volume increased by 44%), circulating platelet-aggregates and a severe bleeding tendency. Also, vessel occlusion was deficient in the FeCl3-induced thrombosis model. Platelet aggregation induced by thrombin or collagen was defective for KI-mice at all doses. KI-mice manifested a loss of high molecular weight multimers and increased multimer degradation. In a model of VWF-string formation, the number of platelets/string and string-lifetime were surprisingly enhanced in KI-mice, suggesting that proteolysis of VWF/p.V1316M is differentially regulated in the circulation versus the endothelial surface. Furthermore, we observed increased leukocyte recruitment during an inflammatory response induced by the reverse passive Arthus reaction. This points to an active role of VWF/p.V1316M in the exfiltration of leukocytes under inflammatory conditions. In conclusion, our genetically-engineered VWD-type 2B mice represent an original model to study the consequences of spontaneous VWF-platelet interactions and the physiopathology of this human disease. PMID:27212476

  1. Mutation in the gene encoding the. alpha. chain of platelet glycoprotein Ib in platelet-type von Willebrand disease

    SciTech Connect

    Miller, J.L.; Cunningham, D.; Lyle, V.A.; Finch, C.N. )

    1991-06-01

    Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor (vWF) by patient platelets. Although the platelet glycoprotein (GP) Ib/IX complex is known to constitute the platelet's ristocetin-dependent receptor for vWF, a unique structural abnormality within this complex has not previously been identified in PT-vWD. Using the poly merase chain reaction to amplify genomic DNA coding for the {alpha} chain of GP Ib (GP IB{alpha}) and then sequencing the amplified DNA following cloning into M13mp18 and M13mp19 phage vectors, the authors have found a single point mutation in the GP Ib{alpha} coding region of PT-vWD DNA resulting in the substitution of valine for glycine at residue 233. This substitution within the vWF-binding region of GP Ib{alpha} is likely to exert a significant influence on the conformation of the resulting protein. Competitive oligonucleotide primer assay for this mutation showed a homozygous wild-type pattern in genomic DNA from the 161 normal volunteers studied and from 6 phenotypically normal members of a PT-vWD family. All 7 affected members of this family studied were heterozygous for the mutant allele. Platelet GP Ib{alpha} mRNA reverse-transcribed and studied by competitive oligonucleotide primer assay showed similar expression of the mutant and wild-type alleles in the affected PT-vWD patients. Absence in the normal population, tight linkage with phenotypic expression of disease, and absence of any additional abnormality of GP Ib{alpha} in these patients identify the glycine-to-valine substitution as a point mutation underlying functional abnormality of the vWF receptor in PT-vWD.

  2. Validation of a von Willebrand factor antigen enzyme-linked immunosorbent assay and newly developed collagen-binding assay

    PubMed Central

    Burgess, Hilary; Wood, Darren

    2008-01-01

    No single test is comprehensive enough to detect all of the variants of von Willebrand Disease (VWD), making determination of both concentration and function of von Willebrand Factor (VWF) important for an accurate diagnosis. The objective of the study was to validate a newly developed VWF collagen binding assay (VWF:CB) and VWF antigen enzyme-linked immunosorbent assay (ELISA) developed at the Ontario Veterinary College (OVC VWF:Ag). Linearity, sensitivity, and coefficients of variation were determined. The Asserachrom VWF:Ag ELISA was used as the reference assay for this study. Concordance correlation and Bland-Altman plots were used to evaluate agreement between both VWF:Ag assays. The VWF:CB accuracy was assessed by degree of association with the VWF:Ag assays, and the VWF:Ag to VWF:CB ratio. All assays were assessed for their ability to distinguish between VWD negative and VWD positive patients. Linearity, intra-assay coefficients of variation, and inter-assay coefficients of variation were acceptable for both the newly developed VWF:CB (R2 = 0.97, average CV = 4.4, and 15, respectively) and OVC VWF:Ag assays (R2 = 0.96, average CV = 7.9, and 5.9, respectively). Agreement between the OVC VWF:Ag assay and reference assay was excellent (ρc = 0.89), and although differences between assay results precluded interchangeable use of the assays, both successfully distinguished VWD positive and VWD negative dogs (P < 0.0001). The VWF:CB showed a strong association with both VWF:Ag assays (R2 = 0.86, 0.82) and VWF:Ag to VWF:CB ratios (≤ 1) were as expected. The excellent performance of both assays in this validation study confirm their reliability and potential for clinical application. PMID:19086374

  3. A genetically-engineered von Willebrand disease type 2B mouse model displays defects in hemostasis and inflammation.

    PubMed

    Adam, Frédéric; Casari, Caterina; Prévost, Nicolas; Kauskot, Alexandre; Loubière, Cécile; Legendre, Paulette; Repérant, Christelle; Baruch, Dominique; Rosa, Jean-Philippe; Bryckaert, Marijke; de Groot, Philip G; Christophe, Olivier D; Lenting, Peter J; Denis, Cécile V

    2016-01-01

    von Willebrand disease (VWD)-type 2B is characterized by gain-of-function mutations in the von Willebrand factor (VWF) A1-domain, leading to increased affinity for its platelet-receptor, glycoprotein Ibα. We engineered the first knock-in (KI) murine model for VWD-type 2B by introducing the p.V1316M mutation in murine VWF. Homozygous KI-mice replicated human VWD-type 2B with macrothrombocytopenia (platelet counts reduced by 55%, platelet volume increased by 44%), circulating platelet-aggregates and a severe bleeding tendency. Also, vessel occlusion was deficient in the FeCl3-induced thrombosis model. Platelet aggregation induced by thrombin or collagen was defective for KI-mice at all doses. KI-mice manifested a loss of high molecular weight multimers and increased multimer degradation. In a model of VWF-string formation, the number of platelets/string and string-lifetime were surprisingly enhanced in KI-mice, suggesting that proteolysis of VWF/p.V1316M is differentially regulated in the circulation versus the endothelial surface. Furthermore, we observed increased leukocyte recruitment during an inflammatory response induced by the reverse passive Arthus reaction. This points to an active role of VWF/p.V1316M in the exfiltration of leukocytes under inflammatory conditions. In conclusion, our genetically-engineered VWD-type 2B mice represent an original model to study the consequences of spontaneous VWF-platelet interactions and the physiopathology of this human disease. PMID:27212476

  4. Cost–consequence analysis of long-term prophylaxis in the treatment of von Willebrand disease in the Italian context

    PubMed Central

    Schinco, Piercarla; Cultrera, Dorina; Valeri, Federica; Borchiellini, Alessandra; Mantuano, Michela; Gorla, Francesca; Savarese, Alessia; Teruzzi, Cristina

    2015-01-01

    Purpose Prophylaxis with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is a potential approach for patients with severe von Willebrand disease (VWD). As far as we are aware, to date there have been no pharmacoeconomic analyses in order to assess the economic impact of treatments for severe VWD. The analysis presented here estimates the cost–benefit ratio of VWF with a low FVIII content when compared with VWF/FVIII concentrates currently used in Italy for long-term prophylaxis in patients with severe VWD. Methods A cost–consequence analysis was undertaken to assess the economic impact of the treatment of severe VWD from the perspective both of the Italian National Health Service and society. The analysis was based on four case reports of long-term prophylaxis with VWD with VWF/FVIII concentrates and VWF with a low FVIII content. The costs per patient included direct and indirect costs for each treatment. Results Considering the four case reports, health care costs (without cost of treatment) and indirect costs per patient per year were lower with VWF with a low FVIII content than VWF/FVIII concentrates. The total health care costs (without cost of treatment) and indirect costs avoided with VWF with a low FVIII content per patient per year ranged from €2,295 to €17,530 and from €1,867 to €4,978, respectively. Conclusion VWF with a low FVIII content seems to be a cost-effective treatment option for patients with severe VWD. Although the drug cost per se is higher, the use of VWF with a low FVIII content is associated with decreased consumption of hospital resources and fewer lost working days due to bleedings and consequently with an improvement of the quality of life of the patients. PMID:25565871

  5. Loss of cysteine 584 impairs the storage and release, but not the synthesis of von Willebrand factor.

    PubMed

    Daidone, V; Barbon, G; Pontara, E; Cattini, G M; Gallinaro, L; Zampese, E; Pizzo, P; Casonato, A

    2014-12-01

    Cysteines play a key part in von Willebrand factor (VWF) dimerisation and polymerisation, and their loss may severely affect VWF structure and function. We report on three patients with type 3 von Willebrand disease carrying the new c.1751G>T missense mutation that induces the substitution of cysteine 584 by phenylalanine (C584F), and the deletion of seven nucleotides in exon 7 (c.729_735del), producing a premature stop codon at position 454 (E244Lfs*211). VWF was almost undetectable in the patients' plasma and platelets, while a single, poorly represented, oligomer emerged on plasma VWF multimer analysis. No post-DDAVP increase in VWF and factor VIII was observed. Expressing human recombinant C584F-VWF in HEK293T cells showed that C584F-VWF was synthesised and multimerised but not secreted - apart from the first oligomer, which was slightly represented in the conditioned medium, with a pattern similar to the patients' plasma VWF. The in vitro expression of the E244Lfs*211-VWF revealed a defective synthesis of the mutated VWF, with a behavior typical of loss of function mutations. Cellular trafficking, investigated in HEK293 cells, indicated a normal C584F-VWF content in the endoplasmic reticulum and Golgi apparatus, confirming the synthesis and multimerisation of C584F-VWF. No pseudo-Weibel Palade bodies were demonstrable, however, suggesting that C584F mutation impairs the storage of C584F-VWF. These findings point to cysteine 584 having a role in the release of VWF and its targeting to pseudo-Weibel Palade bodies in vitro, as well as in its storage and release by endothelial cells in vivo. PMID:25230768

  6. [Perioperative therapy of von Willebrand disease. Demonstration of pathophysiology, clinical problems and therapy options using two case reports].

    PubMed

    Kleinschmidt, S; Fuchs-Buder, T; Wilhelm, W; Seyfert, U T; Mörsdorf, S

    2002-10-01

    Von Willebrand disease (vWD) is the most widespread inherited bleeding disorder caused by quantitative or qualitative abnormalities of von Willebrand factor (vWF), an adhesive glycoprotein found in blood plasma and platelets and participating in primary and secondary/endothelium haemostasis as well. Although bleeding symptoms are often mild or moderate, patients with vWD represent a very heterogenous group with different phenotypes and a wide variability of the clinical pattern. In accordance with different defects of vWF, vWD is classified into various types and subtypes. This is illustrated by two case reports of patients with different types of vWD. Two main therapeutic options are available for the prevention and treatment of bleeding: desmopressin (DDAVP) and replacement therapy with plasma concentrates containing both factor VIII and vWF. DDAVP is the treatment of choice for most patients with type 1, representing about 80% of all patients with vWD. In patients with most types of type 2 and in all patients of type 3, DDAVP alone is ineffective or even contraindicated, and it is usually necessary to switch to plasma concentrates. Although treatment of vWD seems to be relatively simple in most cases, the exact diagnosis and phenotype characterization requires specialized or expert laboratory facilities. Furthermore, no reliable screening method for the diagnosis of vWD exists. Acquired vWD has similar clinical features and laboratory findings to the congenital forms and is mostly associated with lymphoproliferative or autoimmune disorders or neoplasia. PMID:12395174

  7. Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease. Results of a cohort study.

    PubMed

    Halimeh, Susan; Krümpel, Anne; Rott, Hannelore; Bogdanova, Nadja; Budde, Ulrich; Manner, Daniela; Faeser, Britta; Mesters, Rolf; Nowak-Göttl, Ulrike

    2011-04-01

    In patients with von Willebrand disease (VWD) replacement therapy with factor VIII/von Willebrand (VWF) concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes (spontaneous, peri- or postoperative) were diagnosed with VWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. In all patients, decision for initiating prophylaxis was based on a bleeding score > 2 prior to diagnosis, concomitant with recurrent bleeds associated with anaemia in patients with on-demand VWD therapy. We report results on secondary prophylactic VWF replacement therapy applied in 32 patients [children n=13; adolescents n=7; adults n=12] with VWD [type 1: 4; type 2: 15; type 3: 13], 15 of which were females, and nine of these at the reproductive period. Eight patients were treated with Humate P® or Wilate® (n=24). Median [min-max] dose [vWF:RCo] was 40 [20-47] IU/kg, 23 patients were given substitution therapy twice weekly, seven patients three times a week, and two children four times per week. Within a 12-month-period haemoglobin concentrations returned to normal values. Median duration of prophylaxis was three years. Recurrent bleeding episodes stopped in 31 of 32 patients, whereas inhibitors developed in one. Following a 12-month observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the pre-prophylaxis/pre-diagnostic values. The use of secondary prophylactic VWF replacement therapy is an effective tolerated treatment modality, highly beneficial for patients with VWD, who present with recurrent bleeding events during on-demand therapy. PMID:21301780

  8. von Willebrand Factor-Rich Platelet Thrombi in the Liver Cause Sinusoidal Obstruction Syndrome following Oxaliplatin-Based Chemotherapy

    PubMed Central

    Nishigori, Naoto; Matsumoto, Masanori; Koyama, Fumikazu; Hayakawa, Masaki; Hatakeyayama, Kinta; Ko, Saiho; Fujimura, Yoshihiro; Nakajima, Yoshiyuki

    2015-01-01

    Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC). Sinusoidal obstruction syndrome (SOS) due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI) in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs) from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF) and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6) and without (n = 17) bevacizumab were analyzed. CALI (n = 6) and splenomegaly (n = 9) were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag) and serum aspartate aminotransferase (AST) levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9), but not in patients without splenomegaly (n = 14). Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin-based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation. PMID:26580395

  9. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture.

    PubMed

    Veyradier, Agnès; Boisseau, Pierre; Fressinaud, Edith; Caron, Claudine; Ternisien, Catherine; Giraud, Mathilde; Zawadzki, Christophe; Trossaert, Marc; Itzhar-Baïkian, Nathalie; Dreyfus, Marie; d'Oiron, Roseline; Borel-Derlon, Annie; Susen, Sophie; Bezieau, Stéphane; Denis, Cécile V; Goudemand, Jenny

    2016-03-01

    von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50 IU/dL). The French reference center for VWD performed a laboratory phenotypic and genotypic analysis in 1167 VWD patients (670 families) selected by their basic biologic phenotype: type 3, type 2, and type 1 with VWF levels <30 IU/dL. In these patients indeed, to achieve an accurate diagnosis of VWD type and subtype is crucial for the management (treatment and genetic counseling). A phenotype/genotype correlation was present in 99.3% of cases; 323 distinct VWF sequence variations (58% of novel) were identified (missense 67% versus truncating 33%). The distribution of VWD types was: 25% of type 1, 8% of type 3, 66% of type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% of undetermined type. Type 1 VWD was related either to a defective synthesis/secretion or to an accelerated clearance of VWF. In type 3 VWD, bi-allelic mutations of VWF were found in almost all patients. In type 2A, the most frequent mechanism was a hyper-proteolysis of VWF. Type 2B showed 85% of patients with deleterious mutations (distinct from type 2B New York). Type 2M was linked to a defective binding of VWF to platelet glycoprotein Ib or to collagen. Type 2N VWD included almost half type 2N/3. This biologic study emphasizes the complex mechanisms for both quantitative and qualitative VWF defects in VWD. In addition, this study provides a new epidemiologic picture of the most bleeding forms of VWD in which qualitative

  10. Identification and Characterization of Novel Variations in Platelet G-Protein Coupled Receptor (GPCR) Genes in Patients Historically Diagnosed with Type 1 von Willebrand Disease

    PubMed Central

    Leo, Vincenzo C.; Sabi, Essa; Cunningham, Margaret R.; Eikenboom, Jeroen C.; Lethagen, Stefan; Schneppenheim, Reinhard; Goodeve, Anne C.; Watson, Steve P.; Mundell, Stuart J.; Daly, Martina E.

    2015-01-01

    The clinical expression of type 1 von Willebrand disease may be modified by co-inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12) could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =), both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N) was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =). Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder. PMID:26630678

  11. Identification and Characterization of Novel Variations in Platelet G-Protein Coupled Receptor (GPCR) Genes in Patients Historically Diagnosed with Type 1 von Willebrand Disease.

    PubMed

    Stockley, Jacqueline; Nisar, Shaista P; Leo, Vincenzo C; Sabi, Essa; Cunningham, Margaret R; Eikenboom, Jeroen C; Lethagen, Stefan; Schneppenheim, Reinhard; Goodeve, Anne C; Watson, Steve P; Mundell, Stuart J; Daly, Martina E

    2015-01-01

    The clinical expression of type 1 von Willebrand disease may be modified by co-inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12) could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =), both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N) was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =). Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder. PMID:26630678

  12. The spider hemolymph clot proteome reveals high concentrations of hemocyanin and von Willebrand factor-like proteins.

    PubMed

    Sanggaard, Kristian W; Dyrlund, Thomas F; Bechsgaard, Jesper S; Scavenius, Carsten; Wang, Tobias; Bilde, Trine; Enghild, Jan J

    2016-02-01

    Arthropods include chelicerates, crustaceans, and insects that all have open circulation systems and thus require different properties of their coagulation system than vertebrates. Although the clotting reaction in the chelicerate horseshoe crab (Family: Limulidae) has been described in details, the overall protein composition of the resulting clot has not been analyzed for any of the chelicerates. The largest class among the chelicerates is the arachnids, which includes spiders, ticks, mites, and scorpions. Here, we use a mass spectrometry-based approach to characterize the spider hemolymph clot proteome from the Brazilian whiteknee tarantula, Acanthoscurria geniculata. We focused on the insoluble part of the clot and demonstrated high concentrations of proteins homologous to the hemostasis-related and multimerization-prone von Willebrand factor. These proteins, which include hemolectins and vitellogenin homologous, were previously identified as essential components of the hemolymph clot in crustaceans and insects. Their presence in the spider hemolymph clot suggests that the origin of these proteins' function in coagulation predates the split between chelicerates and mandibulata. The clot proteome reveals that the major proteinaceous component is the oxygen-transporting and phenoloxidase-displaying abundant hemolymph protein hemocyanin, suggesting that this protein also plays a role in clot biology. Furthermore, quantification of the peptidome after coagulation revealed the simultaneous activation of both the innate immune system and the coagulation system. In general, many of the identified clot-proteins are related to the innate immune system, and our results support the previously suggested crosstalk between immunity and coagulation in arthropods. PMID:26621385

  13. High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion.

    PubMed

    Chung, Dominic W; Chen, Junmei; Ling, Minhua; Fu, Xiaoyun; Blevins, Teri; Parsons, Scott; Le, Jennie; Harris, Jeff; Martin, Thomas R; Konkle, Barbara A; Zheng, Ying; López, José A

    2016-02-01

    The ability of von Willebrand factor (VWF) to initiate platelet adhesion depends on the number of monomers in individual VWF multimers and on the self-association of individual VWF multimers into larger structures. VWF self-association is accelerated by shear stress. We observed that VWF self-association occurs during adsorption of VWF onto surfaces, assembly of secreted VWF into hyperadhesive VWF strings on the endothelial surface, and incorporation of fluid-phase VWF into VWF fibers. VWF adsorption under static conditions increased with increased VWF purity and was prevented by a component of plasma. We identified that component as high-density lipoprotein (HDL) and its major apolipoprotein ApoA-I. HDL and ApoA-I also prevented VWF on the endothelium from self-associating into longer strands and inhibited the attachment of fluid-phase VWF onto vessel wall strands. Platelet adhesion to VWF fibers was reduced in proportion to the reduction in self-associated VWF. In a mouse model of thrombotic microangiopathy, HDL also largely prevented the thrombocytopenia induced by injection of high doses of human VWF. Finally, a potential role for ApoA-I in microvascular occlusion associated with thrombotic thrombocytopenic purpura and sepsis was revealed by the inverse relationship between the concentration of ApoA-I and that of hyperadhesive VWF. These results suggest that interference with VWF self-association would be a new approach to treating thrombotic disorders. PMID:26552698

  14. Expression of terminal alpha2-6-linked sialic acid on von Willebrand factor specifically enhances proteolysis by ADAMTS13.

    PubMed

    McGrath, Rachel T; McKinnon, Thomas A J; Byrne, Barry; O'Kennedy, Richard; Terraube, Virginie; McRae, Emily; Preston, Roger J S; Laffan, Mike A; O'Donnell, James S

    2010-04-01

    von Willebrand factor (VWF) multimeric composition is regulated in plasma by ADAMTS13. VWF deglycosylation enhances proteolysis by ADAMTS13. In this study, the role of terminal sialic acid residues on VWF glycans in mediating proteolysis by ADAMTS13 was investigated. Quantification and distribution of VWF sialylation was examined by sequential digestion and high-performance liquid chromatography analysis. Total sialic acid expression on VWF was 167nmol/mg, of which the majority (80.1%) was present on N-linked glycan chains. Enzymatic desialylation of VWF by alpha2-3,6,8,9 neuraminidase (Neu-VWF) markedly impaired ADAMTS13-mediated VWF proteolysis. Neu-VWF collagen binding activity was reduced to 50% (+/- 14%) by ADAMTS13, compared with 11% (+/- 7%) for untreated VWF. Despite this, Neu-VWF exhibited increased susceptibility to other proteases, including trypsin, chymotrypsin, and cathepsin B. VWF expressing different blood groups exhibit altered ADAMTS13 proteolysis rates (O > or = B > A > or = AB). However, ABO blood group regulation of ADAMTS13 proteolysis was ablated on VWF desialylation, as both Neu-O-VWF and Neu-AB-VWF were cleaved by ADAMTS13 at identical rates. These novel data show that sialic acid protects VWF against proteolysis by serine and cysteine proteases but specifically enhances susceptibility to ADAMTS13 proteolysis. Quantitative variation in VWF sialylation therefore represents a key determinant of VWF multimeric composition and, as such, may be of pathophysiologic significance. PMID:19965639

  15. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor

    PubMed Central

    Xiang, Yaozu; Cheng, Jijun; Wang, Dandan; Hu, Xiaoyue; Xie, Yi; Stitham, Jeremiah; Atteya, Gourg; Du, Jing; Tang, Wai Ho; Lee, Seung Hee; Leslie, Kristen; Spollett, Geralyn; Liu, Zejian; Herzog, Erica; Herzog, Raimund I.; Lu, Jun; Martin, Kathleen A.

    2015-01-01

    An elevated level of von Willebrand factor (VWF) in diabetic patients is associated with increased risk of thrombotic cardiovascular events. The underlying mechanism of how VWF expression is upregulated in diabetes mellitus is poorly understood. We now report that hyperglycemia-induced repression of microRNA-24 (miR-24) increases VWF expression and secretion in diabetes mellitus. In diabetic patients and diabetic mouse models (streptozotocin/high-fat diet-induced and db/db mice), miR-24 is reduced in both tissues and plasma. Knockdown of miR-24 in mice leads to increased VWF mRNA and protein levels and enhanced platelet tethering (spontaneous thrombosis). miR-24 tightly controls VWF levels through pleiotropic effects, including direct binding to the 3′ untranslated region of VWF and targeting FURIN and the histamine H1 receptor, known regulators of VWF processing and secretion in endothelial cells. We present a novel mechanism for miR-24 downregulation through hyperglycemia-induced activation of aldose reductase, reactive oxygen species, and c-Myc. These findings support a critical role for hyperglycemic repression of miR-24 in VWF-induced pathology. miR-24 represents a novel therapeutic target to prevent adverse thrombotic events in patients with diabetes mellitus. PMID:25814526

  16. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor.

    PubMed

    Xiang, Yaozu; Cheng, Jijun; Wang, Dandan; Hu, Xiaoyue; Xie, Yi; Stitham, Jeremiah; Atteya, Gourg; Du, Jing; Tang, Wai Ho; Lee, Seung Hee; Leslie, Kristen; Spollett, Geralyn; Liu, Zejian; Herzog, Erica; Herzog, Raimund I; Lu, Jun; Martin, Kathleen A; Hwa, John

    2015-05-28

    An elevated level of von Willebrand factor (VWF) in diabetic patients is associated with increased risk of thrombotic cardiovascular events. The underlying mechanism of how VWF expression is upregulated in diabetes mellitus is poorly understood. We now report that hyperglycemia-induced repression of microRNA-24 (miR-24) increases VWF expression and secretion in diabetes mellitus. In diabetic patients and diabetic mouse models (streptozotocin/high-fat diet-induced and db/db mice), miR-24 is reduced in both tissues and plasma. Knockdown of miR-24 in mice leads to increased VWF mRNA and protein levels and enhanced platelet tethering (spontaneous thrombosis). miR-24 tightly controls VWF levels through pleiotropic effects, including direct binding to the 3' untranslated region of VWF and targeting FURIN and the histamine H1 receptor, known regulators of VWF processing and secretion in endothelial cells. We present a novel mechanism for miR-24 downregulation through hyperglycemia-induced activation of aldose reductase, reactive oxygen species, and c-Myc. These findings support a critical role for hyperglycemic repression of miR-24 in VWF-induced pathology. miR-24 represents a novel therapeutic target to prevent adverse thrombotic events in patients with diabetes mellitus. PMID:25814526

  17. Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells

    PubMed Central

    Lopes da Silva, Mafalda; O'Connor, Marie N.; Kriston-Vizi, Janos; White, Ian J.; Al-Shawi, Raya; Simons, J. Paul; Mössinger, Julia; Haucke, Volker

    2016-01-01

    ABSTRACT Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function have been identified, the role of lipids is almost unknown. We examined two key phosphatidylinositol kinases that control phosphatidylinositol 4-phosphate levels at the trans-Golgi network, the site of WPB biogenesis. RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIα and PI4KIIβ in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. When stimulated with histamine, these cells release normal levels of VWF yet, under flow, form very few platelet-catching VWF strings. In PI4KIIα-deficient mice, immuno-microscopy revealed that VWF packaging is also perturbed and these mice exhibit increased blood loss after tail cut compared to controls. This is the first demonstration that lipid kinases can control the biosynthesis of VWF and the formation of WPBs that are capable of full haemostatic function. PMID:27068535

  18. von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

    PubMed Central

    Chauhan, Anil K.; Kisucka, Janka; Lamb, Colin B.; Bergmeier, Wolfgang

    2007-01-01

    von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using gene-targeted mice, we show that in ferric chloride–injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF−/− mice when compared with wild type (WT). We also observed increased embolization in the VWF−/− mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF−/− venules did not occlude. Transgenic platelets lacking the VWF receptor GPIbα extracellular domain showed decreased adhesion to injured veins. But, after a delay, all the injured venules occluded in these transgenic mice. Thus, VWF likely uses other adhesion receptors besides GPIbα in thrombus growth under venous shear conditions. Our studies document crucial roles for VWF and FVIII in experimental thrombosis under venous flow conditions in vivo. PMID:17119108

  19. Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells

    PubMed Central

    Ferraro, Francesco; Mafalda Lopes da, Silva; Grimes, William; Lee, Hwee Kuan; Ketteler, Robin; Kriston-Vizi, Janos; Cutler, Daniel F.

    2016-01-01

    Changes in the size of cellular organelles are often linked to modifications in their function. Endothelial cells store von Willebrand Factor (vWF), a glycoprotein essential to haemostasis in Weibel-Palade bodies (WPBs), cigar-shaped secretory granules that are generated in a wide range of sizes. We recently showed that forcing changes in the size of WPBs modifies the activity of this cargo. We now find that endothelial cells treated with statins produce shorter WPBs and that the vWF they release at exocytosis displays a reduced capability to recruit platelets to the endothelial cell surface. Investigating other functional consequences of size changes of WPBs, we also report that the endothelial surface-associated vWF formed at exocytosis recruits soluble plasma vWF and that this process is reduced by treatments that shorten WPBs, statins included. These results indicate that the post-exocytic adhesive activity of vWF towards platelets and plasma vWF at the endothelial surface reflects the size of their storage organelle. Our findings therefore show that changes in WPB size, by influencing the adhesive activity of its vWF cargo, may represent a novel mode of regulation of platelet aggregation at the vascular wall. PMID:27576551

  20. Circulating adhesion molecules ICAM-1, E-selectin, and von Willebrand factor in Henoch-Schönlein purpura.

    PubMed Central

    Söylemezoglu, O; Sultan, N; Gursel, T; Buyan, N; Hasanoglu, E

    1996-01-01

    Adhesion molecules play an important part in leucocyte transendothelial migration and thus may provide a useful marker of surface expression at inflammatory sites. In 20 patients with Henoch-Schönlein purpura serum intercellular adhesion molecule 1 (ICAM-1), E-selectin, and plasma von Willebrand factor (vWF) were determined by ELISA during the active and inactive phase of the disease. Twelve healthy children were studied as a control group. Serum ICAM-1 concentrations increased during the active phase of the disease and differed significantly compared with the inactive phase (p < 0.05). However ICAM-1 in the active phase did not differ significantly compared with controls (p = 0.08). Serum E-selectin concentrations did not differ in the active and inactive phase of the disease. By contrast, vWF increased in the active phase of the disease and differed significantly compared with inactive disease and control groups (p < 0.01). Considering the adhesion molecules and vWF, only vWF correlated well with the C reactive protein measurement in the active phase, which is considered a good marker of disease activity. These data suggest that plasma vWF is a good marker of vascular inflammation and endothelial damage. Circulating ICAM-1 might be an additional parameter in some of the patients. PMID:9014604

  1. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans.

    PubMed

    Bauer, Alexander T; Suckau, Jan; Frank, Kathrin; Desch, Anna; Goertz, Lukas; Wagner, Andreas H; Hecker, Markus; Goerge, Tobias; Umansky, Ludmila; Beckhove, Philipp; Utikal, Jochen; Gorzelanny, Christian; Diaz-Valdes, Nancy; Umansky, Viktor; Schneider, Stefan W

    2015-05-14

    Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation. PMID:25977583

  2. Acute hyperglycemia alters von Willebrand factor but not the fibrinolytic system in elderly subjects with normal or impaired glucose tolerance.

    PubMed

    Coppola, Ludovico; Coppola, Antonino; Grassia, Antonio; Mastrolorenzo, Luigia; Lettieri, Biagio; De Lucia, Domenico; De Nanzio, Annarita; Gombos, Giorgio

    2004-10-01

    To assess whether acute hyperglycemia affects fibrinolytic balance in elderly subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT), 40 non-obese elderly subjects (20 NGT, age 68 +/- 8 years; and 20 IGT, age 69 +/- 11 years) were studied. On two experimental days, randomly allocated and spaced 1 week apart, plasma concentrations of glucose, insulin, fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor type 1 and von Willebrand factor (vWF) were measured in each subject at baseline (0) and 30, 60, 90, 120 min after the ingestion of 75 g glucose or a similarly sweet dose of aspartame (250 mg) (control test). In both NGT and IGT elderly subjects, tissue plasminogen activator, plasminogen activator inhibitor type 1 and fibrinogen plasma levels did not significantly change after both oral aspartame and glucose load. In IGT subjects, vWF plasmatic levels decreased after glucose (not aspartame) oral load, reaching the minimum level at 90 min after load (82.7 +/- 7.8 versus 93.7 +/- 10.2, P <0.01). These results demonstrate that acute hyperglycemia does not modify plasma fibrinolysis in elderly subjects. The decrease of plasma concentration of vWF in IGT elderly subjects requires cautious interpretation and further extensive investigations. PMID:15613917

  3. Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells.

    PubMed

    Ferraro, Francesco; Mafalda Lopes da, Silva; Grimes, William; Lee, Hwee Kuan; Ketteler, Robin; Kriston-Vizi, Janos; Cutler, Daniel F

    2016-01-01

    Changes in the size of cellular organelles are often linked to modifications in their function. Endothelial cells store von Willebrand Factor (vWF), a glycoprotein essential to haemostasis in Weibel-Palade bodies (WPBs), cigar-shaped secretory granules that are generated in a wide range of sizes. We recently showed that forcing changes in the size of WPBs modifies the activity of this cargo. We now find that endothelial cells treated with statins produce shorter WPBs and that the vWF they release at exocytosis displays a reduced capability to recruit platelets to the endothelial cell surface. Investigating other functional consequences of size changes of WPBs, we also report that the endothelial surface-associated vWF formed at exocytosis recruits soluble plasma vWF and that this process is reduced by treatments that shorten WPBs, statins included. These results indicate that the post-exocytic adhesive activity of vWF towards platelets and plasma vWF at the endothelial surface reflects the size of their storage organelle. Our findings therefore show that changes in WPB size, by influencing the adhesive activity of its vWF cargo, may represent a novel mode of regulation of platelet aggregation at the vascular wall. PMID:27576551

  4. Cell type-specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor.

    PubMed

    Hough, Christine; Cuthbert, Carla D; Notley, Colleen; Brown, Christine; Hegadorn, Carol; Berber, Ergul; Lillicrap, David

    2005-02-15

    Mechanisms of tissue-restricted patterns of von Willebrand factor (VWF) expression involve activators and repressors that limit expression to endothelial cells and megakaryocytes. The relative transcriptional activity of the proximal VWF promoter was assessed in VWF-producing and -nonproducing cells, and promoter activity was highest in endothelial cells followed by megakaryocytes. Only basal VWF promoter activity was seen in nonendothelial cells. Here we identify a negative response element located at nucleotides (nts) +96/+105 and demonstrate, using chromatin immunoprecipitation (ChIP) analysis, that in vivo this sequence interacts with the E4BP4 transcriptional repressor. Differences in size and relative abundance of nuclear E4BP4 were observed. In HepG2 cells, low levels of larger forms of E4BP4 are present that directly interact with the negative response element. In VWF-expressing cells, high levels of smaller forms predominate with no evidence of direct DNA binding. However, in endothelial cells, mutation of the VWF E4BP4 binding motif not only restores but also further elevates VWF promoter activity, suggesting that E4BP4 may be part of a coordinated binding complex. These observations implicate this binding motif in repressing both activated and basal levels of VWF transcription by different cell type-specific mechanisms, and support the hypothesis that E4BP4 sequesters negative regulators of transcription, thereby enhancing activated gene expression. PMID:15498853

  5. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients.

    PubMed

    Auerswald, Günter; Spranger, Torsten; Brackmann, Hans-Hermann

    2003-06-01

    Besides preventing bleeding episodes, common goals of the treatment of hemophilia include integrating of patients into a normal social life and optimizing their quality of life. Sufficient amounts of factor VIII (FVIII) concentrates, whether recombinant or plasma-derived, are continuously needed. Guidelines for quality assurance of treatment will be a cornerstone to maintain optimal clinical management of patients especially considering financial aspects. Advances in manufacturing technologies have made possible general availability of modern concentrates for the management of hemophilia A patients. Safety, cost and continuous supply of concentrates must be considered when deciding on a product for replacement therapy. As todays' products have reached an excellent margin of safety with regard to virus transmission, the development and treatment of inhibitors is currently the main concern for physicians and patients. The incidence of inhibitors is influenced by various patient-related factors such as mutation type or severity of the disease. Plasma-derived FVIII concentrates containing von Willebrand factor (VWF) may have clinical advantages over pure FVIII concentrates with regard to inhibitor development and inhibitor eradication. Clinical trials comparing FVIII/VWF concentrates with pure FVIII concentrates are lacking, thus a lower inhibitor incidence has not yet been proven. Data from Germany on immune tolerance induction with FVIII/VWF concentrates indicate higher success rates with these than with pure FVIII concentrates. In addition FVIII/VWF concentrates are the therapy of choice when immune tolerance therapy with pure FVIII products is not successful. PMID:12826531

  6. Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review.

    PubMed

    Franchini, Massimo; Lippi, Giuseppe

    2010-11-01

    The development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients. PMID:20838738

  7. 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. PMID:8611460

  8. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease.

    PubMed

    Lak, M; Peyvandi, F; Mannucci, P M

    2000-12-01

    Type 3 is the most severe form of von Willebrand disease (VWD) transmitted as an autosomal recessive trait. We collected data on the clinical manifestations of type 3 VWD by examining 385 patients from 300 Iranian kindreds, who were compared with 100 age-matched patients with severe haemophilia A. Joint and muscle bleeding was less frequent than in haemophiliacs, perhaps because factor VIII levels were in general higher (median value 4% vs. 1% or less). Mucosal tract haemorrhages such as epistaxis and menorrhagia were the most prevalent symptoms in VWD. Post-circumcision and oral cavity bleeding occurred frequently when prophylactic replacement therapy was not carried out or was inadequate. The course of pregnancy was usually uneventful, but increased bleeding occurred at parturition when affected women were treated with replacement therapy for less than 3-4 d. Ten of 385 (2.6%) of these multitransfused patients developed an alloantibody to VWF and 55% are chronically infected with the hepatitis C virus. PMID:11167767

  9. Quantification of perioperative changes in von Willebrand factor and factor VIII during elective orthopaedic surgery in normal individuals

    PubMed Central

    Kahlon, A.; Grabell, J.; Tuttle, A.; Engen, D.; Hopman, W.; Lillicrap, D.; James, P.

    2014-01-01

    Summary von Willebrand’s disease (VWD) patients undergoing major surgery are prophylactically treated to promote haemostasis. There is variability in perioperative clinical practice; however, most guidelines suggest replacing the deficient factor to a level of 1.0 IU mL−1 (or 100%). A review of the literature reveals a paucity of well constructed descriptive data quantifying the changes in coagulation that occur in response to surgical stress. The aim of this study was to quantify the changes in haemostatic variables occurring in response to elective orthopaedic surgery in normal individuals. Eligible subjects >18 years of age undergoing total hip or knee replacement were recruited. Blood samples were drawn at five time points: baseline, preoperatively, 30 min after surgical incision, 30 min postoperatively, postoperative day (POD) 1. Analyses included t-tests and repeated measures anova. Overall 30 patients, 21 women and 9 men, with a mean age of 65 were included in the final analysis. All von Willebrand factor (VWF) variables were seen to significantly decrease intraoperatively and increase postoperatively. VWF multimers showed a statistically significant decrease in high molecular weight multimers intraoperatively and an increase postoperatively. On subgroup analysis, age, gender and anaesthesia type were significantly correlated with changes in VWF parameters. Data presented in the current study establish a physiological baseline for VWF parameters in the normal population and demonstrate mean VWF/factor VIII levels greater than 1.0 IU mL−1 intraoperatively. As such, current management in VWD patients does not appear to mimic the normal physiological response to surgery. PMID:23711418

  10. von Willebrand disease in a pediatric-based population--comparison of type 1 diagnostic criteria and use of the PFA-100 and a von Willebrand factor/collagen-binding assay.

    PubMed

    Dean, J A; Blanchette, V S; Carcao, M D; Stain, A M; Sparling, C R; Siekmann, J; Turecek, P L; Lillicrap, D; Rand, M L

    2000-09-01

    Definitive diagnosis of type 1 von Willebrand Disease (VWD) remains a problem. Provisional consensus guidelines for the diagnosis of definite and possible type 1 VWD were prepared by the Scientific Subcommittee on von Willebrand factor (VWF) of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) during the 1996 annual meeting for the specific purpose of further evaluation in retrospective and prospective studies by a Working Party on Diagnostic Criteria (1996 Annual Report of the SSC/ISTH Subcommittee on VWF). In the first phase of this study, we compared 2 definitions of type 1 VWD. each with 3 criteria: significant bleeding history, laboratory investigations, and family history. Using the ISTH consensus guidelines for type 1 VWD definition, significantly fewer patients were diagnosed with definite type 1 disease as compared to our "in house" Hospital for Sick Children (HSC) criteria (4 vs. 31). While we recognize that the provisional ISTH consensus guidelines were not intended for clinical use, we believe that the results of our studies are of interest and will assist in any future refinements to the ISTH guidelines. In the second phase of this study, we investigated the utility of 2 new tests, a laboratory screening test and a functional test, for VWD in our well characterized, pediatric-based population. The Platelet Function Analyzer (PFA-100) provides an in vitro measure of primary hemostasis under conditions of high shear, using disposable cartridges containing collagen and either epinephrine or ADP. All tested subjects with types 2 or 3 VWD had prolonged PFA-100 closure times (CTs) with both cartridge types (n = 17) and prolonged bleeding times (n = 14). In subjects with definite type 1 VWD, 20/24 (83%) had prolonged CTs with the collagen/ADP cartridge (19/24 (79%) with collagen/epinephrine), compared with 7/26 (27%) with prolonged bleeding times. In subjects with definite types 1, 2, or 3 VWD

  11. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA).

    PubMed

    Nichols, W L; Hultin, M B; James, A H; Manco-Johnson, M J; Montgomery, R R; Ortel, T L; Rick, M E; Sadler, J E; Weinstein, M; Yawn, B P

    2008-03-01

    von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child-bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence-based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information. PMID:18315614

  12. Gene silencing of endothelial von Willebrand Factor attenuates angiotensin II-induced endothelin-1 expression in porcine aortic endothelial cells.

    PubMed

    Dushpanova, Anar; Agostini, Silvia; Ciofini, Enrica; Cabiati, Manuela; Casieri, Valentina; Matteucci, Marco; Del Ry, Silvia; Clerico, Aldo; Berti, Sergio; Lionetti, Vincenzo

    2016-01-01

    Expression of endothelin (ET)-1 is increased in endothelial cells exposed to angiotensin II (Ang II), leading to endothelial dysfunction and cardiovascular disorders. Since von Willebrand Factor (vWF) blockade improves endothelial function in coronary patients, we hypothesized that targeting endothelial vWF with short interference RNA (siRNA) prevents Ang II-induced ET-1 upregulation. Nearly 65 ± 2% silencing of vWF in porcine aortic endothelial cells (PAOECs) was achieved with vWF-specific siRNA without affecting cell viability and growth. While showing ET-1 similar to wild type cells at rest, vWF-silenced cells did not present ET-1 upregulation during exposure to Ang II (100 nM/24 h), preserving levels of endothelial nitric oxide synthase activity similar to wild type. vWF silencing prevented AngII-induced increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity and superoxide anion (O2-) levels, known triggers of ET-1 expression. Moreover, no increase in O2- or ET-1 levels was found in silenced cells treated with AngII or NOX-agonist phorbol ester (PMA 5 nM/48 h). Finally, vWF was required for overexpression of NOX4 and NOX2 in response to AngII and PMA. In conclusion, endothelial vWF knockdown prevented Ang II-induced ET-1 upregulation through attenuation of NOX-mediated O2- production. Our findings reveal a new role of vWF in preventing of Ang II-induced endothelial dysfunction. PMID:27443965

  13. Molecular Imaging of Platelet-Endothelial Interactions and Endothelial Von Willebrand Factor In Early and Mid-Stage Atherosclerosis

    PubMed Central

    Shim, Chi Young; Liu, Ya Ni; Atkinson, Tamara; Xie, Aris; Foster, Ted; Davidson, Brian P.; Treible, Mackenzie; Qi, Yue; López, José A.; Munday, Adam; Ruggeri, Zaverio; Lindner, Jonathan R.

    2015-01-01

    Background Non-thrombotic platelet-endothelial interactions may contribute to atherosclerotic plaque development, although in vivo studies examining mechanism without platelet pre-activation are lacking. Using in vivo molecular imaging at various stages of atherosclerosis, we quantified platelet-endothelial interactions and evaluated the contribution of major adhesion pathways. Methods and Results Mice deficient for the LDL-receptor and Apobec-1 were studied as an age-dependent model of atherosclerosis at 10, 20, 30, and 40 wks of age, which provided progressive increase in stage from very early fatty streak (10 wks) to large complex plaques without rupture (40 wks). Platelet-targeted contrast ultrasound molecular imaging of the thoracic aorta performed with microbubbles targeted to GPIbα demonstrated selective signal enhancement as early as 10 weeks of age. This signal increased progressively with age (almost 8-fold increase from 10 to 40 weeks, ANOVA p<0.001). Specificity for platelet targeting was confirmed by the reduction in platelet-targeted signal commensurate with the decrease in platelet count after immunodepletion with anti-GPIb or anti-CD41 antibody. Inhibition of P-selectin in 20 and 40 wk atherosclerotic mice resulted in a small (15-30%) reduction in platelet signal. Molecular imaging with microbubbles targeted to the A1 domain of von Willebrand factor (VWF) demonstrated selective signal enhancement at all time points which did not significantly increase with age. Treatment of 20 and 40 week mice with recombinant ADAMTS13 eliminated platelet and VWF molecular imaging signal. Conclusions Platelet-endothelial interactions occur in early atherosclerosis. These interactions are in part due to endothelial VWF large multimers which can be reversed with exogenous ADAMTS13. PMID:26156014

  14. Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey.

    PubMed

    Stoof, S C M; van Steenbergen, H W; Zwagemaker, A; Sanders, Y V; Cannegieter, S C; Duvekot, J J; Leebeek, F W G; Peters, M; Kruip, M J H A; Eikenboom, J

    2015-07-01

    Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are <0.50 IU mL(-1) , prophylactic treatment is indicated and administered according to international guidelines. However, optimal dose and duration are unknown and bleeding may still occur. The aim of this study was to investigate the outcome in women with von Willebrand disease (VWD) or haemophilia carriership treated according to current practice guidelines. From the period 2002-2011, 185 deliveries in 154 VWD women or haemophilia carriers were retrospectively included. Data on blood loss, bleeding disorder characteristics and obstetric risk factors were obtained. The outcome was primary PPH, defined as blood loss ≥500 mL within 24 h postpartum and severe PPH as blood loss ≥1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL(-1) cut-off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2-6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population. PMID:25688733

  15. von Willebrand factor (VWF) propeptide binding to VWF D′D3 domain attenuates platelet activation and adhesion

    PubMed Central

    Madabhushi, Sri R.; Shang, Chengwei; Dayananda, Kannayakanahalli M.; Rittenhouse-Olson, Kate; Murphy, Mary; Ryan, Thomas E.; Montgomery, Robert R.

    2012-01-01

    Noncovalent association between the von Willebrand factor (VWF) propeptide (VWFpp) and mature VWF aids N-terminal multimerization and protein compartmentalization in storage granules. This association is currently thought to dissipate after secretion into blood. In the present study, we examined this proposition by quantifying the affinity and kinetics of VWFpp binding to mature VWF using surface plasmon resonance and by developing novel anti-VWF D′D3 mAbs. Our results show that the only binding site for VWFpp in mature VWF is in its D′D3 domain. At pH 6.2 and 10mM Ca2+, conditions mimicking intracellular compartments, VWFpp-VWF binding occurs with high affinity (KD = 0.2nM, koff = 8 × 10−5 s−1). Significant, albeit weaker, binding (KD = 25nM, koff = 4 × 10−3 s−1) occurs under physiologic conditions of pH 7.4 and 2.5mM Ca2+. This interaction was also observed in human plasma (KD = 50nM). The addition of recombinant VWFpp in both flow-chamber–based platelet adhesion assays and viscometer-based shear-induced platelet aggregation and activation studies reduced platelet adhesion and activation partially. Anti-D′D3 mAb DD3.1, which blocks VWFpp binding to VWF-D′D3, also abrogated platelet adhesion, as shown by shear-induced platelet aggregation and activation studies. Our data demonstrate that VWFpp binding to mature VWF occurs in the circulation, which can regulate the hemostatic potential of VWF by reducing VWF binding to platelet GpIbα. PMID:22452980

  16. Minimum wound size for clotting: flowing blood coagulates on a single collagen fiber presenting tissue factor and von Willebrand factor.

    PubMed

    Zhu, Shu; Tomaiuolo, Maurizio; Diamond, Scott L

    2016-08-01

    It is unknown if a lower size limit exists for human blood coagulation under flow over physiological vessel wall triggers as small as a single collagen fiber. Prior determinations of the smallest sized surface stimuli necessary for clotting of human blood, defined as the patch size threshold, have not deployed whole blood, hemodynamic flow, and platelet adhesive stimuli. For whole blood perfused in microfluidic devices, we report that steady venous flow (wall shear rate, 100 s(-1)) was sufficient to drive platelet deposition on 20 micron long zones of collagen fibers or on a single fiber. With tissue factor (TF)-coated collagen, flowing blood generated robust platelet deposits, platelet-localized thrombin, and fibrin on a single collagen fiber, thus demonstrating the absence of a physiological patch size threshold under venous flow. In contrast, at arterial wall shear rate (1000 s(-1)) with TF present, essentially no platelet or fibrin deposition occurred on 20 micron collagen zones or on a single collagen fiber, demonstrating a patch threshold, which was overcome by pre-coating the collagen with von Willebrand factor (vWF). For venous flows, human blood can clot on one of the smallest biological units of a single collagen fiber presenting TF. For arterial flows, vWF together with TF allows human blood to generate thrombin and fibrin on a patch stimulus as limited as a single collagen fiber. vWF-dependent platelet adhesion represents a particle-based sensing mechanism of micron-scale stimuli that then allows amplification of the molecular components of TF-driven thrombin and fibrin production under arterial flow. PMID:27339024

  17. Direct observation of von Willebrand factor elongation and fiber formation on collagen during acute whole blood exposure to pathological flow

    PubMed Central

    Colace, T. V.; Diamond, S. L.

    2013-01-01

    Objective In severe stenosis, von Willebrand Factor (vWF) experiences millisecond exposures to pathological wall shear rates (γw). We sought to evaluate the deposition of vWF onto collagen surfaces under flow in these environments. Methods and Results Distinct from shear experiments that last many seconds, we deployed microfluidic devices for single-pass perfusion of whole blood or platelet free plasma (PFP) over fibrillar type 1 collagen (< 50 msec transit time) at pathological γw or spatial wall shear rate gradient (grad γw). Using fluorescent anti-vWF, long thick vWF fibers (>20 μm) bound to collagen were visualized at constant γw > 30,000 s−1 during perfusion of PFP, a process enhanced by EDTA. Rapid acceleration or deceleration of EDTA-PFP at grad γw = ± 5.5 × 105 to 4.3 × 107 s−1/cm did not promote vWF deposition. At 19,400 s−1, EDTA-blood perfusion resulted in rolling vWF-platelet nets, while blood perfusion (normal Ca2+) generated large vWF/platelet deposits that repeatedly embolized and were blocked by anti-GPIb or the α IIbβ3 inhibitor GR144053 and did not require grad γw. Blood perfusion at venous shear rate (200 s−1) produced a stable platelet deposit that was a substrate for massive but unstable vWF-platelet aggregates when flow was increased to 7800 s−1. Conclusion Triggered by collagen and enhanced by platelet GPIb and α IIbβ3, vWF fiber formation occurred during acute exposures to pathological γw and did not require gradients in wall shear rate. PMID:23104847

  18. Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis.

    PubMed

    Kastritis, Efstathios; Papassotiriou, Ioannis; Terpos, Evangelos; Roussou, Maria; Gavriatopoulou, Maria; Komitopoulou, Anna; Skevaki, Chrysanthi; Eleutherakis-Papaiakovou, Evangelos; Pamboucas, Constantinos; Psimenou, Erasmia; Manios, Efstathios; Giannouli, Stavroula; Politou, Marianna; Gakiopoulou, Harikleia; Papadopoulou, Elektra; Stamatelopoulos, Kimon; Tasidou, Anna; Dimopoulos, Meletios A

    2016-07-21

    Cardiac dysfunction determines prognosis in amyloid light-chain (AL) amyloidosis. The heart is the central organ of the vascular system in which endothelium function is critical for the circulatory homeostasis, but there are limited data on endothelial function in AL amyloidosis. von Willebrand factor (VWF) has been considered as a marker of endothelial activation and dysfunction, whereas a disintegrin and metalloproteinase with thrombospondin type-1 repeats 13 (ADAMTS-13) cleaves VWF multimers, but both have been associated with prognosis in cardiovascular disease. We measured the serum levels of VWF (VWF:Ag) and ADAMTS-13 antigens in 111 newly diagnosed patients with AL amyloidosis. The levels of VWF:Ag were significantly higher than in healthy controls; 76% of patients with AL had VWF:Ag levels higher than the upper levels of controls. There was no significant association of VWF:Ag levels with patterns of organ involvement, free light-chain levels, the levels of cardiac biomarkers, or renal dysfunction but correlated with low systolic blood pressure. VWF:Ag levels ≥230.0 U/dL were associated with higher probability of early death and poor survival independently of cardiac biomarkers and low systolic blood pressure (SBP). Moreover, among patients with Mayo stage III or stage IIIB (that is stage III with N-terminal pro-brain natriuretic peptide [NTproBNP] >8500 pg/mL) disease, VWF:Ag identified subgroups of patients with very poor outcome. Low ADAMTS-13 levels correlated with high levels of NTproBNP but had no independent prognostic significance. In conclusion, high VWF:Ag levels, probably representing endothelial dysfunction, are associated with prognosis in patients with AL amyloidosis, independently of other features of the disease or cardiac biomarkers. PMID:27166361

  19. Gene silencing of endothelial von Willebrand Factor attenuates angiotensin II-induced endothelin-1 expression in porcine aortic endothelial cells

    PubMed Central

    Dushpanova, Anar; Agostini, Silvia; Ciofini, Enrica; Cabiati, Manuela; Casieri, Valentina; Matteucci, Marco; Del Ry, Silvia; Clerico, Aldo; Berti, Sergio; Lionetti, Vincenzo

    2016-01-01

    Expression of endothelin (ET)-1 is increased in endothelial cells exposed to angiotensin II (Ang II), leading to endothelial dysfunction and cardiovascular disorders. Since von Willebrand Factor (vWF) blockade improves endothelial function in coronary patients, we hypothesized that targeting endothelial vWF with short interference RNA (siRNA) prevents Ang II-induced ET-1 upregulation. Nearly 65 ± 2% silencing of vWF in porcine aortic endothelial cells (PAOECs) was achieved with vWF-specific siRNA without affecting cell viability and growth. While showing ET-1 similar to wild type cells at rest, vWF-silenced cells did not present ET-1 upregulation during exposure to Ang II (100 nM/24 h), preserving levels of endothelial nitric oxide synthase activity similar to wild type. vWF silencing prevented AngII-induced increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity and superoxide anion (O2−) levels, known triggers of ET-1 expression. Moreover, no increase in O2− or ET-1 levels was found in silenced cells treated with AngII or NOX-agonist phorbol ester (PMA 5 nM/48 h). Finally, vWF was required for overexpression of NOX4 and NOX2 in response to AngII and PMA. In conclusion, endothelial vWF knockdown prevented Ang II-induced ET-1 upregulation through attenuation of NOX-mediated O2− production. Our findings reveal a new role of vWF in preventing of Ang II-induced endothelial dysfunction. PMID:27443965

  20. Domain-and species-specific monoclonal antibodies recognize the Von Willebrand Factor-C domain of CCN5.

    PubMed

    Wei, Lan; McKeon, Frank; Russo, Joshua W; Lemire, Joan; Castellot, John

    2009-03-01

    The CCN family of proteins typically consists of four distinct peptide domains: an insulin-like growth factor binding protein-type (IGFBP) domain, a Von Willebrand Factor C (VWC) domain, a thrombospondin type 1 repeat (TSP1) domain, and a carboxy-terminal (CT) domain. The six family members participate in many processes, including proliferation, motility, cell-matrix signaling, angiogenesis, and wound healing. Accumulating evidence suggests that truncated and alternatively spliced isoforms are responsible for the diverse functions of CCN proteins in both normal and pathophysiologic states. Analysis of the properties and functions of individual CCN domains further corroborates this idea. CCN5 is unique among the CCN family members because it lacks the CT-domain. To dissect the domain functions of CCN5, we are developing domain-specific mouse monoclonal antibodies. Monoclonal antibodies have the advantages of great specificity, reproducibility, and ease of long-term storage and production. In this communication, we injected mixtures of GST-fused rat CCN5 domains into mice to generate monoclonal antibodies. To identify the domains recognized by the antibodies, we constructed serial expression plasmids that express dual-tagged rat CCN5 domains. All of the monoclonal antibodies generated to date recognize the VWC domain, indicating it is the most highly immunogenic of the CCN5 domains. We characterized one particular clone, 22H10, and found that it recognizes mouse and rat CCN5, but not human recombinant CCN5. Purified 22H10 was successfully applied in Western Blot analysis, immunofluorescence of cultured cells and tissues, and immunoprecipitation, indicating that it will be a useful tool for domain analysis and studies of mouse-human tumor models. PMID:19401828

  1. Immunohistochemistry of von Willebrand factor in the lungs with regard to the cause of death in forensic autopsy.

    PubMed

    Quan, Li; Ishikawa, Takaki; Zhao, Dong; Michiue, Tomomi; Yoshida, Chiemi; Chen, Jian-hua; Wang, Qi; Zhu, Bao-Li; Maeda, Hitoshi

    2009-04-01

    Pulmonary microvascular injury is involved in severe trauma or disease. The present study investigated the immunohistochemical distribution of von Willebrand factor (vWF) and platelet CD61 factor in forensic autopsy cases (n=157, >18 years of age, within 48 h postmortem), which comprised fatalities from blunt and sharp instrument injuries, strangulation, fire fatality and acute cardiac death (ACD). vWF immunoreactivity was clearly detected in the endothelia of large vessels (LV, phi>200 microm), small vessels (SV, phi 40-200 microm) and capillaries (Cap, phi<40 microm). Cap-vWF positivity was also detected in microthrombi with CD61 immunopositivity. The vWF positivity was higher in non-edema areas than in the edema area in the lungs. For acute deaths, Cap-vWF positivity of non-edema areas was frequently detected for strangulation (n=8/13, 61.5%), fire fatality (n=11/26, 42.3%) and ACD (n=8/15, 53.3%), but was infrequent for blunt and sharp instrument injuries (n=6/27, 22.5%, and n=2/15, 13.3%, respectively), irrespective of the complication of chest injury. However, for non-acute deaths, Cap-vWF positivity was more frequent for non-chest blunt injury (n=12/27, 44.4%) than for blunt chest injury (n=3/13, 23.1%) and sharp instrument injury (n=0/10, 0%). For fire fatality, Cap-vWF positivity was relatively frequent in cases with a lower blood carboxyhemoglobin (COHb) level of <60% (n=6/14, 42.8%) than in cases with a higher COHb level of >60% (n=3/12, 25.0%). These findings suggest that Cap-vWF positivity is closely related to the death process involving pulmonary microvascular injury. PMID:19261528

  2. Pif97, a von Willebrand and Peritrophin Biomineralization Protein, Organizes Mineral Nanoparticles and Creates Intracrystalline Nanochambers.

    PubMed

    Chang, Eric P; Evans, John Spencer

    2015-09-01

    The formation of the mollusk nacre layer involves the assembly and organization of mineral nanoparticles into fracture-toughened mesoscale-sized aragonite tablets that possess intracrystalline nanoporosities. At least one nacre protein family, known as the framework proteome, is strategically located as part of a macromolecular coating around each nacre tablet and is believed to participate in tablet formation. Here, we report new studies of a recombinant form (rPif97) of a unique Japanese pearl oyster (Pinctada fucata) nacre framework biomineralization protein, Pif97. This unique protein possesses both a von Willlebrand factor type A domain (vWA, F23-Y161) and a Peritrophin A chitin-binding domain (PAC, E234-D298). rPif97 self-associates or aggregates to form amorphous protein phases that organize both amorphous and single-crystal calcium carbonate nanoparticles in vitro. Further, in the presence of nucleating calcite crystals, rPif97 protein phases deposit onto these crystals and become occluded over time, forming nanochambers within the crystal interior. The formation of these mineral-modifying amorphous protein phases is linked to the presence of intrinsic disorder and amyloid-like cross-β-strand aggregation-prone regions, and three-dimensional modeling indicates that both the vWA and PAC domains are accessible for intermolecular interactions. Thus, the vWA- and PAC-containing Pif97 protein exhibits key functionalities that would allow its participation in mollusk nacre layer tablet assembly and porosity formation. PMID:26258941

  3. Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF.

    PubMed

    Yago, Tadayuki; Lou, Jizhong; Wu, Tao; Yang, Jun; Miner, Jonathan J; Coburn, Leslie; López, José A; Cruz, Miguel A; Dong, Jing-Fei; McIntire, Larry V; McEver, Rodger P; Zhu, Cheng

    2008-09-01

    Arterial blood flow enhances glycoprotein Ibalpha (GPIbalpha) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIbalpha/vWF bonds first prolonged ("catch") and then shortened ("slip") bond lifetimes. Two type 2B vWD A1 domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIbalpha dissociating from the A1 domain suggested mechanisms for catch bonds and their conversion by the A1 domain mutations. Catch bonds caused platelets and GPIbalpha-coated microspheres to roll more slowly on WT vWF and WT A1 domains as flow increased from suboptimal levels, explaining flow-enhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant A1 domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant A1 domains, but not WT A1 domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif-13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIbalpha on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding. PMID:18725999

  4. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial

    PubMed Central

    Mannucci, Pier Mannuccio; Kempton, Christine; Millar, Carolyn; Romond, Edward; Shapiro, Amy; Birschmann, Ingvild; Ragni, Margaret V.; Gill, Joan Cox; Yee, Thynn Thynn; Klamroth, Robert; Wong, Wing-Yen; Chapman, Miranda; Engl, Werner; Turecek, Peter L.; Suiter, Tobias M.

    2013-01-01

    Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF–binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post–rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved. This trial was registered at www.clinicaltrials.gov as #NCT00816660. PMID:23777763

  5. A Mechanism for Localized Dynamics-driven Affinity Regulation of the Binding of von Willebrand Factor to Platelet Glycoprotein Ibα*

    PubMed Central

    Liu, Guangjian; Fang, Ying; Wu, Jianhua

    2013-01-01

    Binding of the A1 domain of von Willebrand factor (vWF) to glycoprotein Ibα (GPIbα) results in platelet adhesion, activation, and aggregation that initiates primary hemostasis. Both the elevated shear stress and the mutations associated with type 2B von Willebrand disease enhance the interaction between A1 and GPIbα. Through molecular dynamics simulations for wild-type vWF-A1 and its eight gain of function mutants (R543Q, I546V, ΔSS, etc.), we found that the gain of function mutations destabilize the N-terminal arm, increase a clock pendulum-like movement of the α2-helix, and turn a closed A1 conformation into a partially open one favoring binding to GPIbα. The residue Arg578 at the α2-helix behaves as a pivot in the destabilization of the N-terminal arm and a consequent dynamic change of the α2-helix. These results suggest a localized dynamics-driven affinity regulation mechanism for vWF-GPIbα interaction. Allosteric drugs controlling this intrinsic protein dynamics may be effective in blocking the GPIb-vWF interaction. PMID:23902764

  6. Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischaemic heart disease.

    PubMed Central

    Bridges, A B; McLaren, M; Scott, N A; Pringle, T H; McNeill, G P; Belch, J J

    1993-01-01

    OBJECTIVES--To determine whether plasma concentrations of tissue plasminogen activator antigen, von Willebrand factor antigen, and prostacyclin stimulating factor and plasminogen activator inhibitor activity show circadian variation in men with ischaemic heart disease. DESIGN--Blood samples were obtained every four hours for 24 hours from 10 men with ischaemic heart disease. The men were ambulant from 08:10 until 00:00 when they went to bed and they remained in bed until 08:00 the following morning. PATIENTS--Ten men with positive diagnostic exercise tolerance tests with no significant past history, who were not regularly taking any medical treatment except for glyceryl trinitrate. RESULTS--There was significant circadian variation in plasminogen activator inhibitor activity (p = 0.001) (peak value 04:00 and trough value 20:00), but not in plasma concentrations of tissue plasminogen activator antigen, von Willebrand factor, or prostacyclin stimulating factor. CONCLUSION--Men with ischaemic heart disease showed a significant circadian variation in fibrinolysis. The combination of peak values of plasminogen activator inhibitor activity and failure of plasma concentrations of tissue plasminogen activator antigen to increase in the early morning must predispose to thrombosis at this time. The circadian variation in fibrinolysis may contribute to the increased incidence of myocardial infarction in the morning. PMID:8435236

  7. Le rôle du médecin anesthésiste-réanimateur dans la prise en charge de la femme enceinte porteuse de la maladie de Von Willebrand

    PubMed Central

    Baouahi, Hanane; Zerqouni, Yassine; Doumiri, Mouhcine; Oudghiri, Nezha; Saoud, Anas Tazi

    2015-01-01

    La maladie de Von Willebrand (VWD) est la maladie hémorragique constitutionnelle de l'hémostase la plus fréquente. Elle est liée à un déficit, soit quantitatif, soit qualitatif en facteur willebrand (VWF). Elle se caractérise par son extrême hétérogénéité sur les plans clinique, phénotypique et génotypique. La grossesse et surtout le péri-partum représente une période à risque hémorragique pour ces femmes. Nous rapportons le cas d'une parturiente présentant une maladie de Von Willebrand de type 1 documentée, la difficulté du choix du mode d'accouchement et de la technique anesthésique a été revue. PMID:26977242

  8. Production and functional activity of a recombinant von Willebrand factor-A domain from human complement factor B.

    PubMed Central

    Williams, S C; Hinshelwood, J; Perkins, S J; Sim, R B

    1999-01-01

    Factor B is a five-domain 90 kDa serine protease proenzyme which is part of the human serum complement system. It binds to other complement proteins C3b and properdin, and is activated by the protease factor D. The fourth domain of factor B is homologous to the type A domain of von Willebrand Factor (vWF-A). A full-length human factor B cDNA clone was used to amplify the region encoding the vWF-A domain (amino acids 229-444 of factor B). A fusion protein expression system was then used to generate it in high yield in Escherichia coli, where thrombin cleavage was used to separate the vWF-A domain from its fusion protein partner. A second vWF-A domain with improved stability and solubility was created using a Cys(267)-->Ser mutation and a four-residue C-terminal extension of the first vWF-A domain. The recombinant domains were investigated by analytical gel filtration, sucrose density centrifugation and analytical ultracentrifugation, in order to show that both domains were monomeric and possessed compact structures that were consistent with known vWF-A crystal structures. This expression system and its characterization permitted the first investigation of the function of the isolated vWF-A domain. It was able to inhibit substantially the binding of (125)I-labelled factor B to immobilized C3b. This demonstrated both the presence of a C3b binding site in this portion of factor B and a ligand-binding property of the vWF-A domain. The site at which factor D cleaves factor B is close to the N-terminus of both recombinant vWF-A domains. Factor D was shown to cleave the vWF-A domain in the presence or absence of C3b, whereas the cleavage of intact factor B under the same conditions occurs only in the presence of C3b. PMID:10477273

  9. von Willebrand Disease

    MedlinePlus

    ... have vWD, talk with your doctor before taking medicine for pain or fever. Don't take aspirin and ibuprofen ... bleeding. It's usually OK to take acetaminophen for pain or fever, since it has no effect on platelet function. Medicines for vWD Some people with more serious vWD ...

  10. von Willebrand Factor Test

    MedlinePlus

    ... Platelet Count , Platelet Function Tests , Complete Blood Count , Coagulation Factor VIII , PT , PTT At a Glance Test ... a protein , one of several components of the coagulation system that work together to stop bleeding and ...

  11. Von Willebrand disease

    MedlinePlus

    ... LE, Heslop HE, Weitz JI, Anastasi J, eds. Hematology: Basic Principles and Practice . 6th ed. Philadelphia, PA: ... 2/1/2016 Updated by: Todd Gersten, MD, Hematology/Oncology, Florida Cancer Specialists & Research Institute, Wellington, FL. ...

  12. Evidence that a secondary binding and protecting site for factor VIII on von Willebrand factor is highly unlikely.

    PubMed Central

    Layet, S; Girma, J P; Obert, B; Peynaud-Debayle, E; Bihoreau, N; Meyer, D

    1992-01-01

    A binding domain for Factor VIII (F.VIII) has been previously identified on the N-terminal portion of human von Willebrand Factor (vWF) subunit [amino acids (AA) 1-272]. In order to characterize other possible structures of vWF involved in its capacity to bind and to protect F.VIII against human activated protein C (APC), we used a series of purified vWF fragments overlapping the whole sequence of the subunit. Among those were fragments SpIII (dimer; AA 1-1365), SpII (dimer; AA 1366-2050) and SpI (monomer; AA 911-1365) generated by Staphylococcus aureus V8 proteinase, a P34 species (monomer; AA 1-272) obtained with plasmin, a monomeric 39/34 kDa dispase fragment (AA 480-718) and a tetrameric III-T2 fragment (AA 273-511/674-728) produced from SpIII by trypsin. Three other fragments without precise extremities were located using selected monoclonal antibodies to vWF. Two C-terminal fragments of 270 and 260 kDa, overlapping SpI and SpII, were respectively generated from vWF with trypsin and protease 1 from Crotalus atrox venom. An N-terminal 120 kDa fragment, overlapping P34 and 39/34 kDa fragments, was produced by protease 1. Our results show that vWF bound to F.VIII and protected it from degradation by APC in a dose-dependent way. Among the C-terminal and central vWF fragments (SpII, tryptic 270 kDa, 260 kDa, SpI, 39/34 kDa and III-T2), none had the capacity to bind or to protect F.VIII, even at high concentrations. The three N-terminal fragments (SpIII, 120 kDa and P34) bound to F.VIII in a dose-dependent and saturable fashion. SpIII and the 120 kDa fragment had the capacity to protect F.VIII in a dose-dependent way. In contrast, the P34 species did not significantly protect F.VIII, even when using high concentrations of the fragment. In conclusion, the N-terminal end of vWF subunit (AA 1-272) plays a crucial role in binding to F.VIII, but requires additional structures of the 120 kDa fragment to protect it against APC. In addition, the presence of a secondary

  13. Acquired von Willebrand disease during CentriMag support is associated with high prevalence of bleeding during support and after transition to heart replacement therapy.

    PubMed

    Morrison, Kerry A; Jorde, Ulrich P; Garan, Arthur R; Takayama, Hiroo; Naka, Yoshifumi; Uriel, Nir

    2014-01-01

    The Levitronix CentriMag is a magnetically levitated centrifugal-flow pump that can be implanted rapidly in the operating room for both right and left ventricular support. Recently, continuous-flow pumps have been associated with excessive bleeding, which can be at least partially explained by acquired von Willebrand disease (vWD). We investigated whether acquired vWD occurs during CentriMag support and determined the frequency of bleeding complications during device support as well as after transition to long-term support. We found that acquired vWD is common early post CentriMag implantation and is associated with frequent bleeding events and high requirement of blood products. PMID:24577372

  14. Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site.

    PubMed Central

    Wise, R J; Barr, P J; Wong, P A; Kiefer, M C; Brake, A J; Kaufman, R J

    1990-01-01

    Intracellular proteolytic processing of precursor polypeptides is an essential step in the maturation of many proteins, including plasma proteins, hormones, neuropeptides, and growth factors. Most frequently, propeptide cleavage occurs after paired basic amino acid residues. To date, no mammalian propeptide processing enzyme with such specificity has been purified or cloned and functionally characterized. We report the isolation and functional expression of a cDNA encoding a propeptide-cleaving enzyme from a human liver cell line. The encoded protein, called PACE (paired basic amino acid cleaving enzyme), has structural homology to the well-characterized subtilisin-like protease Kex2 from yeast. The functional specificity of PACE for mediating propeptide cleavage at paired basic amino acid residues was demonstrated by the enhancement of propeptide processing of human von Willebrand factor when coexpressed with PACE in COS-1 cells. Images PMID:2251280

  15. H1N1 influenza (swine flu)-associated thrombotic microangiopathy with a markedly high plasma ratio of von Willebrand factor to ADAMTS13.

    PubMed

    Akiyama, Rui; Komori, Isao; Hiramoto, Ryugo; Isonishi, Ayami; Matsumoto, Masanori; Fujimura, Yoshihiro

    2011-01-01

    We describe an 18-year-old woman infected with H1N1 influenza followed by thrombotic microangiopathy. During the acute phase, her plasma levels of von Willebrand factor (VWF) were remarkably elevated, whereas those of ADAMTS13 were reduced without its inhibitors, generating a markedly high ratio of VWF to ADAMTS13 in circulation. A retrospective analysis established the following hypothesis: an influenza-mediated cytokine storm induced an enhanced release of unusually large VWF multimers (UL-VWFM) from vascular endothelial cells, generating platelet thrombi in microcirculatures under high shear stress. Plasma exchange removed UL-VWFM and cytokines, and rescued her life. This report sheds a light on a hitherto unrecognized influenza complication. PMID:21422695

  16. Bleeding complications after arthroscopy in a JAK2V617F-positive patient with essential thrombocythemia and acquired von Willebrand syndrome (AVWS).

    PubMed

    Rupa-Matysek, Joanna; Lewandowski, Krzysztof; Lewandowska, Maria; Wojtasińska, Ewelina; Wojtaszewska, Marzena Liliana; Walczak, Michał; Bykowska, Ksenia; Komarnicki, Mieczysław

    2015-04-01

    Acquired von Willebrand syndrome (AVWS) is an acquired bleeding disorder with clinical and laboratory features similar to those of the inherited form of the disease. AVWS is reported in many disorders, most frequently in myeloproliferative neoplasms and in, among others, essential thrombocythemia (ET). Interestingly, ET is associated with both the thrombotic and haemorrhagic complications, which occur in 20 % and 5-30 % of patients, respectively. The present report concerns a 38-year-old man, suffering from ET, who presented with two episodes of post-arthroscopic joint bleeding after synovectomy required for the treatment of synovial hypertrophy and chronic left knee joint synovitis. We discuss the current diagnostic approaches, as well as the risk factors predisposing to bleeding and its management, in patients with essential thrombocythemia. PMID:25432436

  17. The p.R1819_C1948delinsS mutation makes von Willebrand factor ADAMTS13-resistant and reduces its collagen-binding capacity.

    PubMed

    Daidone, Viviana; Saga, Giorgia; Barbon, Giovanni; Pontara, Elena; Cattini, Maria G; Morpurgo, Margherita; Zanotti, Giuseppe; Casonato, Alessandra

    2015-08-01

    This report concerns abnormal ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) and collagen interactions coinciding with the p.R1819_C1948delinsS von Willebrand factor (VWF) mutation associated with the deletion of the C-terminus of the A3 domain (amino acids 1819-1947) in a patient with a history of bleeding. The von Willebrand disease (VWD) phenotype of the patient featured low plasma and platelet VWF, multimers with smears extending over the highest normal oligomers in plasma, but not platelets, and an impaired collagen-binding capacity. In vitro full-length p.R1819_C1948delinsS VWF expression showed impaired VWF release, increased cellular content with normally-multimerized VWF and impaired collagen binding. The recombinant p.R1819_C1948delinsS VWF fragment, extending from domains A2 to B3 (p.R1819_C1948delinsS A2-B3 VWF), was completely resistant to proteolysis by ADAMTS13 in the presence of 1·5 mol/l urea, unlike its normal counterpart. The defect stems from impaired ADAMTS13 binding to p.R1819_C1948delinsS A2-B3, analysed under static conditions. Partial deletion of the C-terminus of the A3 domain thus makes VWF resistant to ADAMTS13, interfering with ADAMTS13 binding to VWF, and impairing the collagen-binding capacity of VWF. The p.R1819_C1948delinsS mutation has both haemorrhagic features (defective collagen binding, reduced VWF levels) and prothrombotic (ADAMTS13 resistance) features, and the latter probably mitigate the patient's bleeding symptoms. PMID:25904363

  18. GPIbα-vWF rolling under shear stress shows differences between type 2B and 2M von Willebrand disease.

    PubMed

    Coburn, L A; Damaraju, V S; Dozic, S; Eskin, S G; Cruz, M A; McIntire, L V

    2011-01-19

    Both type 2B and type 2M von Willebrand disease result in bleeding disorders; however, whereas type 2B has increased binding affinity between platelet glycoprotein Ibα and von Willebrand factor (vWF), type 2M has decreased binding affinity between these two molecules. We used R687E type 2B and G561S type 2M vWF-A1 mutations to study binding between flowing platelets and insolubilized vWF mutants. We measured rolling velocities, mean stop times, and mean go times at 37°C using high-speed video microscopy. The rolling velocities for wt-wt interactions first decrease, reach a minimum, and then increase with increasing shear stress, indicating a catch-slip transition. By changing the viscosity, we were able to quantify the effects of force versus shear rate for rolling velocities and mean stop times. Platelet interactions with loss-of-function vWF-A1 retain the catch-slip bond transition seen in wt-wt interactions, but at a higher shear stress compared with the wt-wt transition. The mean stop time for all vWF-A1 molecules reveals catch-slip transitions at different shear stresses (gain-of-function vWF-A1 < wt vWF-A1< loss-of-function vWF-A1). The shift in the catch-slip transition may indicate changes in how the different mutants become conformationally active, indicating different mechanisms leading to similar bleeding characteristics. PMID:21244826

  19. The N-terminal flanking region of the A1 domain regulates the force-dependent binding of von Willebrand factor to platelet glycoprotein Ibα.

    PubMed

    Ju, Lining; Dong, Jing-fei; Cruz, Miguel A; Zhu, Cheng

    2013-11-01

    Binding of platelet glycoprotein Ibα (GPIbα) to von Willebrand factor (VWF) initiates platelet adhesion to disrupted vascular surface under arterial blood flow. Flow exerts forces on the platelet that are transmitted to VWF-GPIbα bonds, which regulate their dissociation. Mutations in VWF and/or GPIbα may alter the mechanical regulation of platelet adhesion to cause hemostatic defects as found in patients with von Willebrand disease (VWD). Using a biomembrane force probe, we observed biphasic force-decelerated (catch) and force-accelerated (slip) dissociation of GPIbα from VWF. The VWF A1 domain that contains the N-terminal flanking sequence Gln(1238)-Glu(1260) (1238-A1) formed triphasic slip-catch-slip bonds with GPIbα. By comparison, using a short form of A1 that deletes this sequence (1261-A1) abolished the catch bond, destabilizing its binding to GPIbα at high forces. Importantly, shear-dependent platelet rolling velocities on these VWF ligands in a flow chamber system mirrored the force-dependent single-bond lifetimes. Adding the Gln(1238)-Glu(1260) peptide, which interacted with GPIbα and 1261-A1 but not 1238-A1, to whole blood decreased platelet attachment under shear stress. Soluble Gln(1238)-Glu(1260) reduced the lifetimes of GPIbα bonds with VWF and 1238-A1 but rescued the catch bond of GPIbα with 1261-A1. A type 2B VWD 1238-A1 mutation eliminated the catch bond by prolonging lifetimes at low forces, a type 2M VWD 1238-A1 mutation shifted the respective slip-catch and catch-slip transition points to higher forces, whereas a platelet type VWD GPIbα mutation enhanced the bond lifetime in the entire force regime. These data reveal the structural determinants of VWF activation by hemodynamic force of the circulation. PMID:24062306

  20. Efficacy and safety during formulation switch of a pasteurized VWF/FVIII concentrate: results from an Italian prospective observational study in patients with von Willebrand disease.

    PubMed

    Castaman, G; Coppola, A; Zanon, E; Boeri, E; Musso, M; Siragusa, S; Federici, A B; Mancuso, G; Barillari, G; Biasoli, C; Feola, G; Franchini, M; Moratelli, S; Gamba, G; Schinco, P; Valdrè, L; Dragani, A; Mazzucconi, G; Tagliaferri, A; Morfini, M

    2013-01-01

    Von Willebrand disease (VWD) is an inherited bleeding disorder caused by the quantitative or qualitative deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived VWF/factor VIII (FVIII) concentrates is required in patients unresponsive to desmopressin. To assess the efficacy, safety and ease of use of a new, volume-reduced (VR) formulation of VWF/FVIII concentrate Haemate(®) P in patients requiring treatment for bleeding or prophylaxis for recurrent bleeding or for invasive procedures. Pharmacoeconomic variables were also recorded. Data were analysed using descriptive statistics. This was a multicentre, prospective, observational study. Consecutively enrolled patients received Haemate(®) P VR according to their needs, and were followed for 24 months. Of the 121 patients enrolled, 25.6% had type 3 VWD and more than 40% had severe disease. All patients were followed for 2 years, for a total of 521 visits. On-demand treatment was given to 61.9% of patients, secondary long-term prophylaxis to 25.6% and prophylaxis for surgery, dental or invasive procedures to 45.5%. The response to treatment was rated as good to excellent in >93-99% of interventions. The new formulation was well tolerated by all patients with no report of drug-related adverse events. The switch to volume-reduced Haemate(®) P was easy to perform and infusion duration was decreased twofold compared with the previous formulation. Volume-reduced Haemate(®) P was at least as effective and well-tolerated as the previous formulation. PMID:22957493

  1. Crystallization and preliminary X-ray analysis of the complex of the first von Willebrand type C domain bound to bone morphogenetic protein 2

    SciTech Connect

    Qiu, Li-yan; Zhang, Jin-li; Kotzsch, Alexander; Sebald, Walter; Mueller, Thomas D.

    2008-04-01

    Crystals of the complex of the first von Willebrand type C domain (VWC1) of crossveinless 2 (CV2) bound to bone morphogenetic protein 2 (BMP2) exist in two tetragonal crystal forms belonging to either space group P4{sub 1}2{sub 1}2 or I4{sub 1}, with one complete BMP2 dimer and two CV2 VWC1 domains per asymmetric unit, and diffract to 2.6 Å resolution. Crossveinless 2 (CV2) is a member of the chordin family, a protein superfamily that modulates the activity of bone morphogenetic proteins such as BMP2. The BMPs represent a large group of secreted proteins that control many steps during embryonal development and in tissue and organ homeostasis in the adult organism. The gene encoding the first von Willebrand type C domain (VWC1) of CV2 was cloned, expressed in Escherichia coli and purified to homogeneity. The binary complex of CV2 VWC1 and BMP2 was purified and subjected to crystallization. Crystals of SeMet-labelled proteins were obtained in two different forms belonging to the tetragonal space groups P4{sub 1}2{sub 1}2 and I4{sub 1}, with unit-cell parameters a = b = 86.7, c = 139.2 Å and a = b = 83.7, c = 139.6 Å, respectively. Initial analysis suggests that a complete binary complex consisting of one BMP2 dimer bound to two CV2 VWC1 domains is present in the asymmetric unit.

  2. Is the assessment of von Willebrand disease prevalence an achievable challenge? The example of the French Basque Country where blood group O and factor XI deficiency are highly prevalent.

    PubMed

    Bauduer, F; Ducout, L

    2004-10-01

    The diagnosis of type I von Willebrand disease (VWD) is not straightforward because of the absence of a single clear-cut biological criteria and the interference of several acquired conditions on phenotype expression. We illustrate here this challenge with the French Basque population characterised by a marked high frequency in both blood group O and factor XI deficiency. From this example one may question the validity of epidemiological studies reporting on VWD prevalence. PMID:15456482

  3. Granulocyte proteases do not process endothelial cell-derived unusually large von Willebrand factor multimers to plasma vWF in vivo.

    PubMed

    Phillips, M D; Vu, C; Nolasco, L; Moake, J L

    1991-06-01

    The unusually large von Willebrand factor (ULvWF) multimers present within endothelial cells and platelets are larger than the vWF multimers normally found in adult human plasma. Furthermore, ULvWF multimers are cleared rapidly from the circulation if they are released by intense endothelial cell stimulation. The mechanisms by which the ULvWF multimers are processed to large plasma vWF multimers are not known. It has been demonstrated that granulocyte proteases are capable of decreasing vWF multimer size in vitro, and that some patients with myeloproliferative syndromes have a relative absence of large plasma vWF multimers in sodium citrate-anticoagulated plasma samples. In order to assess the influence of granulocyte proteases on vWF multimer size, we evaluated the vWF multimeric patterns in 94 plasma samples from 60 patients with neutrophil counts that were either considerably elevated or extremely reduced. In 83 of 94 plasma samples, the vWF multimeric patterns were normal. No patients with very low neutrophil counts had ULvWF multimers present. These observations suggest that granulocyte proteases are not likely to be involved in vivo in the processing of ULvWF multimers from endothelial cells to the smaller vWF forms in circulation. PMID:2069167

  4. A Structural Explanation for the Antithrombotic Activity of ARC1172, a DNA Aptamer that Binds von Willebrand Factor Domain A1

    PubMed Central

    Huang, Ren-Huai; Fremont, Daved H.; Diener, John L.; Schaub, Robert G.; Sadler, J. Evan

    2013-01-01

    Summary ARC1172 is a 41-mer DNA aptamer selected to bind the A1 domain of von Willebrand factor (VWF). A derivative of ARC1172 with modifications to increase intravascular survival inhibits carotid artery thrombosis in a Cynomolgus macaque model and inhibits VWF-dependent platelet aggregation in humans, suggesting that such aptamers may be useful to prevent or treat thrombosis. In the crystal structure of a VWF A1-ARC1172 complex, the aptamer adopts a three-stem structure of mainly B-form DNA with three noncanonical base pairs and 9 unpaired residues, 6 of which are stabilized by base-base or base-deoxyribose stacking interactions. The aptamer-protein interface is characterized by cation-π interactions involving Arg, Lys and Gln residues, often stabilized by H-bonds with adjacent bases. The ARC1172 binding site on the A1 domain overlaps with that of botrocetin and clashes with glycoprotein Ibα binding at an adjacent site, which accounts for the antithrombotic activity of ARC1172 and related aptamers. PMID:19913482

  5. Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study.

    PubMed

    Daly, Martina E; Dawood, Ban B; Lester, William A; Peake, Ian R; Rodeghiero, Francesco; Goodeve, Anne C; Makris, Michael; Wilde, Jonathan T; Mumford, Andrew D; Watson, Stephen P; Mundell, Stuart J

    2009-04-23

    We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY12) contribute to the bleeding tendency in 92 index cases enrolled in the European MCMDM-1VWD study. A heterozygous mutation, predicting a lysine to glutamate (K174E) substitution in P2Y(12), was identified in one case with mild type 1 von Willebrand disease (VWD) and a VWF defect. Platelets from the index case and relatives carrying the K174E defect changed shape in response to ADP, but showed reduced and reversible aggregation in response to 10 muM ADP, unlike the maximal, sustained aggregation observed in controls. The reduced response was associated with an approximate 50% reduction in binding of [(3)H]2MeS-ADP to P2Y(12), whereas binding to the P2Y(1) receptor was normal. A hemagglutinin-tagged K174E P2Y(12) variant showed surface expression in CHO cells, markedly reduced binding to [(3)H]2MeS-ADP, and minimal ADP-mediated inhibition of forskolin-induced adenylyl cyclase activity. Our results provide further evidence for locus heterogeneity in type 1 VWD. PMID:19237732

  6. Role of factor VIII-von Willebrand factor and fibronectin in the interaction of platelets in flowing blood with monomeric and fibrillar human collagen types I and III.

    PubMed

    Houdijk, W P; Sakariassen, K S; Nievelstein, P F; Sixma, J J

    1985-02-01

    Platelet adhesion to monomeric collagen types I and III, which were purified from human umbilical arteries, was studied in a perfusion chamber under well defined flow conditions. For this purpose, glass coverslips were coated with 20-30 micrograms/cm2 of collagen types I and III by spraying a solution of these collagens with a retouching air brush. Platelet deposition increased with the time of perfusion. Adhesion to both collagen types was similar in the first 3 min, but increased platelet deposition occurred on collagen type III after 3 min due to thrombus formation. Adhesion at a shear rate of 800 s-1 was strongly impaired with plasma of a patient with von Willebrand's disease or with fibronectin-free plasma. Addition of purified fibronectin to fibronectin-free plasma restored adhesion to the level obtained with normal plasma. Platelet deposition in normal plasma increased with increasing shear rates. Platelet deposition in VWD-plasma was normal at 490 s-1, but there was no increase at higher shear rates. Platelet deposition in fibronectin-free plasma was diminished at all shear rates studied from 490 to 1,300 s-1. Perfusion with a human albumin solution (HAS) to which purified Factor VIII-von Willebrand factor complex (FVIII-VWF) and fibronectin had been added gave similar platelet deposition as with normal plasma. Preincubation of collagen with FVIII-VWF and perfusion with HAS containing fibronectin, or, conversely, preincubation with fibronectin and perfusion with HAS containing FVIII-VWF, also resulted in adhesion similar to that observed in normal plasma. Similar adhesion was also observed after preincubation with both FVIII-VWF and fibronectin and subsequent perfusion with HAS alone. Sequential preincubations with first FVIII-VWF and then fibronectin, or with first fibronectin and then FVIII-VWF followed by perfusion with HAS, also gave a similar adhesion as observed with normal plasma. These data indicate that platelet adhesion to monomeric collagen types

  7. Role of factor VIII-von Willebrand factor and fibronectin in the interaction of platelets in flowing blood with monomeric and fibrillar human collagen types I and III.

    PubMed Central

    Houdijk, W P; Sakariassen, K S; Nievelstein, P F; Sixma, J J

    1985-01-01

    Platelet adhesion to monomeric collagen types I and III, which were purified from human umbilical arteries, was studied in a perfusion chamber under well defined flow conditions. For this purpose, glass coverslips were coated with 20-30 micrograms/cm2 of collagen types I and III by spraying a solution of these collagens with a retouching air brush. Platelet deposition increased with the time of perfusion. Adhesion to both collagen types was similar in the first 3 min, but increased platelet deposition occurred on collagen type III after 3 min due to thrombus formation. Adhesion at a shear rate of 800 s-1 was strongly impaired with plasma of a patient with von Willebrand's disease or with fibronectin-free plasma. Addition of purified fibronectin to fibronectin-free plasma restored adhesion to the level obtained with normal plasma. Platelet deposition in normal plasma increased with increasing shear rates. Platelet deposition in VWD-plasma was normal at 490 s-1, but there was no increase at higher shear rates. Platelet deposition in fibronectin-free plasma was diminished at all shear rates studied from 490 to 1,300 s-1. Perfusion with a human albumin solution (HAS) to which purified Factor VIII-von Willebrand factor complex (FVIII-VWF) and fibronectin had been added gave similar platelet deposition as with normal plasma. Preincubation of collagen with FVIII-VWF and perfusion with HAS containing fibronectin, or, conversely, preincubation with fibronectin and perfusion with HAS containing FVIII-VWF, also resulted in adhesion similar to that observed in normal plasma. Similar adhesion was also observed after preincubation with both FVIII-VWF and fibronectin and subsequent perfusion with HAS alone. Sequential preincubations with first FVIII-VWF and then fibronectin, or with first fibronectin and then FVIII-VWF followed by perfusion with HAS, also gave a similar adhesion as observed with normal plasma. These data indicate that platelet adhesion to monomeric collagen types

  8. 1-Desamino-8-D-arginine vasopressin (DDAVP) infusion in type IIB von Willebrand's disease: shortening of bleeding time and induction of a variable pseudothrombocytopenia.

    PubMed

    Casonato, A; Sartori, M T; de Marco, L; Girolami, A

    1990-08-13

    We have investigated the effects of 1-desamino-8-D-arginine vasopressin (DDAVP) infusion on platelet count and bleeding time in 4 patients with type IIB von Willebrand's disease (vWd). Three of four patients showed a normalization of the bleeding time within 1 h after the infusion, while bleeding time was not modified in the fourth. In accordance with the literature, thrombocytopenia was observed after DDAVP infusion, but this thrombocytopenia was due to the anticoagulants used for blood collection. In two patients (F.I., G.F.) no thrombocytopenia was observed when platelets were counted by fingerstick method but there was a 20% platelet decrease in blood samples collected in sodium citrate and a 50% decrease in samples collected in EDTA. Dramatic falls in platelet counts (70-95%) were observed in the additional two patients (C.A., D.Z.) after DDAVP infusion, when both sodium citrate or EDTA were used as anticoagulants. In the latter two patients there was also a 50% decrease in platelet count when the fingerstick method was used. The decrease in the patient's platelet count in EDTA samples after DDAVP infusion could be prevented, in part, by the previous additions of an anti GPIb monoclonal antibody and an anti GPIIb-IIIa monoclonal antibody. Thus, the thrombocytopenia observed in the four IIB vWd patients studied after DDAVP infusion seems to be, at least partially, a pseudothrombocytopenia depending on the calcium concentration in the blood samples and the availability of GPIb and GPIIb-IIIa receptors. These findings and the normalization of the bleeding time observed in three of the four patients has led us to reconsider the possible use of DDAVP in the treatment of our IIB vwd patients. PMID:2274916

  9. Genetic variants associated with Von Willebrand factor levels in healthy men and women identified using the HumanCVD BeadChip.

    PubMed

    Zabaneh, Delilah; Gaunt, Tom R; Kumari, Meena; Drenos, Fotios; Shah, Sonia; Berry, Diane; Power, Chris; Hypponen, Elina; Shah, Tina; Palmen, Jutta; Pallas, Jacky; Talmud, Philippa J; Casas, Juan Pablo; Sofat, Reecha; Lowe, Gordon; Rumley, Ann; Morris, Richard W; Whincup, Peter H; Rodriguez, Santiago; Ebrahim, Shah; Marmot, Michael G; Smith, George Davey; Lawlor, Debbie A; Kivimaki, Mika; Whittaker, John; Hingorani, Aroon D; Day, Ian N; Humphries, Steve E

    2011-07-01

    We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels. PMID:21534939

  10. Apoptotic Platelet Events Are Not Observed in Severe von Willebrand Disease-Type 2B Mutation p.V1316M

    PubMed Central

    Berrou, Eliane; Kauskot, Alexandre; Adam, Frédéric; Harel, Amélie; Legendre, Paulette; Lavenu Bombled, Cécile; Rothschild, Chantal; Prevost, Nicolas; Christophe, Olivier D.; Lenting, Peter J.; Denis, Cécile V.; Rosa, Jean-Philippe; Bryckaert, Marijke

    2015-01-01

    Thrombocytopenia and increased platelet clearance observed in von Willebrand disease-type 2B (VWD-2B) may be explained by platelet apoptosis triggered by the constitutive binding of VWF to its receptor, glycoprotein Ib (GPIb). Apoptosis was assessed in platelets from two patients with a severe VWD-2B mutation VWF/p.V1316M and from mice transiently expressing VWF/p.V1316M. We now report that the VWD-2B mutation VWF/p.V1316M which binds spontaneously to its receptor GPIbα does not induce apoptosis. In 2 unrelated patients (P1 and P2) exhibiting different VWF plasma levels (70% and 36%, respectively, compared with normal pooled human plasma given as 100%), inner transmembrane depolarization of mitochondria, characteristic of apoptotic events was undetectable in platelets, whether washed or in whole blood. No or a moderate phosphatidyl serine (PS) exposure as measured by annexin-V staining was observed for P1 and P2, respectively. Expression of pro-apoptotic proteins Bak and Bax, and caspase-3 activity were similar to control platelets. In the VWD-2B mouse model expressing high levels of mVWF/p.V1316M (423%), similar to what is found in inflammatory pathologies, no significant difference was observed between mice expressing mVWF/WT and mVWF/p.V1316M. These results strongly argue against apoptosis as a mechanism for the thrombocytopenia of severe VWD-2B exhibiting the VWF/p.V1316M mutation. PMID:26645283

  11. Analysis of the role of von Willebrand factor, platelet glycoprotein VI-, and α2β1-mediated collagen binding in thrombus formation

    PubMed Central

    Shida, Yasuaki; Rydz, Natalia; Stegner, David; Brown, Christine; Mewburn, Jeffrey; Sponagle, Kate; Danisment, Ozge; Crawford, Bredon; Vidal, Barbara; Hegadorn, Carol A.; Pruss, Cynthia M.; Nieswandt, Bernhard

    2014-01-01

    Rare missense mutations in the von Willebrand factor (VWF) A3 domain that disrupt collagen binding have been found in patients with a mild bleeding phenotype. However, the analysis of these aberrant VWF-collagen interactions has been limited. Here, we have developed mouse models of collagen-binding mutants and analyzed the function of the A3 domain using comprehensive in vitro and in vivo approaches. Five loss-of-function (p.S1731T, p.W1745C, p.S1783A, p.H1786D, A3 deletion) and 1 gain-of-function (p.L1757A) variants were generated in the mouse VWF complementary DNA. The results of these various assays were consistent, although the magnitude of the effects were different: the gain-of-function (p.L1757A) variant showed consistent enhanced collagen binding whereas the loss-of-function mutants showed variable degrees of functional deficit. We further analyzed the impact of direct platelet-collagen binding by blocking glycoprotein VI (GPVI) and integrin α2β1 in our ferric chloride murine thrombosis model. The inhibition of GPVI demonstrated a comparable functional defect in thrombosis formation to the VWF−/− mice whereas α2β1 inhibition demonstrated a milder bleeding phenotype. Furthermore, a delayed and markedly reduced thrombogenic response was still evident in VWF−/−, GPVI, and α2β1 blocked animals, suggesting that alternative primary hemostatic mechanisms can partially rescue the bleeding phenotype associated with these defects. PMID:25051961

  12. Preserved Expression of mRNA Coding von Willebrand Factor–Cleaving Protease ADAMTS13 by Selenite and Activated Protein C

    PubMed Central

    Ekaney, Michael L; Bockmeyer, Clemens L; Sossdorf, Maik; Reuken, Philipp A; Conradi, Florian; Schuerholz, Tobias; Blaess, Markus F; Friedman, Scott L; Lösche, Wolfgang; Bauer, Michael; Claus, Ralf A

    2015-01-01

    In sepsis, the severity-dependent decrease of von Willebrand factor (VWF)–inactivating protease, a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), results in platelet aggregation and consumption, leading to sepsis-associated thrombotic microangiopathy (TMA) and organ failure. Previous reports assessing its functional deficiency have pinpointed involvement of autoantibodies or mutations to propagate thrombotic thrombocytopenic purpura (TTP). However, mechanisms of acquired ADAMTS13 deficiency during host response remain unclear. To enhance understanding of ADAMTS13 deficiency in sepsis, we evaluated changes in expression of mRNA coding ADAMTS13 during septic conditions using primary cellular sources of the protease. We hypothesized that proinflammatory cytokines and constituents of serum from septic patients affect the transcriptional level of ADAMTS13 in vitro, and previously recommended therapeutic agents as adjunctive therapy for sepsis interact therewith. Cultured hepatic stellate cells (HSCs), endothelial cells (HMEC) and human precision-cut liver slices as an ex vivo model were stimulated with sepsis prototypic cytokines, bacterial endotoxin and pooled serum obtained from septic patients. Stimulation resulted in a significant decrease in ADAMTS13 mRNA between 10% and 80% of basal transcriptional rates. Costimulation of selenite or recombinant activated protein C (APC) with serum prevented ADAMTS13 decrease in HSCs and increased ADAMTS13 transcripts in HMEC. In archived clinical samples, the activity of ADAMTS13 in septic patients treated with APC (n = 5) increased with an accompanying decrease in VWF propeptide as surrogate for improved endothelial function. In conclusion, proinflammatory conditions of sepsis repress mRNA coding ADAMTS13 and the ameliorating effect by selenite and APC may support the concept for identification of beneficial mechanisms triggered by these drugs at a molecular level. PMID:25860876

  13. Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

    PubMed Central

    Nichols, Timothy C.; Dillow, Aaron M.; Franck, Helen W.G.; Merricks, Elizabeth P.; Raymer, Robin A.; Bellinger, Dwight A.; Arruda, Valder R.; High, Katherine A.

    2011-01-01

    Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders. PMID:19293459

  14. Generation and Optimization of the Self-Administered Bleeding Assessment Tool (Self-BAT) and its Validation as a Screening Test for von Willebrand Disease

    PubMed Central

    Deforest, Meghan; Grabell, Julie; Albert, Shirren; Young, Jane; Tuttle, Angie; Hopman, Wilma M.; James, Paula D.

    2015-01-01

    Summary Introduction/Aim Our aim was to generate, optimize and validate a self-administered bleeding assessment tool (BAT) for von Willebrand disease (VWD). Methods In Phase 1, medical terminology in the expert-administered ISTH-BAT was converted to a grade 4 reading level to produce the first version of the Self-BAT which was then optimized to ensure agreement with the ISTH-BAT. In Phase 2, the normal range of bleeding scores was determined and test-retest reliability analyzed. In Phase 3, the optimized Self-BAT was tested as a screening tool for first time referrals to the Hematology clinic. Results BS from the final optimized version of the Self-BAT showed an excellent intra-class correlation coefficient (ICC) of 0.87 with ISTH-BAT BS in Phase 1. In Phase 2, the normal range of bleeding scores for the optimized Self-BAT was determined to be 0 to +5 for females and 0 to +3 for males and excellent test-retest reliability was shown (ICC = 0.95). In Phase 3, we showed that a positive Self-BAT BS (≥ 6 for females, ≥ 4 for males) has a sensitivity of 78%, specificity of 23%, positive predictive value (PPV) of 0.15 and negative predictive value (NPV) of 0.86 for VWD; these figures improved when just the females were analyzed; sensitivity of 100%, specificity of 21%, PPV=0.17 and NPV=1.0. Conclusion We show an optimized Self-BAT can generate comparable BS to the expert-administered ISTH-BAT and is a reliable, effective screening tool to incorporate into the assessment of individuals, particularly women, referred for a possible bleeding disorder. PMID:26179127

  15. Development of acquired von Willebrand syndrome during short-term micro axial pump support: implications for bleeding in a patient bridged to a long-term continuous-flow left ventricular assist device.

    PubMed

    Davis, Mary E; Haglund, Nicholas A; Tricarico, Nicole M; Keebler, Mary E; Maltais, Simon

    2014-01-01

    Percutaneous continuous-flow (CF) micro axial blood pumps, like the Impella 5.0, are commonly used for short-term (ST) mechanical circulatory support in patients with acute decompensated heart failure. The Impella device often serves as a bridge to implantation of a long-term (LT) CF left ventricular assist device (CF-LVAD), such as the centrifugal-flow HeartWare (HVAD). All patients supported with axial CF-LVADs develop acquired von Willebrand syndrome (AVWS) as a result of mechanical shear stress. Increased shear stress leads to excessive proteolysis of von Willebrand factor and loss of high molecular weight multimers, thus contributing to platelet dysfunction and increased gastrointestinal bleeding. Bleeding events associated with AVWS have been reported in patients supported with LT CF-LVADs; however, the relation between early perioperative bleeding complications and AVWS remains poorly characterized in ST CF-LVADs. We sought to describe the relation between the development of AVWS and excessive intraoperative bleeding in a patient who was sequentially bridged with an ST micro axial device to a LT centrifugal CF-LVAD. This case highlights the importance of monitoring these hemostatic changes when bridging to LT CF-LVADs. PMID:24614358

  16. Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test.

    PubMed

    Mathieu, Sophie; Crampe, Carine; Dargaud, Yesim; Lavigne-Lissalde, Géraldine; Escuriola-Ettingshausen, Carmen; Tardy, Brigitte; Meley, Roland; Thouvenin, Sandrine; Stephan, Jean L; Berger, Claire

    2015-12-01

    Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI. PMID:26517064

  17. Early increase precedes a depletion of endothelin-1 but not of von Willebrand factor in cutaneous microvessels of diabetic patients. A quantitative immunohistochemical study.

    PubMed

    Properzi, G; Terenghi, G; Gu, X H; Poccia, G; Pasqua, R; Francavilla, S; Polak, J M

    1995-02-01

    Endothelin-1 (ET-1) is a vasoconstrictor peptide which is produced by endothelial cells. The subcellular distribution of ET-1 in human skin and the variation of immunostaining for ET-1 by light microscopy in skin biopsies of diabetic patients have been analysed using immunohistochemistry and image analysis quantification. Skin biopsies were collected from 17 patients with type 1 diabetes of different durations and with presence or absence of microangiopathy in the retina; skin biopsies of healthy subjects were utilized as controls. The distribution of ET-1 immunoreactivity (IR) at both light and electron microscopy was compared to that of von Willebrand factor (vWf), a general marker of total cutaneous microvessels. Immunohistochemistry revealed that in controls the distribution of immunostaining was similar for ET-1 and vWf, being localized to microvessels in all areas of the skin. However, at the electron microscopical level ET-1-IR was localized in the endothelial cytoplasm rather than in specific organelles, while vWf immunostaining was associated with Weibel-Palade bodies. ET-1-IR was observed in 4/8 (50 per cent) biopsies from healthy subjects; this increased to 81.8 per cent in biopsies of patients affected by diabetes for less than 10 years and decreased to 16.6 per cent in patients with diabetes for more than 10 years. Quantification of ET-1 staining showed a significant decrease of ET-1-IR in patients affected by diabetes for more than 10 years compared with those affected by diabetes for less than 10 years (P < 0.05). Also, the percentage of biopsies showing positive ET-1 staining was lower in patients with retinopathy than in patients without retinopathy. On the contrary, vWf-IR was observed in all skin specimens and its quantification showed no differences between diabetic patients and controls. These changes are not related to variations in the number of blood vessels, and it is suggested that they reflect a possible functional alteration of the

  18. Acquired von Willebrand disease--hemostatic management of major orthopedic surgery with high-dose immunoglobulin, desmopressin, and continuous factor concentrate infusion.

    PubMed

    Frank, Rolf Dario; Kunz, Dagmar; Wirtz, Dieter Christian

    2002-05-01

    Acquired von Willebrand disease (aVWD) is a rare bleeding disorder that mimics congenital VWD in previously healthy individuals; it is most frequently associated with monoclonal gammopathy. Hemostatic therapy of aVWD is challenging due to the extremely shortened half-life of endogenous and exogenous VWF. High-dose intravenous immunoglobulin (ivIG) is recommended as the treatment of choice, usually rapidly normalizing coagulation; but in case of failure, alternative treatment options are not well explored. We report successful major orthopedic surgery in a 61-year-old woman with multiple myeloma IgG lambda and aVWD. IvIG alone failed to correct hemostasis. However, ivIG pretreatment improved the VWF ristocetin cofactor (VWF:RCo) half-life from only 1.5 hr to more than 4 hr, allowing desmopressin infusions twice daily to maintain sufficient VWF:RCo levels. Because of diminishing desmopressin effect, we attempted for the first time in aVWD a continuous VWF/FVIII infusion (Haemate HS), 2.1-2.7 FVIII U/kg/hr or 51-64 U/kg/day, respectively 4.6-6.0 VWF:RCo U/kg/hr or 110-145 U/kg/day) to reach constant factor levels. The steady-state clearance was 2.4 mL/kg/hr for FVIII:C and 13.5 mL/kg/hr for VWF:RCo. During surgery, VWF:RCo, FVIII:C, and PFA-100 closure time were normalized. Until day 5, VWF:RCo was kept above 50%, from day 6 to 10 at least 30% activity were attained. FVIII:C levels were always >70%. The clinical course was uneventful without bleeding. Two weeks after hip surgery the patient was discharged from the hospital without complaints. The therapy described can be recommended as safe and feasible for further evaluation in aVWD patients who are hyporesponsive to ivIG treatment alone. Continuous VWF/FVIII infusion can improve substitution therapy in aVWD. PMID:11994985

  19. Living with von Willebrand Disease

    MedlinePlus

    ... Awareness Resources Contact The Health Information Center Health Professionals Systematic Evidence Reviews & Clinical Practice Guidelines Resources Continuing Education Researchers Funding Training & Career Development Division of Intramural Research Research Resources Research Meeting ...

  20. Assessment of the Olfactory Function in Italian Patients with Type 3 von Willebrand Disease Caused by a Homozygous 253 Kb Deletion Involving VWF and TMEM16B/ANO2

    PubMed Central

    Cenedese, Valentina; Mezzavilla, Massimo; Morgan, Anna; Marino, Renato; Ettorre, Cosimo Pietro; Margaglione, Maurizio; Gasparini, Paolo; Menini, Anna

    2015-01-01

    Type 3 Von Willebrand disease is an autosomal recessive disease caused by the virtual absence of the von Willebrand factor (VWF). A rare 253 kb gene deletion on chromosome 12, identified only in Italian and German families, involves both the VWF gene and the N-terminus of the neighbouring TMEM16B/ANO2 gene, a member of the family named transmembrane 16 (TMEM16) or anoctamin (ANO). TMEM16B is a calcium-activated chloride channel expressed in the olfactory epithelium. As a patient homozygous for the 253 kb deletion has been reported to have an olfactory impairment possibly related to the partial deletion of TMEM16B, we assessed the olfactory function in other patients using the University of Pennsylvania Smell Identification Test (UPSIT). The average UPSIT score of 4 homozygous patients was significantly lower than that of 5 healthy subjects with similar sex, age and education. However, 4 other members of the same family, 3 heterozygous for the deletion and 1 wild type, had a slightly reduced olfactory function indicating that socio-cultural or other factors were likely to be responsible for the observed difference. These results show that the ability to identify odorants of the homozygous patients for the deletion was not significantly different from that of the other members of the family, showing that the 253 kb deletion does not affect the olfactory performance. As other genes may compensate for the lack of TMEM16B, we identified some predicted functional partners from in silico studies of the protein-protein network of TMEM16B. Calculation of diversity for the corresponding genes for individuals of the 1000 Genomes Project showed that TMEM16B has the highest level of diversity among all genes of the network, indicating that TMEM16B may not be under purifying selection and suggesting that other genes in the network could compensate for its function for olfactory ability. PMID:25635880

  1. Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor.

    PubMed

    Shinagawa, Atsushi; Kojima, Hiroshi; Berndt, Michael C; Kaneko, Shin; Suzukawa, Kazumi; Hasegawa, Yuichi; Shigeta, Osamu; Nagasawa, Toshiro

    2005-05-01

    We have identified a patient with IgD lambda-type multiple myeloma who was characterized by a severe bleeding tendency, especially after puncture of arterial vessels. Both the bleeding time (>25 min) and activated partial thromboplastin time (APTT) were prolonged. To clarify the underlying pathogenesis, we purified the APTT-prolonging activity from the patient's serum. The purified protein was a highly negatively-charged homodimer of the lambda light chain. The lambda dimer protein (M-protein) inhibited ristocetinand high shear-induced platelet aggregation, dependent on platelet glycoprotein Ibalpha (GPIbalpha), but not epinephrine-, collagen-, ADP-, thrombin-, or botrocetin-induced platelet aggregation. The lambda dimer protein inhibited the binding of platelets to immobilized or ristocetin-treated von Willebrand factor (VWF). Furthermore, a 39/34 kD fragment of VWF encompassing the A1 domain specifically bound to the immobilized lambda dimer protein in the presence of ristocetin, suggesting that the lambda dimer protein directly binds to the A1 domain of VWF. To help elucidate the binding site within the A1 domain, binding of ristocetin-treated VWF to the immobilized lambda dimer protein was assayed in the presence of various anti-A1 domain monoclonal antibodies. Based on these data, we conclude that the lambda dimer protein binds to the region of the A1 domain composed of helices alpha3 and alpha4 and thus interferes with VWF-GPIbalpha interaction. The existence of a protein that inhibits high shear-induced platelet aggregation in acquired von Willebrand disease (VWD) has only rarely been reported. The results suggest that the hemostatic function in arteries with high shear force is profoundly disrupted if the binding of GPIbalpha to VWF is abrogated, supporting the relevance of shear-induced VWF interaction with GPIbalpha in the initiation of the hemostatic process. PMID:15886805

  2. Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-κB.

    PubMed

    Shahidi, Minoo; Mohsen Razavi, Seyed; Hayat, Parisa

    2016-09-01

    Although certain evidence has indicated a role for angiogenesis in the pathophysiology of hematopoietic malignancies, its role in chronic lymphocytic leukemia (CLL) prognosis is yet to be defined. To our knowledge, the effects of CLL plasma on cell culture have not been addressed. Therefore, we investigated the effects of CLL plasma on cell cycle regulation and von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs). Since nuclear factor-kappa B (NF-κB) transcription factor has been a therapeutic target for treatment of cancer, we inhibited NF-κB using small interfering RNA to clarify if there is a role for this factor in probable effects. The cells were treated with the plasma of patients with CLL. Subsequently, cell cycle phase distribution, vWF secretion, expression, and storage were detected using ELISA, flow cytometry, and immunohistochemical staining. In addition, NF-κB was inhibited using small interfering RNA. Plasma treatment promoted cell cycle progression by decreasing the cell number in G1 phase, while increasing the cell number in S phase and G2M phase. A significant increase of vWF expression, secretion, and storage was found, associated with the vWF levels of patients' plasma. We found that induction of cell cycle promotion, but not vWF expression and secretion, was partially suppressed by this inhibition. We found that endothelial cell cycle and vWF expression and secretion affected by CLL plasma and NF-κB play a role in the former. These findings would be useful for understanding the prognostic importance of plasma angiogenic factor levels in CLL. PMID:27472040

  3. How Is von Willebrand Disease Treated?

    MedlinePlus

    ... need treatment only if you have surgery, tooth extraction, or an accident. Medicines are used to: Increase ... used to stop bleeding after minor surgery, tooth extraction, or an injury. These medicines may be used ...

  4. Genetics Home Reference: von Willebrand disease

    MedlinePlus

    ... PubMed Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler ... JE, Yawn BP, James AH, Hultin MB, Manco-Johnson MJ, Weinstein M. Clinical and laboratory diagnosis of ...

  5. Platelet GpIbα Binding to von Willebrand Factor Under Fluid Shear: Contributions of the D'D3‐Domain, A1‐Domain Flanking Peptide and O‐Linked Glycans

    PubMed Central

    Madabhushi, Sri R.; Zhang, Changjie; Kelkar, Anju; Dayananda, Kannayakanahalli M.; Neelamegham, Sriram

    2014-01-01

    Background Von Willebrand Factor (VWF) A1‐domain binding to platelet receptor GpIbα is an important fluid‐shear dependent interaction that regulates both soluble VWF binding to platelets, and platelet tethering onto immobilized VWF. We evaluated the roles of different structural elements at the N‐terminus of the A1‐domain in regulating shear dependent platelet binding. Specifically, the focus was on the VWF D′D3‐domain, A1‐domain N‐terminal flanking peptide (NFP), and O‐glycans on this peptide. Methods and Results Full‐length dimeric VWF (ΔPro‐VWF), dimeric VWF lacking the D′D3 domain (ΔD′D3‐VWF), and ΔD′D3‐VWF variants lacking either the NFP (ΔD′D3NFP─‐VWF) or just O‐glycans on this peptide (ΔD′D3OG─‐VWF) were expressed. Monomeric VWF‐A1 and D′D3‐A1 were also produced. In ELISA, the apparent dissociation constant (KD) of soluble ΔPro‐VWF binding to immobilized GpIbα (KD≈100 nmol/L) was 50‐ to 100‐fold higher than other proteins lacking the D′D3 domain (KD~0.7 to 2.5 nmol/L). Additionally, in surface plasmon resonance studies, the on‐rate of D′D3‐A1 binding to immobilized GpIbα (kon=1.8±0.4×104 (mol/L)−1·s−1; KD=1.7 μmol/L) was reduced compared with the single VWF‐A1 domain (kon=5.1±0.4×104 (mol/L)−1·s−1; KD=1.2 μmol/L). Thus, VWF‐D′D3 primarily controls soluble VWF binding to GpIbα. In contrast, upon VWF immobilization, all molecular features regulated A1‐GpIbα binding. Here, in ELISA, the number of apparent A1‐domain sites available for binding GpIbα on ΔPro‐VWF was ≈50% that of the ΔD′D3‐VWF variants. In microfluidics based platelet adhesion measurements on immobilized VWF and thrombus formation assays on collagen, human platelet recruitment varied as ΔPro‐VWF<ΔD′D3‐VWF<ΔD′D3NFP─‐VWF<ΔD′D3OG─‐VWF. Conclusions Whereas VWF‐D′D3 is the major regulator of soluble VWF binding to platelet GpIbα, both the D′D3‐domain and N

  6. Evaluation of von Willebrand Factor and von Willebrand Factor Propeptide in Models of Vascular Endothelial Cell Activation, Perturbation, and/or Injury

    PubMed Central

    Brott, David A.; Katein, Anne; Thomas, Heath; Lawton, Michael; Montgomery, Robert R.; Richardson, Rudy J.; Louden, Calvert S.

    2014-01-01

    Pharmacologically, vasoactive agents targeting endothelial and/or smooth muscle cells (SMC) are known to cause acute drug-induced vascular injury (DIVI) and the resulting pathology is due to endothelial cell (EC) perturbation, activation, and/or injury. Alteration in EC structure and/or function may be a critical event in vascular injury and, therefore, evaluation of the circulatory kinetic profile and secretory pattern of EC-specific proteins such as VWF and VWFpp could serve as acute vascular injury biomarkers. In rat and dog models of DIVI, this profile was determined using pharmacologically diverse agents associated with functional stimulation/perturbation (DDAVP), pathological activation (lipopolysaccharide [LPS]/endotoxin), and structural damage (fenoldopam [FD], dopamine [DA], and potassium channel opener (PCO) ZD6169). In rats, FD caused moderate DIVI and time-related increase in plasma VWF levels ∼33% while in control rats VWF increased ∼5%. In dogs, VWF levels transiently increased ∼30% when there was morphologic evidence of DIVI by DA or ZD6169. However, in dogs, VWFpp increased >60-fold (LPS) and >6-fold (DDAVP), respectively. This was in comparison to smaller dynamic 1.38-fold (LPS) and 0.54-fold (DDAVP) increases seen in plasma VWF. Furthermore, DA was associated with a dose-dependent increase in plasma VWFpp. In summary, VWF and VWFpp can discriminate between physiological and pathological perturbation, activation, and injury to ECs. PMID:24499802

  7. Modification of the platelet binding domain of von Willebrand Factor (vWF)

    SciTech Connect

    Silverman, C.; Mascelli, M.A.; Karl, D.W.; Kirby, E.P.

    1986-05-01

    Bovine vWF has been modified with /sup 125/I-Bolton Hunter reagent (I/sup */-BHR) with a concomittant loss of its platelet agglutinating activity and a reduction in its ability to bind to platelets. BHR labels free alpha and epsilon amino groups. The I/sup */-BHR-vWF migrated as a single band of M/sub r/ = 210kD on reduced SDS polyacrylamide gels. Its multimeric composition on SDS agarose gels was identical to unlabeled vWF. Incorporation of an average of 1.2 moles of I/sup */-BHR/subunit vWF at pH 8.5 caused a 50% loss of platelet agglutinating activity. This represents less than 2% of the 118 lysine residues in each subunit vWF. No I/sup */-BHR was released after treatment with 1M hydroxylamine which would cleave O-acylated tyrosines. Digestion of both unlabeled and I/sup */-BHR-vWF with Protease 1, a metalloprotease from the venom of western diamondback rattlesnake, produces two fragments which have an M/sub r/ of 250kD and 200kD. The 250kD fragment contains the platelet binding site and is composed of 3 peptide chains with M/sub r/ 125kD, 78kD and 45kD. Gels of the 250kD fragment from I/sup */-BHR-vWF revealed radioactivity predominantly in the 125kD fragment, suggesting that the platelet binding site resides on the 125kD fragment.

  8. Immunoradiometric assay of factor VIII related antigen, with observations in 32 patients with von Willebrand's disease.

    PubMed

    Ruggeri, Z M; Mannucci, P M; Jeffcoate, S L; Ingram, G I

    1976-06-01

    A solid phase non-competitive immunoradiometric assay (IRMA) has been developed which allows measurement of factor VIII related antigen (VIIIR:AG) levels in normal plasma as low as 2.5 x 10(-4) U/ml. The assay is based on the extraction of VIIIR:AG from test plasma by means of polystrene tubes coated with a specific unlabelled anti-VIIIR:AG rabbit antiserum and subsequent labelling of the extracted antigen with 125I-labelled anti-VIIIR:AG rabbit IgG. PMID:1083743

  9. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher von Braun with Dr. Eberhard Rees and R.W. Cook at a press conference concerning Dr. Von Braun's assignment to NASA headquarters and Dr. Rees' subsequent assignment as Marshall Center director.

  10. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher Von Braun (left) and Fred W. Kelley examine a ST-100 Stellar Instrument Platform in the astrionics lab. Dr. Von Braun, then deputy associate administrator for planning, NASA, was visiting on the anniversary of the establishment of the Marshall Space Flight Center.

  11. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1968-01-01

    Dr. Wernher Von Braun, stands in front of a Saturn IB Launch Vehicle at Kennedy Space Center (KSC). Dr. Von Braun was Marshall's first Center Director (1960-1970). Under his leadership Marshall was responsible for the development of the Saturn rockets, the Skylab project and getting the United States into Space and landing on the moon with the Apollo missions.

  12. Dr. Wernher von Braun

    NASA Technical Reports Server (NTRS)

    2004-01-01

    Dr. von Braun is looking out from a 10th floor window of building 4200 at the Marshall Space Flight Center (MSFC). He was the first Center Director and served as the Director from July 1960 through February 1970. Following World War II, Dr. von Braun and his German colleagues arrived in the United States under the Project Paperclip (American acquisition of German rocket experts) to continue their rocket development work. In 1950, von Braun and his German Rocket Team (also called the Peenemuende Team) were transferred from Ft. Bliss, Texas to Huntsville, Alabama to work for the Army's rocket program at Redstone Arsenal and later, NASA's Marshall Space Flight Center (MSFC). Under Dr. von Braun's leadership, MSFC developed the Saturn V launch vehicle, which placed the first men, two American astronauts, on the Moon. Wernher von Braun's life was dedicated to expanding man's knowledge through the exploration of space.

  13. Increased von Willebrand factor antigen and high molecular weight multimers in sickle cell disease associated with nocturnal hypoxemia.

    PubMed

    Krishnan, Suba; Siegel, Jamie; Pullen, Gene; Hevelow, Megan; Dampier, Carlton; Stuart, Marie

    2008-01-01

    We evaluated vWF profiles in children and adolescents with SCD and sleep hypoxemia. Mean vWF:Ag levels were significantly elevated in the SCD-hypoxemia group when compared with SCD-normoxia and control groups (p=0.007); and correlated inversely with pulse oximetry (r=-0.54, p=0.01). Densitographic analyses of vWF multimer distribution also showed an inverse correlation between %HMW-multimers and oxygen saturation (r=-0.62, p=0.03). The previously reported association between nocturnal desaturation and SCD vascular complications, including stroke, may be influenced by hypoxemic modulation of vWF as noted in this study. PMID:18230405

  14. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice.

    PubMed

    Chen, Junmei; Reheman, Adili; Gushiken, Francisca C; Nolasco, Leticia; Fu, Xiaoyun; Moake, Joel L; Ni, Heyu; López, José A

    2011-02-01

    Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by systemic microvascular thrombosis caused by adhesion of platelets to ultra-large vWF (ULVWF) multimers. These multimers accumulate because of a deficiency of the processing enzyme ADAMTS13. vWF protein forms long multimers from homodimers that first form through C-terminal disulfide bonds and then join through their N termini by further disulfide bonding. N-acetylcysteine (NAC) is an FDA-approved drug that has long been used to treat chronic obstructive lung disease and acetaminophen toxicity and is known to function in the former disorder by reducing mucin multimers. Here, we examined whether NAC could reduce vWF multimers, which polymerize in a manner similar to mucins. In vitro, NAC reduced soluble plasma-type vWF multimers in a concentration-dependent manner and rapidly degraded ULVWF multimer strings extruded from activated ECs. The effect was preceded by reduction of the intrachain disulfide bond encompassing the platelet-binding A1 domain. NAC also inhibited vWF-dependent platelet aggregation and collagen binding. Injection of NAC into ADAMTS13-deficient mice led to the rapid resolution of thrombi produced by ionophore treatment of the mesenteric venules and reduced plasma vWF multimers. These results suggest that NAC may be a rapid and effective treatment for patients with TTP. PMID:21266777

  15. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher Von Braun (right), Deputy Associate Administrator for planning, National Aeronautics and Space Administration, inspects the mockup of the Saturn Workshop during a visit marking the 10th anniversary of the Marshall Center. Shown with Dr. Von Braun, from left to right, are Karl Heimburg, Director of the astronautics lab; Herman K. Weidner, Director of Science and Engineering, and George Hardy of the Astronautics lab.

  16. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher Von Braun (right), Deputy Associate Administrator for Planning, National Aeronautics and Space Administration, inspects the mockup of the Saturn Workshop during a visit marking the 10th anniversary of the Marshall Center. Shown with Dr. Von Braun, from left to right, are Karl Heimburg, Director of the Astronautics Lab; Herman K. Weidner, Director of Science and Engineering, and George Hardy of the Astronautics Lab.

  17. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    A camerman catches Dr. Wernher Von Braun, Director of the Marshall Space Flight Center, his son, Peter, and daughter, Martgrit, as they arrive at the employee picnic held to celebrate man's first landing on the moon 6 days earlier. In the foreground is David R. Newby, Director of Administration and Technical Services at the Marshall Space Flight Center.

  18. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Shown viewing the Apollo telescope mockup are, from left to right, Charles Donlan, deputy associate administrator for manned space flight; Dr. Wernher Von Braun, Marshall Space Flight Center director; William Horton, astrionics lab; Dr. Thomas Paine, NASA deputy administrator; Warner Kuers, director of the ME lab.

  19. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Marshall Space Flight Center director Wernher Von Braun and his family were honored with a series of events prior to his relocation to Washington, D.C. where he was assigned duties at NASA headquarters as deputy associate administrator for planning. Here he is shown with General Richard Drury and Hazel Toftoy, widow of General H.N. Toftoy.

  20. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1968-01-01

    Dr. Wernher von Braun, Director of the Marshall Space Flight Center, explains the purpose of a thermal curtain in the mockup of a Saturn I workshop to U.S. Representative Armistead Seldon of Alabama. The Congressman visited the Marshall Center on March 2, 1968 to tour the workshop and to visit Marshall Center facilities.

  1. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1968-01-01

    U.S. Representative Armistead Seldon (D.-Al) inspects the food preparation area of the Saturn I workshop mockup during a visit to the Marshall Space Flight Center. Explaining the operation of the food preparation area to the congressman is Dr. Wernher Von Braun, Marshall Space Flight Center director.

  2. Analytik von Lebensmittelallergenen

    NASA Astrophysics Data System (ADS)

    Demmel, Anja; Hahn, Alexandra

    Ansonsten harmlose Lebensmittel oder deren Bestandteile können bei von Lebensmittelallergien betroffenen Personen Überempfindlichkeitsreaktionen auslösen. Hierbei kann es sich um immunvermittelte Lebensmittelallergien oder um Intoleranzen gegenüber bestimmten Lebensmittelbestandteilen handeln. Ein Beispiel für Letzteres ist die Laktoseintoleranz, welche durch einen Enzymdefekt hervorgerufen wird [1]. Im Gegensatz hierzu handelt es sich bei Lebensmittelallergien um Sofortreaktionen, die durch IgE-Antikörper gegen Antigene aus den Lebensmitteln hervorgerufen werden und zu verschiedenen körperlichen Beschwerden führen können. Bei den Antigenen, welche von den von Allergikern produzierten IgE-Antikörpern erkannt werden, handelt es sich vor allem um Proteine [2]. Symptome IgE-vermittelter Reaktionen können zum Beispiel Hautausschlag, eine Schwellung der Schleimhäute oder das sogenannte orale Allergiesyndrom mit allergischen Reaktionen an der Mundschleimhaut und im Magen-Darm-Trakt sein [3]. Die hierbei auftretenden Beschwerden reichen von einem Brennen im Mund und einer Schwellung der Lippen und der Zunge bis zu Atemnot verursachenden Schwellungen im Kehlkopfbereich. In besonders schlimmen Fällen können allergische Reaktionen zu einem anaphylaktischen Schock und zum Tod durch Kreislaufversagen führen [4]. Während klassische Nahrungsallergene häufig komplexe Reaktionen zur Folge haben, ist bei Pollen-assoziierten Nahrungsmittelallergien das orale Allergiesyndrom vorherrschend.

  3. Dr. von Braun at 'Wernher von Braun Day' Celebration

    NASA Technical Reports Server (NTRS)

    1970-01-01

    In 1970 Marshall Space Flight Center (MSFC) Director Dr. Wernher von Braun (right) was reassigned to NASA Headquarters to serve as Deputy Associate Administrator for Plarning. Prior to his transfer, Dr. von Braun was honored for his career in Huntsville, Alabama, with the celebration of 'Wernher von Braun Day.' Among those participating were Alabama Governor Albert Brewer (left) and Alabama Senator John Sparkman (center). (Courtesy of Huntsville/Madison County Public library)

  4. Von Willlebrand Adhesion to Surfaces at High Shear Rates Is Controlled by Long-Lived Bonds

    PubMed Central

    Sing, Charles E.; Selvidge, Jennifer G.; Alexander-Katz, Alfredo

    2013-01-01

    Von Willebrand factor (vWF) adsorbs and immobilizes platelets at sites of injury under high-shear-rate conditions. It has been recently demonstrated that single vWF molecules only adsorb significantly to collagen above a threshold shear, and here we explain such counterintuitive behavior using a coarse-grained simulation and a phenomenological theory. We find that shear-induced adsorption only occurs if the vWF-surface bonds are slip-resistant such that force-induced unbinding is suppressed, which occurs in many biological bonds (i.e., catch bonds). Our results quantitatively match experimental observations and may be important to understand the activation and mechanical regulation of vWF activity during blood clotting. PMID:24047999

  5. von Willebrand’s disease: a report from a meeting in the Åland islands

    PubMed Central

    BERNTORP, E.; PEAKE, I.; BUDDE, U.; LAFFAN, M.; MONTGOMERY, R.; WINDYGA, J.; GOODEVE, A.; PETRINI, P.; DEPKA, M.VON; MIESBACH, W.; LILLICRAP, D.; FEDERICI, A. B.; LASSILA, R.; WHITE, G.

    2014-01-01

    Summary von Willebrand’s disease (VWD) is probably the most common bleeding disorder, with some studies indicating that up to 1% of the population may have the condition. Over recent years interest in VWD has fallen compared to that of haemophilia, partly the result of focus on blood-borne diseases such as HIV and hepatitis. Now the time has come to revisit VWD, and in view of this some 60 international physicians with clinical and scientific interest in VWD met over 4 days in 2010 in the Åland islands to discuss state-of-the-art issues in the disease. The Åland islands are where Erik von Willebrand had first observed a bleeding disorder in a number of members of a family from Föglö, and 2010 was also the 140th anniversary of his birth. This report summarizes the main papers presented at the symposium; topics ranged from genetics and biochemistry through to classification of VWD, pharmacokinetics and laboratory assays used in the diagnosis of the disease, inhibitors, treatment guidelines in different age groups including the elderly who often have comorbid conditions that present challenges, and prophylaxis. Other topics included managing surgeries in patients with VWD and the role of FVIII in VWF replacement, a controversial subject. PMID:22906074

  6. Theodore von Karman

    NASA Technical Reports Server (NTRS)

    1950-01-01

    Dr. Theodore von Karman, co-founder of the Jet Propulsion Laboratory (JPL) Pasadena, California was an aeronautical theoretician. His contributions in the fields of aerodynamics and aeronautical engineering are well documented and well known to every aerospace engineer. He was the first winner of the prestigious U.S. Medal of Science presented to him by President John F. Kennedy. As well as being co-founder of JPL, he also was principal founder of a major rocket propulsion firm (Aerojet-General Corp.), the top science advisor to the U.S. Air Force during its transition to jet propulsion aircraft and the top science advisor to NATO. He was, during much of this time, the fountainhead of aerodynamic thought as head of the Guggenheim Aeronautical Laboratory at the California Institute of Technology (GALCIT) in Pasadena, California. In the May 1956 issue of the Journal of Aeronautical Sciences, it was said of him that 'No other man has had so great an impact on the development of aeronautical science in this country. Hundreds of young men became his students and scientific collaborators and were inspired to greater effort.' Dr. William H. Pickering, then director of JPL said in 1960 'We wouldn't have an aeronautical science as we know it today, if it weren't for Dr. Thoedore von Karman.' Under his guidance, Caltech's 10 foot wind tunnel was designed, built and operated. Industry firms such as Douglas, Northrop, Hughes, Lockheed, North American, Vultee and Consolidated all tested new aeronautical designs and concepts in GALCIT's tunnel. Even Boeing's own high-speed wind tunnel was heavily influenced by suggestions from von Karman. The National Advisory Committee for Aeronautics (NACA) became so concerned about GALCIT's growing influence over West coast aviation, it erected the Ames Laboratory in Sunnyvale, California in part to deter an ever widening aeronautical gap that had formed between NACA and GALCIT. From 1936 to 1940, Caltech stood alone as the only university

  7. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Thomas Paine, Deputy Administrator of the National Aeronautics and Space Administration, examines an ordinary man's shoe outfitted for use in the Saturn I workshop. Pictured from the left in the Saturn I workshop mockup are William Brooksbank, propulsion and vehicle engineering laboratory; Dr. Paine; Dr. Wernher Von Braun, Marshall Center director; Colonel Clare F. Farley, Executive Officer in the Office Of The Administrator; and Charles J. Donlan, Deputy Associate Administrator for Manned Space Flight, Technical. the shoe Dr. Paine is holding has a unique fastener built into the sole to allow an astronaut to move about on the workshop floor and to remain in one position if he desires.

  8. John von Neumann Birthday Centennial

    SciTech Connect

    Grcar, Joseph F.

    2004-11-12

    In celebration of John von Neumann's 100th birthday, a series of four lectures were presented on the evening of February 10, 2003 during the SIAM Conference on Computational Science and Engineering in San Diego. The venue was appropriate because von Neumann spent much of the later part of his life, in the 1950's, as an unofficial ambassador for computational science. He was then the only senior American scientist who had experience with the new computers (digital, electronic, and programmable) and a vision of their future importance. No doubt he would have relished the chance to attend a meeting such as this. The first speaker, William Aspray, described the ''interesting times'' during which computers were invented. His remarks were based on his history [1] of this period in von Neumann's life. We were honored to have John von Neumann's daughter, Marina von Neumann-Whitman, as our second speaker. Other accounts of von Neumann's life can be found in books by two of his colleagues [2] and [3]. Our third speaker, Peter Lax, provided both mathematical and international perspectives on John von Neumann's career. Finally, Pete Stewart spoke about von Neumann's numerical error analysis [4] in the context of later work; this talk did not lend itself to transcription, but readers may consult the historical notes in [5]. Our thanks to all the speakers for a remarkable evening. We are grateful to the DOE Applied Mathematical Sciences (AMS) program for partially supporting these lectures. Thanks are also due to SIAM and William Kolata, to our emcee, Gene Golub, to Paul Saylor for recording and editing, and to Barbara Lytle for the transcriptions. More about von Neumann's work can be learned from the recent American Mathematical Society proceedings [6].

  9. Extraktion von DNA

    NASA Astrophysics Data System (ADS)

    Pöpping, Bert; Unterberger, Claudia

    Eine DNA-gestützte Analytik spielt im Lebensmittelbereich eine große Rolle. So wird die PCR bzw. die Real Time PCR z. B. für den Nachweis von Krankheitserreger in Lebensmitteln, zur Tier- und Pflanzenartendifferenzierung und den Nachweis von gentechnologisch veränderten Organismen eingesetzt [1]. Grundvoraussetzung für die sehr sensitiven molekularbiologischen Methoden ist eine saubere und kontaminationsfreie Nukleinsäure [2]. Die Qualität der Nukleinsäure entscheidet über Erfolg und Misserfolg der anschließenden molekularbiologischen Analytik. Deshalb werden im Bereich der Lebensmittelanalytik hohe Anforderungen an das jeweilige DNA-Extraktionsprotokoll gestellt. Durch die Anwendung eines geeigneten Extraktionsverfahrens soll die nachzuweisende DNA möglichst in hochmolekularer Form und frei von die nachfolgende Analytik hemmenden Substanzen vorliegen [1]. Gerade hier stellt die Natur der Lebensmittelmatrix eine besondere Herausforderung dar. Matrixkomponenten wie Fette, Zucker, Proteine und sekundäre Inhaltsstoffe erschweren die DNA-Extraktion und können, wenn sie nicht durch die Extraktion vollständig entfernt werden, zu einer Inhibierung der PCR führen [3]. Des Weiteren müssen auf der Matrixoberfläche vorhandene DNA-abbauende Enzyme gehemmt werden [1]. Daneben spielt der Einfluss verschiedener chemischer und physikalischer Parameter (pH-Wert, Temperatur, Enzyme, Scherkräfte) bei der Lebensmittelproduktion eine große Rolle für die Qualität der extrahierten DNA. So führen z. B. hohe Temperaturen und saure pH-Werte während der Lebensmittelverarbeitung zu einer Fragmentierung der DNA. Auch die physikalischen und chemischen Bedingungen der verwendeten Extraktionsmethode beeinflussen die Qualität der DNA [2]. Bleiben nach der Extraktion organische Lösungsmittel (Phenol, Ethanol), Enzyme, Proteine oder Salze zurück, können diese ebenfalls eine nachfolgende PCR inhibieren. Um eine Inhibition der PCR auszuschließen, sollten in der

  10. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1960-01-01

    On September 8, 1960 President Dwight D. Eisenhower visited Huntsville, Alabama to dedicate a new NASA field center in honor of General George C. Marshall, Eisenhower's wartime colleague and the founder of the famous Marshall Plan for European recover after World War II. The new George C. Marshall Space Flight Center was placed under the control of Dr. Wernher Von Braun shown here talking with President Eisenhower. As parto f his remarks dedicating the center, President Eisenhowe refereed to General Marshall as a 'man of yar, yet a builder of peace'. the Marshall Center's first major assignment including building the huge Saturn V rocket that launched human beings on their first journey to the surface of the moon in 1969.

  11. von Hippel-Lindau syndrome.

    PubMed

    Chou, Angela; Toon, Christopher; Pickett, Justine; Gill, Anthony J

    2013-01-01

    von Hippel-Lindau (VHL) disease is an autosomal-dominant familial cancer syndrome associated with mutations of the VHL tumor suppressor gene (3p25-26). Its estimated incidence ranges from 1 in 36,000 to 1 in 53,000 with a penetrance of up to 95% by age 60. Genotype-phenotype correlation divides VHL into two broad clinical subtypes. Type 1 VHL is predominantly associated with large deletion or truncation mutations which result in an encoded protein with very little or no activity. It is associated with retinal and CNS hemangioblastoma and renal cell carcinoma but not pheochromocytoma. Type 2 is usually associated with missense mutations encoding a protein with limited activity and includes pheochromocytoma. It is further classified into three other subtypes (2A, 2B, 2C) based on the presence of hemangioblastoma and renal cell carcinoma. Visceral cysts in the kidney, pancreas and epididymis, nonfunctioning pancreatic neuroendocrine tumors which often show distinctive clear cell cytology, endolymphatic sac tumors and head and neck paragangliomas are well recognized but less common presenting features. Surveillance of carriers can reduce the burden of disease and is best performed in specialist referral centers with due consideration given to both the complex molecular pathogenesis and psychosocial aspects of the disease. PMID:23652669

  12. von Braun and German Publisher

    NASA Technical Reports Server (NTRS)

    1969-01-01

    In this photograph, Guenter Ogger of Capitol Magazine, West Germany, greets Marshall Space Flight Center Director, Dr. Wernher von Braun. Mr. Ogger interviewed the famous rocket scientist for his magazine.

  13. Von Hippel-Lindau Disease.

    PubMed

    Findeis-Hosey, Jennifer J; McMahon, Kelly Q; Findeis, Sarah K

    2016-06-01

    Von Hippel-Lindau disease is an autosomal dominant syndrome which occurs secondary to germline mutations in the VHL tumor suppressor gene, located on chromosome 3. Clinically von Hippel-Lindau disease is characterized by an increased risk of developing simple visceral cysts, most commonly in the pancreas and kidneys, in addition to an increased risk of developing neoplasms, often with clear cell features, in a multitude of organ systems. The most common neoplasms are cerebellar and retinal hemangioblastomas, adrenal pheochromocytomas, clear cell renal cell carcinomas, pancreatic neuroendocrine tumors, pancreatic serous cystadenomas, and endolymphatic sac tumors. These lesions most commonly present during adulthood; however, screening and surveillance for the development of these lesions should begin in the pediatric years for patients with von Hippel-Lindau disease. In this review article, the genetics and most common neoplasms of von Hippel-Lindau disease are reviewed, with an eye towards implications for the pediatric patient. PMID:27617152

  14. Die Kosmogonie Anton von Zachs.

    NASA Astrophysics Data System (ADS)

    Brosche, P.

    In his "Cosmogenische Betrachtungen" (1804), Anton von Zach rediscovered - probably independently - some aspects of the theories of Kant and Laplace. More originally, he envisaged also the consequences of an era of heavy impacts in the early history of the Earth.

  15. Pregnancy and von Gierke's disease.

    PubMed

    Farber, M; Knuppel, R A; Binkiewicz, A; Kennison, R D

    1976-02-01

    A detailed description of the course of pregnancy in a patient with von Gierke's disease is presented. Careful dietary control together with proper management of the hematologic complications of the disease led to a successful outcome. PMID:1061911

  16. A G{sub +3}-to-T donor splice site mutation leads to skipping of exon 50 in von Willebrand factor mRNA

    SciTech Connect

    Mertes, G.; Schwaab, R.; Brackmann, H.H.; Ludwig, M.

    1994-11-01

    Genomic DNA was prepared from leukocytes, and platelet-derived total mRNA was isolated by lysis of thrombocytes in 4 M guanidinium hydrochloride followed by precipitation in 2 M lithium chloride twice. PCR reactions were performed using either RT-PCR primers or genomic PCR-primers. Preferential signle-strand amplification for both PCR products was carried out with nested RT-PCR primers.

  17. A factor VIII-derived peptide enables von Willebrand factor (VWF)-binding of artificial platelet nanoconstructs without interfering with VWF-adhesion of natural platelets

    NASA Astrophysics Data System (ADS)

    Haji-Valizadeh, Hassan; Modery-Pawlowski, Christa L.; Sen Gupta, Anirban

    2014-04-01

    There is substantial clinical interest in synthetic platelet analogs for potential application in transfusion medicine. To this end, our research is focused on self-assembled peptide-lipid nanoconstructs that can undergo injury site-selective adhesion and subsequently promote site-directed active platelet aggregation, thus mimicking platelet's primary hemostatic actions. For injury site-selective adhesion, we have utilized a coagulation factor FVIII-derived VWF-binding peptide (VBP). FVIII binds to VWF's D'-D3 domain while natural platelet GPIbα binds to VWF's A1 domain. Therefore, we hypothesized that the VBP-decorated nanoconstructs will adhere to VWF without mutual competition with natural platelets. We further hypothesized that the adherent VBP-decorated constructs can enhance platelet aggregation when co-decorated with a fibrinogen-mimetic peptide (FMP). To test these hypotheses, we used glycocalicin to selectively block VWF's A1 domain and, using fluorescence microscopy, studied the binding of fluorescently labeled VBP-decorated nanoconstructs versus platelets to ristocetin-treated VWF. Subsequently, we co-decorated the nanoconstructs with VBP and FMP and incubated them with human platelets to study construct-mediated enhancement of platelet aggregation. Decoration with VBP resulted in substantial construct adhesion to ristocetin-treated VWF even if the A1-domain was blocked by glycocalicin. In comparison, such A1-blocking resulted in significant reduction of platelet adhesion. Without A1-blocking, the VBP-decorated constructs and natural platelets could adhere to VWF concomitantly. Furthermore, the constructs co-decorated with VBP and FMP enhanced active platelet aggregation. The results indicate significant promise in utilizing the FVIII-derived VBP in developing synthetic platelet analogs that do not interfere with VWF-binding of natural platelets but allow site-directed enhancement of platelet aggregation when combined with FMP.There is substantial clinical interest in synthetic platelet analogs for potential application in transfusion medicine. To this end, our research is focused on self-assembled peptide-lipid nanoconstructs that can undergo injury site-selective adhesion and subsequently promote site-directed active platelet aggregation, thus mimicking platelet's primary hemostatic actions. For injury site-selective adhesion, we have utilized a coagulation factor FVIII-derived VWF-binding peptide (VBP). FVIII binds to VWF's D'-D3 domain while natural platelet GPIbα binds to VWF's A1 domain. Therefore, we hypothesized that the VBP-decorated nanoconstructs will adhere to VWF without mutual competition with natural platelets. We further hypothesized that the adherent VBP-decorated constructs can enhance platelet aggregation when co-decorated with a fibrinogen-mimetic peptide (FMP). To test these hypotheses, we used glycocalicin to selectively block VWF's A1 domain and, using fluorescence microscopy, studied the binding of fluorescently labeled VBP-decorated nanoconstructs versus platelets to ristocetin-treated VWF. Subsequently, we co-decorated the nanoconstructs with VBP and FMP and incubated them with human platelets to study construct-mediated enhancement of platelet aggregation. Decoration with VBP resulted in substantial construct adhesion to ristocetin-treated VWF even if the A1-domain was blocked by glycocalicin. In comparison, such A1-blocking resulted in significant reduction of platelet adhesion. Without A1-blocking, the VBP-decorated constructs and natural platelets could adhere to VWF concomitantly. Furthermore, the constructs co-decorated with VBP and FMP enhanced active platelet aggregation. The results indicate significant promise in utilizing the FVIII-derived VBP in developing synthetic platelet analogs that do not interfere with VWF-binding of natural platelets but allow site-directed enhancement of platelet aggregation when combined with FMP. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr06400j

  18. A factor VIII-derived peptide enables von Willebrand factor (VWF)-binding of artificial platelet nanoconstructs without interfering with VWF-adhesion of natural platelets†

    PubMed Central

    Haji-Valizadeh, Hassa n; Modery-Pawlowski, Christa L.

    2015-01-01

    There is substantial clinical interest in synthetic platelet analogs for potential application in transfusion medicine. To this end, our research is focused on self-assembled peptide–lipid nanoconstructs that can undergo injury site-selective adhesion and subsequently promote site-directed active platelet aggregation, thus mimicking platelet’s primary hemostatic actions. For injury site-selective adhesion, we have utilized a coagulation factor FVIII-derived VWF-binding peptide (VBP). FVIII binds to VWF’s D′–D3 domain while natural platelet GPIbα binds to VWF’s A1 domain. Therefore, we hypothesized that the VBP-decorated nanoconstructs will adhere to VWF without mutual competition with natural platelets. We further hypothesized that the adherent VBP-decorated constructs can enhance platelet aggregation when co-decorated with a fibrinogen-mimetic peptide (FMP). To test these hypotheses, we used glycocalicin to selectively block VWF’s A1 domain and, using fluorescence microscopy, studied the binding of fluorescently labeled VBP-decorated nanoconstructs versus platelets to ristocetin-treated VWF. Subsequently, we co-decorated the nanoconstructs with VBP and FMP and incubated them with human platelets to study construct-mediated enhancement of platelet aggregation. Decoration with VBP resulted in substantial construct adhesion to ristocetin-treated VWF even if the A1-domain was blocked by glycocalicin. In comparison, such A1-blocking resulted in significant reduction of platelet adhesion. Without A1-blocking, the VBP-decorated constructs and natural platelets could adhere to VWF concomitantly. Furthermore, the constructs co-decorated with VBP and FMP enhanced active platelet aggregation. The results indicate significant promise in utilizing the FVIII-derived VBP in developing synthetic platelet analogs that do not interfere with VWF-binding of natural platelets but allow site-directed enhancement of platelet aggregation when combined with FMP. PMID:24658160

  19. Modellierung von Anwenderverhalten im Social Semantic Web

    NASA Astrophysics Data System (ADS)

    Ulbrich, Armin; Höfler, Patrick; Lindstaedt, Stefanie

    Ziel dieses Kapitels ist es, gemeinsame Verwendungsszenarien des Semantic Web und des Social Web zu identifizieren und zu benennen. Dabei wird ein Teilaspekt des Themengebiets im Detail betrachtet: die Nutzung von Services, die Beobachtungen des Verhaltens von Anwendern analysieren, um daraus maschinell interpretierbare Informationen zu erhalten und diese als Modelle zu organisieren. Es werden zunächst einige Eigenschaften und Unterscheidungsmerkmale von Anwenderverhalten und organisierten Modellen dargestellt. Anschließend wird der mögliche wechselseitige Nutzen von Anwenderverhalten und Modellen diskutiert. Den Abschluss bildet eine Betrachtung einiger exemplarischer Software-Services, die heute schon verwendet werden, um Anwenderverhalten in Modelle überzuführen.

  20. Von Neumann was not a Quantum Bayesian.

    PubMed

    Stacey, Blake C

    2016-05-28

    Wikipedia has claimed for over 3 years now that John von Neumann was the 'first quantum Bayesian'. In context, this reads as stating that von Neumann inaugurated QBism, the approach to quantum theory promoted by Fuchs, Mermin and Schack. This essay explores how such a claim is, historically speaking, unsupported. PMID:27091166

  1. Dr. Wernher Von Braun greeting dignitaries.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher Von Braun, left, greets vice president Spiro T. Agnew in the Launch Control Center for the Apollo 14 mission. Between Dr. Von Braun and Mr. Agnew are their Royal Highnesses, The Prince and Princess of Spain. The royal visitors greeted the launch control team in th enter after the launch of Apollo 14.

  2. Dr. Wernher Von Braun at a picnic.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher Von Braun, director of the Marshall Space Flight Center, stakes claim to a table for the picnic celebrating man's first lunar landing. With Dr. Von Braun are his wife, Maria (seated, right), and son, Peter (back to camera). His daughter, Margrit, was also present, but is hidden from view by friends in this view.

  3. Franz Xaver von Zach in England

    NASA Astrophysics Data System (ADS)

    McConnell, Anita

    F.X. von Zach arrived in London in November 1783, and was employed as tutor to George, son of Count von Brühl, the Saxonian commercial diplomat. Von Zach became a part of von Brühl's household, and was thus in close contact with the leading astronomers, horologists, and scientific instrument makers. Before he departed to Gotha in 1788, he was awarded an honorary degree by Oxford University under false pretences, he upset the Astronomer Royal, and was twice rejected by the Royal Society. At von Brühl's country house he was shown the manuscripts of the mathematician Thomas Harriot (d. 1621); but his attempts to publicise them were hampered by his misreadings, and his treatment of the documents caused confusion in England's scientific community, which lasted throughout his lifetime.

  4. Dr. Wernher von Braun Laid to Rest

    NASA Technical Reports Server (NTRS)

    1977-01-01

    Dr. Wernher von Braun served as Marshall Space Flight Center's first director from July 1, 1960 until January 27, 1970, when he was appointed NASA Deputy Associate Administrator for Planning. Following World War II, Dr. von Braun and his German colleagues arrived in the United States under Project Paper Clip to continue their rocket development work. In 1950, von Braun and his rocket team were transferred from Ft. Bliss, Texas to Huntsville, Alabama to work for the Army's rocket program at Redstone Arsenal and later, NASA's Marshall Space Flight Center. Under von Braun's leadership, Marshall developed the Saturn V launch vehicle which took Apollo astronauts to the moon. Dr. von Braun died in Alexandria, Va., on June 16, 1977, seven years after his NASA appointment. This photo was taken at the site where he was laid to rest.

  5. Dr. Wernher von Braun In His Office

    NASA Technical Reports Server (NTRS)

    1964-01-01

    Dr. Wernher von Braun served as Marshall Space Flight Center's first director from July 1, 1960 until January 27, 1970, when he was appointed NASA Deputy Associate Administrator for Planning. Following World War II, Dr. von Braun and his German colleagues arrived in the United States under Project Paperclip to continue their rocket development work. In 1950, von Braun and his rocket team were transferred from Ft. Bliss, Texas to Huntsville, Alabama to work for the Army's rocket program at Redstone Arsenal and later, NASA's Marshall Space Flight Center. Under von Braun's leadership, Marshall developed the Saturn V launch vehicle which took Apollo astronauts to the moon. This photo depicts von Braun in his office at MSFC.

  6. Dr. Wernher von Braun in his Office

    NASA Technical Reports Server (NTRS)

    1960-01-01

    Dr. Wernher von Braun is in his office, with an artist's concept of a lunar lander in background and models of Mercury-Redstone, Juno, and Saturn I. Dr. Wernher von Braun, the first MSFC Director, led a team of German rocket scientists, called the Rocket Team, to the United States, first to Fort Bliss/White Sands, later being transferred to the Army Ballistic Missile Agency at Redstone Arsenal in Huntsville, Alabama. They were further transferred to the newly established NASA/Marshall Space Flight Center (MSFC) in Huntsville, Alabama in 1960, and Dr. von Braun became the first Center Director.

  7. Renaturierung und Management von Heiden

    NASA Astrophysics Data System (ADS)

    Härdtle, Werner; Assmann, Thorsten; van Diggelen, Rudy; von Oheimb, Goddert

    Heiden zählen zu den ältesten und besonders reizvollen Kulturlandschaften Nordwesteuropas. Sie sind bezeichnend für nährstoffarme Böden in wintermilden Gebieten mit hohen Sommerniederschlägen. Während Heiden vor wenigen Jahrhunderten noch weit verbreitet und für manche Landschaften sogar prägend waren, hat sich ihr Areal heute auf wenige, meist in Naturschutzgebieten gelegene Restbestände verkleinert. Zu diesem Rückgang haben maßgeblich Änderungen der Landnutzung, aber auch Nährstoffeinträge aus umgebenden Agrarflächen und atmogene Depositionen beigetragen. In den meisten Ländern der Europäischen Union sind Heiden heute gesetzlich geschützte Ökosysteme, da diese, neben ihrem Erholungswert für den Menschen, Pflanzen- und Tierarten beherbergen, die außerhalb von Heiden nicht oder kaum überlebensfähig sind.

  8. Wally Schirra Greets Dr. Wernher von Braun

    NASA Technical Reports Server (NTRS)

    1968-01-01

    Apollo 7 Commander Walter M. Schirra, Jr., left, greets Dr. Wernher Von Braun, Director, Marshall Space Flight Center and Dr. Kurt Debus, Right, KSC Director, during a prelaunch mission briefing held at the Florida Spaceport.

  9. Von Hippel-Lindau Disease (VHL)

    MedlinePlus

    ... Funding Information Research Programs Training & Career Awards Enhancing Diversity Find People About NINDS NINDS Von Hippel-Lindau ... News From NINDS | Find People | Training | Research | Enhancing Diversity Careers@NINDS | FOIA | Accessibility Policy | Contact Us | Privacy ...

  10. Dr. von Braun With German Rocket Experimenters

    NASA Technical Reports Server (NTRS)

    1930-01-01

    Dr. von Braun was among a famous group of rocket experimenters in Germany in the 1930s. This photograph is believed to be made on the occasion of Herman Oberth's Kegelduese liquid rocket engine being certified as to performance during firing. From left to right are R. Nebel, Dr. Ritter, Mr. Baermueller, Kurt Heinish, Herman Oberth, Klaus Riedel, Wernher von Braun, and an unidentified person.

  11. Dr. von Braun Reviewing Spacecraft Plans

    NASA Technical Reports Server (NTRS)

    1970-01-01

    This photograph was taken after Dr. von Braun moved from his post as Director of the Marshall Space Flight Center (MSFC) to Deputy Associate Administrator for Planning at NASA Headquarters. On June 27, 1970, he visited the MSFC again during the center's 10th anniversary to look at a mockup of the spacecraft that would later be known as Skylab. In this photograph, von Braun is talking with George Hardy of the MSFC Astronautics Lab.

  12. Dr. von Braun Reviewing Spacecraft Plans

    NASA Technical Reports Server (NTRS)

    1970-01-01

    This photograph was taken after Dr. von Braun moved from his post as Director of the Marshall Space Flight Center (MSFC) to Deputy Associate Administrator for Planning at NASA Headquarters. On June 27, 1970, he visited the MSFC again during the center's 10th anniversary to look at a mockup of the spacecraft that would later be known as Skylab. In this photograph, von Braun (left) and Fred W. Kelley examine an ST-100 stellar instrument platform in MSFC's Astrionics Lab.

  13. Childhood Picture of Dr. von Braun

    NASA Technical Reports Server (NTRS)

    1912-01-01

    This is a childhood picture of Dr. von Braun (center) with his brothers. Dr. Wernher von Braun was born in Wirsitz, Germany, March 23, 1912. His childhood dreams of marned space flight were fulfilled when giant Saturn rockets, developed under his direction at NASA's Marshall Space Flight Center, boosted the manned Apollo spacecraft to the Moon. His life was dedicated to expanding man's knowledge through the exploration of space.

  14. Dr. von Braun at the Farewell Ceremony

    NASA Technical Reports Server (NTRS)

    1970-01-01

    Dr. von Braun was honored with a series of farewell events and ceremonies prior to his reassignment to NASA Headquarters in Washington, D.C. Alabama Governor Brewer greets Dr. von Braun following his speech at the front of the Madison County Courthouse in Huntsville, Alabama on February 24, 1970. Behind are Madison County Commissioner James Record, Huntsville Mayor Joe Davis, and U.S. Senator Sparkman.

  15. Archivalische Quellen zum Leben und Werk von Franz Xaver von Zach.

    NASA Astrophysics Data System (ADS)

    Wattenberg, D.; Brosche, P.

    Franz Xaver von Zach (1754 - 1832) gehörte um die Wende vom 18. zum 19. Jahrhundert zu den angesehensten und profiliertesten Astronomen. Anliegen dieser Untersuchung ist es, handschriftliche Quellen von Zachs nachzuweisen - auch wenn Vollständigkeit vorläufig nicht erreicht werden kann.

  16. Dr. Wernher Von Braun with Dr. Christian Barnard.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Christian Barnard Tours Marshall Space Flight Center. Shown in Dr. Von Braun's office are (left to right): Dr. Ernst Sthulinger, a representative from General Electric, Dr. Wernher Von Braun, Dr. Christian Barnard, and Dr. Eberhard Rees.

  17. Dr. von Braun Surrenders to U.S. Army

    NASA Technical Reports Server (NTRS)

    1945-01-01

    Dr. Wernher von Braun surrenders to U.S. Army Counterintelligence persornel of the 44th Infantry Division in Ruette, Bavaria on May 2, 1945. Left to right are Charles Stewart, CIC agent; Dr. Herbert Axster; Dieter Huzel; Dr. von Braun (arm in cast); Magnus von Braun (brother); and Hans Lindenberg.

  18. Dr. Wernher Von Braun talkes with George Hardy.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    George Hardy of the Marshall Space Flight center's Astronautics Laboratory, talks with Dr. Wernher Von Braun (right), deputy associate administrator for planning. Dr. Von Braun was inspecting the mockup of the Saturn workshop during a visit to the Marshall Center. The visit coincided with the 10th anniversary celebration of the center of which Dr. Von Braun was director until March 1, 1970.

  19. Dr. von Braun Reviewing Spacecraft Plans

    NASA Technical Reports Server (NTRS)

    1970-01-01

    This photograph was taken after Dr. von Braun moved from his post as Director of the Marshall Space Flight Center (MSFC) to Deputy Associate Administrator for Planning at NASA Headquarters. On June 27, 1970, he visited the MSFC again during the center's 10th anniversary to look at a mockup of the spacecraft that would later be known as Skylab. With von Braun are (left to right): Herman K. Weidner, director of Science and Engineering at MSFC, and James R. Thompson of the center's Astrionics Laboratory.

  20. Dr. von Braun Reviewing Spacecraft Plans

    NASA Technical Reports Server (NTRS)

    1970-01-01

    This photograph was taken after Dr. von Braun moved from his post as Director of the Marshall Space Flight Center (MSFC) to Deputy Associate Administrator for Planning at NASA Headquarters. On June 27, 1970, he visited the MSFC again during the center's 10th anniversary to look at a mockup of the spacecraft that would later be known as Skylab. In this photo, he is examining an experiment in the mockup. With von Braun are (left to right): James R. Thompson, Richard T. Heckman, and Jack Stokes of the Center's Astrionics Laboratory.

  1. Increased serum levels of interleukin-6 and von Willenbrand Factor in early phase of acute coronary syndrome in a young and multiethnic Malaysian population

    PubMed Central

    Tiong, Wen Ni; Fong, Alan Yean Yip; Sim, Edmund Ui Hang; Chan, Hiang Chuan; Ong, Tiong Kiam; Chang, Boon Cheng; Sim, Kui Hian

    2012-01-01

    Objective Interleukin-6 (IL6; proinflammatory marker), von Willebrand Factor (vWF; endothelial dysfunction marker) and P-selectin (platelet activation marker), may play important roles in defining the pathogenesis of vulnerable plaques in acute coronary syndrome (ACS). This study aims to investigate the expression and relationship of these markers in early phases of ACS in a young and multiethnic Malaysian population. Design Peripheral whole blood mRNA, and serum levels of IL6, vWF and P-selectin were measured in 22 patients with ACS, and in 28 controls with angiographically significant coronary artery disease without previous ACS events. Venous blood from ACS patients was obtained within 1 h of hospital admission. Results No significant differences of IL6, vWF and P-selectin mRNA levels between ACS and controls were seen. ACS patients had significantly higher serum levels of IL6 and vWF (p<0.001), compared with controls. P-selectin correlated with IL6 (r=0.697, p=0.003) and vWF (r=0.497, p=0.05) at mRNA levels, indicating a possible association between these three indices of ACS pathogenesis. Conclusions Increased serum levels of IL6 and vWF suggest that inflammation and endothelial dysfunction may play a prominent role in the pathogenesis of the disease during the early phase of ACS.

  2. A note on derivations of Murray–von Neumann algebras

    PubMed Central

    Kadison, Richard V.; Liu, Zhe

    2014-01-01

    A Murray–von Neumann algebra is the algebra of operators affiliated with a finite von Neumann algebra. In this article, we first present a brief introduction to the theory of derivations of operator algebras from both the physical and mathematical points of view. We then describe our recent work on derivations of Murray–von Neumann algebras. We show that the “extended derivations” of a Murray–von Neumann algebra, those that map the associated finite von Neumann algebra into itself, are inner. In particular, we prove that the only derivation that maps a Murray–von Neumann algebra associated with a factor of type II1 into that factor is 0. Those results are extensions of Singer’s seminal result answering a question of Kaplansky, as applied to von Neumann algebras: The algebra may be noncommutative and may even contain unbounded elements. PMID:24469831

  3. Dr. von Braun Visits Huntsville Boys Club

    NASA Technical Reports Server (NTRS)

    1961-01-01

    Dr. von Braun, Director of Marshall Space Flight Center (MSFC) and chairman of this year's United Givers Fund (UGF) drive at MSFC, takes time out from the problems of sending a man to the Moon to talk baseball with 11-year-old Randy Smith at the Huntsville Boys Club.

  4. Dr. Wernher Von Braun presents a certificate

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher Von Braun (left), director of the Marshall Space Flight Center, presents a humorous certificate to Major General Charles W. Eifler, commanding general of Redstone Arsenal, at the close of a farewell luncheon for the general prior to General Eifler moving to a new European duty station.

  5. Von Gierke's disease: report of case.

    PubMed

    Cudzinowski, L

    1979-01-01

    Von Gierke's disease, or hepatorenal glycogenesis, type I, presents an interesting challenge to the dental practitioner. Showing an incidence of 1/400,000, it is a fairly rare occurrence. It indicates the importance of proper medical consultation in treating these children, and proper dental treatment and preventive programs to alleviate what could be dangerous for these patients. PMID:289662

  6. Herstellung von Chitosan und einige Anwendungen

    NASA Astrophysics Data System (ADS)

    Struszczyk, Marcin Henryk

    2001-05-01

    1. Die Deacetylierung von crabshell - Chitosan führte gleichzeitig zu einem drastischen Abfall der mittleren viscosimetrischen Molmasse ( Mv), insbesondere wenn die Temperatur und die Konzentration an NaOH erhöht werden. Diese Parameter beeinflussten jedoch nicht den Grad der Deacetylierung (DD). Wichtig ist jedoch die Quelle des Ausgangsmaterials: Chitin aus Pandalus borealis ist ein guter Rohstoff für die Herstellung von Chitosan mit niedrigem DD und gleichzeitig hoher mittlerer Mv, während Krill-Chitin (Euphausia superba) ein gutes Ausgangsmaterial zur Herstellung von Chitosan mit hohem DD und niedrigem Mv ist. Chitosan, das aus Insekten (Calliphora erythrocephala), unter milden Bedingungen (Temperatur: 100°C, NaOH-Konzentration: 40 %, Zeit: 1-2h ) hergestellt wurde, hatte die gleichen Eigenschaften hinsichtlich DD und Mv wie das aus Krill hergestellte Chitosan. Der Bedarf an Zeit, Energie und NaOH ist für die Herstellung von Insekten-Chitosan geringer als für crabshell-Chitosan vergleichbare Resultaten für DD und Mv. 2. Chitosan wurde durch den Schimmelpilz Aspergillus fumigatus zu Chitooligomeren fermentiert. Die Ausbeute beträgt 25%. Die Chitooligomere wurden mit Hilfe von HPLC und MALDI-TOF-Massenspektrmetrie identifiziert. Die Fermentationsmischung fördert die Immunität von Pflanzen gegen Bakterien und Virusinfektion. Die Zunahme der Immunität schwankt jedoch je nach System Pflanze-Pathogen. Die Fermentation von Chitosan durch Aspergillus fumigatus könnte eine schnelle und billige Methode zur Herstellung von Chitooligomeren mit guter Reinheit und Ausbeute sein. Eine partiell aufgereinigte Fermentationsmischung dieser Art könnte in der Landwirtschaft als Pathogeninhibitor genutzt werden. Durch kontrollierte Fermentation, die Chitooligomere in definierter Zusammensetzung (d.h. definierter Verteilung des Depolymerisationsgrades) liefert, könnte man zu Mischungen kommen, die für die jeweilige Anwendung eine optimale Bioaktivität besitzen. 3

  7. The Vermilionectomy and the Subsequent Lower Lip Reconstruction Were Introduced by Victor von Bruns and not by von Langenbeck or von Esmarch as Reported Previously

    PubMed Central

    Teschke, Marcus; Feinendegen, Dominik L.

    2016-01-01

    Summary: Vermilionectomy is an established procedure for the management of precancerous lesions of the lip and is often performed simultaneously with a lower lip resection for the treatment of a malignancy. The literature suggests that Dieffenbach or von Langenbeck or von Esmarch was the first to introduce this procedure. A systematic review of the German literature from the 19th century revealed that it was von Bruns who performed the vermilionectomy for the management of lip malignancies for the first time. PMID:27579224

  8. The Vermilionectomy and the Subsequent Lower Lip Reconstruction Were Introduced by Victor von Bruns and not by von Langenbeck or von Esmarch as Reported Previously.

    PubMed

    Roldán, J Camilo; Teschke, Marcus; Feinendegen, Dominik L

    2016-05-01

    Vermilionectomy is an established procedure for the management of precancerous lesions of the lip and is often performed simultaneously with a lower lip resection for the treatment of a malignancy. The literature suggests that Dieffenbach or von Langenbeck or von Esmarch was the first to introduce this procedure. A systematic review of the German literature from the 19th century revealed that it was von Bruns who performed the vermilionectomy for the management of lip malignancies for the first time. PMID:27579224

  9. From the classical to the generalized von Karman and Marguerre-von Karman equations

    NASA Astrophysics Data System (ADS)

    Ciarlet, Philippe G.; Gratie, Liliana

    2006-06-01

    In this work, we describe and analyze two models that were recently proposed for modeling generalized von Karman plates and generalized Marguerre-von Karman shallow shells.First, we briefly review the "classical" von Karman and Marguerre-von Karman equations, their physical meaning, and their mathematical justification. We then consider the more general situation where only a portion of the lateral face of a nonlinearly elastic plate or shallow shell is subjected to boundary conditions of von Karman type, while the remaining portion is free. Using techniques from formal asymptotic analysis, we obtain in each case a two-dimensional boundary value problem that is analogous to, but is more general than, the classical equations.In particular, it is remarkable that the boundary conditions for the Airy function can still be determined on the entire boundary of the nonlinearly elastic plate or shallow shell solely from the data.Following recent joint works, we then reduce these more general equations to a single "cubic" operator equation, which generalizes an equation introduced by Berger and Fife, and whose sole unknown is the vertical displacement of the shell. We next adapt an elegant compactness method due to Lions for establishing the existence of a solution to this operator equation.

  10. Epithelial cells and Von Gierke's disease.

    PubMed

    Negishi, H; Benke, P J

    1977-08-01

    Epithelial cells and not fibroblasts from human liver and amniotic fluid contain inducible glucose-6-phosphatase (G-6-Pase) activity. The diagnosis of Von Gierke's disease has been made in a patient with hepatomegaly utilizing cultured epithelial cells grown from a liver biopsy. G-6-Pase activity in epithelial cells from this patient could not be induced by dibutyryl cyclic AMP and theophylline. This is the first use of epithelial cells for diagnosis of a metabolic disease. G-6-Pase activity in cloned epithelial cells from amniotic fluid increases 2- to 3-fold after 24-hr exposure to dibutyryl cyclic AMP and theophylline. The prenatal diagnosis of Von Gierke's disease may be possible in a laboratory experienced with these techniques if epithelial cell growth is obtained from amniotic fluid. PMID:196249

  11. Herstellung von Chitosan und einige Anwendungen

    NASA Astrophysics Data System (ADS)

    Struszczyk, Marcin Henryk

    2001-05-01

    1. Die Deacetylierung von crabshell - Chitosan führte gleichzeitig zu einem drastischen Abfall der mittleren viscosimetrischen Molmasse ( Mv), insbesondere wenn die Temperatur und die Konzentration an NaOH erhöht werden. Diese Parameter beeinflussten jedoch nicht den Grad der Deacetylierung (DD). Wichtig ist jedoch die Quelle des Ausgangsmaterials: Chitin aus Pandalus borealis ist ein guter Rohstoff für die Herstellung von Chitosan mit niedrigem DD und gleichzeitig hoher mittlerer Mv, während Krill-Chitin (Euphausia superba) ein gutes Ausgangsmaterial zur Herstellung von Chitosan mit hohem DD und niedrigem Mv ist. Chitosan, das aus Insekten (Calliphora erythrocephala), unter milden Bedingungen (Temperatur: 100°C, NaOH-Konzentration: 40 %, Zeit: 1-2h ) hergestellt wurde, hatte die gleichen Eigenschaften hinsichtlich DD und Mv wie das aus Krill hergestellte Chitosan. Der Bedarf an Zeit, Energie und NaOH ist für die Herstellung von Insekten-Chitosan geringer als für crabshell-Chitosan vergleichbare Resultaten für DD und Mv. 2. Chitosan wurde durch den Schimmelpilz Aspergillus fumigatus zu Chitooligomeren fermentiert. Die Ausbeute beträgt 25%. Die Chitooligomere wurden mit Hilfe von HPLC und MALDI-TOF-Massenspektrmetrie identifiziert. Die Fermentationsmischung fördert die Immunität von Pflanzen gegen Bakterien und Virusinfektion. Die Zunahme der Immunität schwankt jedoch je nach System Pflanze-Pathogen. Die Fermentation von Chitosan durch Aspergillus fumigatus könnte eine schnelle und billige Methode zur Herstellung von Chitooligomeren mit guter Reinheit und Ausbeute sein. Eine partiell aufgereinigte Fermentationsmischung dieser Art könnte in der Landwirtschaft als Pathogeninhibitor genutzt werden. Durch kontrollierte Fermentation, die Chitooligomere in definierter Zusammensetzung (d.h. definierter Verteilung des Depolymerisationsgrades) liefert, könnte man zu Mischungen kommen, die für die jeweilige Anwendung eine optimale Bioaktivität besitzen. 3

  12. Gestaltung von Mensch-Maschine-Schnittstellen

    NASA Astrophysics Data System (ADS)

    Bruder, Ralph; Didier, Muriel

    Die Interaktion zwischen Mensch und Maschine erfolgt über Schnittstellen, die dem Fahrer Informationen liefern und ihm behilfich sein sollen, die Fahraufgabe sicher, effektiv und effzient zu bewältigen. Wie die Gestaltung von Anzeigen und Bedienelementen vorgenommen werden muss und worauf während des Entwicklungsprozesses in Bezug auf die Interaktion zwischen Mensch und Maschine Rücksicht genommen werden muss, soll hier geklärt werden.

  13. Dr. von Braun and Army Ballistics Missile Agency (ABMA) Group

    NASA Technical Reports Server (NTRS)

    1959-01-01

    This photograph of Dr. von Braun, shown here to the left of General Bruce Medaris, was taken in the fall of 1959, immediately prior to Medaris' retirement from the Army. At the time, von Braun and his associates worked for the Army Ballistics Missile Agency in Huntsville, Alabama. Those in the photograph have been identified as Ernst Stuhlinger, Frederick von Saurma, Fritz Mueller, Hermarn Weidner, E.W. Neubert (partially hidden), W.A. Mrazek, Karl Heimburg, Arthur Rudolph, Otto Hoberg, von Braun, Oswald Lange, Medaris, Helmut Hoelzer, Hans Maus, E.D. Geissler, Hans Heuter, and George Constan.

  14. The VITRO Score (Von Willebrand Factor Antigen/Thrombocyte Ratio) as a New Marker for Clinically Significant Portal Hypertension in Comparison to Other Non-Invasive Parameters of Fibrosis Including ELF Test

    PubMed Central

    Hametner, Stephanie; Ferlitsch, Arnulf; Ferlitsch, Monika; Etschmaier, Alexandra; Schöfl, Rainer; Ziachehabi, Alexander; Maieron, Andreas

    2016-01-01

    Background Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥10 mmHg, causes major complications. HVPG is not always available, so a non-invasive tool to diagnose CSPH would be useful. VWF-Ag can be used to diagnose. Using the VITRO score (the VWF-Ag/platelet ratio) instead of VWF-Ag itself improves the diagnostic accuracy of detecting cirrhosis/ fibrosis in HCV patients. Aim This study tested the diagnostic accuracy of VITRO score detecting CSPH compared to HVPG measurement. Methods All patients underwent HVPG testing and were categorised as CSPH or no CSPH. The following patient data were determined: CPS, D’Amico stage, VITRO score, APRI and transient elastography (TE). Results The analysis included 236 patients; 170 (72%) were male, and the median age was 57.9 (35.2–76.3; 95% CI). Disease aetiology included ALD (39.4%), HCV (23.4%), NASH (12.3%), other (8.1%) and unknown (11.9%). The CPS showed 140 patients (59.3%) with CPS A; 56 (23.7%) with CPS B; and 18 (7.6%) with CPS C. 136 patients (57.6%) had compensated and 100 (42.4%) had decompensated cirrhosis; 83.9% had HVPG ≥10 mmHg. The VWF-Ag and the VITRO score increased significantly with worsening HVPG categories (P<0.0001). ROC analysis was performed for the detection of CSPH and showed AUC values of 0.92 for TE, 0.86 for VITRO score, 0.79 for VWF-Ag, 0.68 for ELF and 0.62 for APRI. Conclusion The VITRO score is an easy way to diagnose CSPH independently of CPS in routine clinical work and may improve the management of patients with cirrhosis. PMID:26895398

  15. The endothelial cell markers von Willebrand Factor (vWF), CD31 and CD34 are lost in glomerulonephritis and no longer correlate with the morphological indices of glomerular sclerosis, interstitial fibrosis, activity and chronicity.

    PubMed

    Gluhovschi, Cristina; Gluhovschi, Gheorghe; Potencz, Elena; Herman, Diana; Trandafirescu, Virginia; Petrica, Ligia; Velciov, Silvia; Bozdog, Gheorghe; Bob, Flaviu; Vernic, Corina; Cioca, Daniel

    2010-01-01

    Endothelial cells (ECs) are active participants of an inflammatory process in glomeruli. EC damage has been shown to play an important role in the progression of glomerulonephritis (GN). The degree of glomerular and peritubular capillary loss in models of progressive renal disease correlates with the severity of glomerulosclerosis and interstitial fibrosis. The aim of our study was to analyze the association of vWF, CD31 and CD34 immunoreactivity with the morphological indices of glomerular sclerosis, interstitial fibrosis, activity and chronicity in GN. A cross-sectional study of 22 patients with GN was conducted. Conventional stains (hematoxylin-eosin, periodic acid Schiff and Trichrome Gömöri stains) and immunohistochemistry (vWF, CD31 and CD34) were employed on kidney biopsies. Activity and chronicity of GN, as well as glomerular segmental sclerosis and interstitial fibrosis, were evaluated according to a scoring system initially used for lupus nephritis and antineutrophil-cytoplasmic-antibody-associated vasculitis. Immunohistochemistry was assessed using a semi-quantitative score. Statistical analysis was performed using EpiInfo 6.04. The mean patient age was 46.68+/-14.09; 14 patients were male, and eight were female. Performing Spearman's rank correlation test, no correlation was found between each marker and glomerular segmental sclerosis, interstitial fibrosis, activity and chronicity, which suggests a loss of these markers and microvasculature involvement. PMID:20675279

  16. Victor or Villain? Wernher von Braun and the Space Race

    ERIC Educational Resources Information Center

    O'Brien, Jason L.; Sears, Christine E.

    2011-01-01

    Set during the Cold War and space race, this historical role-play focuses on Wernher von Braun's involvement in and culpability for the use of slave laborers to produce V-2 rockets for Nazi Germany. Students will grapple with two central questions. Should von Braun have been allowed to emigrate to the United States given his affiliation with the…

  17. Group Theoretical Interpretation of von Neumann's Theorem on Composite Systems.

    ERIC Educational Resources Information Center

    Bergia, S.; And Others

    1979-01-01

    Shows that von Neumann's mathematical theorem on composite systems acquires a transparent physical meaning with reference to a suitable physical example; a composite system in a state of definite angular momentum. Gives an outline of the theorem, and the results are restated in Dirac's notation, thus generalizing von Neumann's results which were…

  18. DEBUS, KURT H. AND WERNHER VON BRAUN IN SATURN BLOCKHOUSE

    NASA Technical Reports Server (NTRS)

    1965-01-01

    Cape Kennedy - Dr. Wernher von Braun, director of the National Aeronautics and Space Administration's Marshall Space Flight Center, points to a television screen in the Saturn blockhouse. The screen showed Saturn I vehicle, carrying Pegasus satellite into orbit, during launch. Dr. Kurt Debus, director of NASA's Kennedy Space Center, is seated at Dr. von Braun's right.

  19. Genetics Home Reference: von Hippel-Lindau syndrome

    MedlinePlus

    ... Review. Citation on PubMed Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific ... on PubMed or Free article on PubMed Central Richard S, Graff J, Lindau J, Resche F. Von Hippel- ...

  20. Relative von Neumann entropy for evaluating amino acid conservation.

    PubMed

    Johansson, Fredrik; Toh, Hiroyuki

    2010-10-01

    The Shannon entropy is a common way of measuring conservation of sites in multiple sequence alignments, and has also been extended with the relative Shannon entropy to account for background frequencies. The von Neumann entropy is another extension of the Shannon entropy, adapted from quantum mechanics in order to account for amino acid similarities. However, there is yet no relative von Neumann entropy defined for sequence analysis. We introduce a new definition of the von Neumann entropy for use in sequence analysis, which we found to perform better than the previous definition. We also introduce the relative von Neumann entropy and a way of parametrizing this in order to obtain the Shannon entropy, the relative Shannon entropy and the von Neumann entropy at special parameter values. We performed an exhaustive search of this parameter space and found better predictions of catalytic sites compared to any of the previously used entropies. PMID:20981889

  1. Wernher von Braun and Saturn IB on Launch Pad

    NASA Technical Reports Server (NTRS)

    1968-01-01

    Dr. Wernher von Braun stands in front of a Saturn IB launch vehicle at Kennedy Space Flight Center. Dr. von Braun led a team of German rocket scientists, called the Rocket Team, to the United States, first to Fort Bliss/White Sands, later being transferred to the Army Ballistic Missile Agency at Redstone Arsenal in Huntsville, Alabama. They were further transferred to the newly established NASA/Marshall Space Flight Center (MSFC) in Huntsville, Alabama in 1960, and Dr. von Braun became the first Center Director. Under von Braun's direction, MSFC developed the Mercury-Redstone, which put the first American in space; and later the Saturn rockets, Saturn I, Saturn IB, and Saturn V. The Saturn V launch vehicle put the first human on the surface of the Moon, and a modified Saturn V vehicle placed Skylab, the first United States' experimental space station, into Earth orbit. Dr. von Braun was MSFC Director from July 1960 to February 1970.

  2. Dr. von Braun Reviewing Spacecraft Plans

    NASA Technical Reports Server (NTRS)

    1970-01-01

    This photograph was taken after Dr. von Braun moved from his post as Director of the Marshall Space Flight Center (MSFC) to Deputy Associate Administrator for Planning at NASA Headquarters. On June 27, 1970, he visited the MSFC again during the Center's 10th anniversary to look at a mockup of the spacecraft that would later be known as Skylab. Others in the photograph are, from left to right: Karl Heimburg, director of the Astronautics Lab; Hermann K. Weidner, director of Science and Engineering, and George Hardy of the Astronautics Lab.

  3. Dr. von Braun Reviewing Spacecraft Plans

    NASA Technical Reports Server (NTRS)

    1970-01-01

    This photograph was taken after Dr. von Braun moved from his post as Director of the Marshall Space Flight Center (MSFC) to Deputy Associate Administrator for Plarning at NASA Headquarters. On June 27, 1970, he visited the MSFC again to look at a mockup of the spacecraft that would later be known as Skylab. Others in the photograph are, from left to right, James R. Thompson, David Newby, Karl Heimburg, Hermann Weidner, and Jack Stockes. Years later, Thompson would serve as Director of the MSFC.

  4. Approximating incompatible von Neumann measurements simultaneously

    SciTech Connect

    Heinosaari, Teiko; Jivulescu, Maria Anastasia; Reitzner, Daniel; Ziman, Mario

    2010-09-15

    We study the problem of performing orthogonal qubit measurements simultaneously. Since these measurements are incompatible, one has to accept additional imprecision. An optimal joint measurement is the one with the least possible imprecision. All earlier considerations of this problem have concerned only joint measurability of observables, while in this work we also take into account conditional state transformations (i.e., instruments). We characterize the optimal joint instrument for two orthogonal von Neumann instruments as being the Lueders instrument of the optimal joint observable.

  5. [Albrecht von Haller. An illustrious ancestor].

    PubMed

    Peiper, H-J

    2008-05-01

    Albrecht von Haller (1708-1777) was one of the most famous and important men of the eighteenth century. His achievements make him comparable with Lessing and Newton. In Blumenbach's opinion he was one of the enlightenment's greatest thinkers in both versatility and depth. He contributed significantly to developments in medicine, physiology, botany, pharmacology, theology, literature, editing, chronicles, biography, geography, and during his later years in Switzerland jurisprudence and agrarian reform. On the occasion of the 300th anniversary of his birth, important scientific landmarks in his life are described, with special attention to his achievements in the fields of anatomy, physiology, surgery, and experimental research. PMID:18661596

  6. Inattentional blindness and the von Restorff effect.

    PubMed

    Schmidt, Stephen R; Schmidt, Constance R

    2015-02-01

    Sometimes we fail to notice distinctive or unusual items (inattentional blindness), while other times we remember distinctive items more than expected items (the von Restorff effect). A three-factor framework is presented and tested in two experiments in an attempt to reconcile these seemingly contradictory phenomena. Memory for different types of unexpected stimuli was tested after an easy or difficult Stroop color-naming task. Highly arousing taboo words were well remembered even when the difficult Stroop task limited attentional resources. However, a conceptual isolation effect was only observed when the nature of the category change was highlighted by the Stroop task, the Stroop task was easy, and/or the isolated targets enjoyed a retrieval advantage relative to comparison targets. As proposed in the three-factor framework, the arousing qualities of the stimuli, the attentional demands of the primary task, and the relevance of isolated features at encoding and retrieval combine to produce inattentional blindness and the von Restorff effect. PMID:25169672

  7. Approximate von Neumann entropy for directed graphs.

    PubMed

    Ye, Cheng; Wilson, Richard C; Comin, César H; Costa, Luciano da F; Hancock, Edwin R

    2014-05-01

    In this paper, we develop an entropy measure for assessing the structural complexity of directed graphs. Although there are many existing alternative measures for quantifying the structural properties of undirected graphs, there are relatively few corresponding measures for directed graphs. To fill this gap in the literature, we explore an alternative technique that is applicable to directed graphs. We commence by using Chung's generalization of the Laplacian of a directed graph to extend the computation of von Neumann entropy from undirected to directed graphs. We provide a simplified form of the entropy which can be expressed in terms of simple node in-degree and out-degree statistics. Moreover, we find approximate forms of the von Neumann entropy that apply to both weakly and strongly directed graphs, and that can be used to characterize network structure. We illustrate the usefulness of these simplified entropy forms defined in this paper on both artificial and real-world data sets, including structures from protein databases and high energy physics theory citation networks. PMID:25353841

  8. Von Neumann's growth model: Statistical mechanics and biological applications

    NASA Astrophysics Data System (ADS)

    De Martino, A.; Marinari, E.; Romualdi, A.

    2012-09-01

    We review recent work on the statistical mechanics of Von Neumann's growth model and discuss its application to cellular metabolic networks. In this context, we present a detailed analysis of the physiological scenario underlying optimality à la Von Neumann in the metabolism of the bacterium E. coli, showing that optimal solutions are characterized by a considerable microscopic flexibility accompanied by a robust emergent picture for the key physiological functions. This suggests that the ideas behind optimal economic growth in Von Neumann's model can be helpful in uncovering functional organization principles of cell energetics.

  9. Papers of John von Neumann on computers and computer theory

    SciTech Connect

    Von Neumann, J.

    1986-01-01

    This volume brings together John von Neumann's long-out-of-print articles on computer architecture, programming, large-scale computing, and automata theory. A number of significant papers in these areas that were not included in the multivolume John von Neumann: Collected Works (1963) have now been reprinted here. These pioneering articles - written between the mid-1940s and the mid-1950s - are of enduring value not only to computer historians but to computer scientists at the vanguard of current research. Most of today's computers are still constructed in accordance with the '' von Neumann architecture,'' and his technique of flow charting remains basic in the domain.

  10. Valence bond and von Neumann entanglement entropy in Heisenberg ladders.

    PubMed

    Kallin, Ann B; González, Iván; Hastings, Matthew B; Melko, Roger G

    2009-09-11

    We present a direct comparison of the recently proposed valence bond entanglement entropy and the von Neumann entanglement entropy on spin-1/2 Heisenberg systems using quantum Monte Carlo and density-matrix renormalization group simulations. For one-dimensional chains we show that the valence bond entropy can be either less or greater than the von Neumann entropy; hence, it cannot provide a bound on the latter. On ladder geometries, simulations with up to seven legs are sufficient to indicate that the von Neumann entropy in two dimensions obeys an area law, even though the valence bond entanglement entropy has a multiplicative logarithmic correction. PMID:19792398

  11. A von Bertalanffy growth model with a seasonally varying coefficient

    USGS Publications Warehouse

    Cloern, James E.; Nichols, Frederic H.

    1978-01-01

    The von Bertalanffy model of body growth is inappropriate for organisms whose growth is restricted to a seasonal period because it assumes that growth rate is invariant with time. Incorporation of a time-varying coefficient significantly improves the capability of the von Bertalanffy equation to describe changing body size of both the bivalve mollusc Macoma balthicain San Francisco Bay and the flathead sole, Hippoglossoides elassodon, in Washington state. This simple modification of the von Bertalanffy model should offer improved predictions of body growth for a variety of other aquatic animals.

  12. Platelet activation risk index as a prognostic thrombosis indicator.

    PubMed

    Zlobina, K E; Guria, G Th

    2016-01-01

    Platelet activation in blood flow under high, overcritical shear rates is initiated by Von Willebrand factor. Despite the large amount of experimental data that have been obtained, the value of the critical shear rate, above which von Willebrand factor starts to activate platelets, is still controversial. Here, we recommend a theoretical approach to elucidate how the critical blood shear rate is dependent on von Willebrand factor size. We derived a diagram of platelet activation according to the shear rate and von Willebrand factor multimer size. We succeeded in deriving an explicit formula for the dependence of the critical shear rate on von Willebrand factor molecule size. The platelet activation risk index was introduced. This index is dependent on the flow conditions, number of monomers in von Willebrand factor, and platelet sensitivity. Probable medical applications of the platelet activation risk index as a universal prognostic index are discussed. PMID:27461235

  13. Platelet activation risk index as a prognostic thrombosis indicator

    PubMed Central

    Zlobina, K. E.; Guria, G. Th.

    2016-01-01

    Platelet activation in blood flow under high, overcritical shear rates is initiated by Von Willebrand factor. Despite the large amount of experimental data that have been obtained, the value of the critical shear rate, above which von Willebrand factor starts to activate platelets, is still controversial. Here, we recommend a theoretical approach to elucidate how the critical blood shear rate is dependent on von Willebrand factor size. We derived a diagram of platelet activation according to the shear rate and von Willebrand factor multimer size. We succeeded in deriving an explicit formula for the dependence of the critical shear rate on von Willebrand factor molecule size. The platelet activation risk index was introduced. This index is dependent on the flow conditions, number of monomers in von Willebrand factor, and platelet sensitivity. Probable medical applications of the platelet activation risk index as a universal prognostic index are discussed. PMID:27461235

  14. Johann Philipp von Wurzelbau (1651-1725)

    NASA Astrophysics Data System (ADS)

    Gaab, Hans

    During the turn of the 17th to the 18th century, Johann Philipp von Wurzelbau was the best-known astronomer in Nuremberg. He was a trained merchant, who busied himself in his free hours with astronomy. In the 1680s he became known for his accurate observations of lunar and solar eclipses. At the end of the 1680s he left his trade, and from 1691, he was completely occupied with astronomy. To that end, he constructed a small octagonal observing tower on the roof of his house at Spitzenberg 4. He took the measurement of the solar path and determined the geographical coordinates of Nuremberg. The calendar reform also played a major role in his life.

  15. Hermann von Helmholtz and his students

    NASA Astrophysics Data System (ADS)

    Mulligan, Joseph F.

    1989-01-01

    During the years 1871-1888, when Hermann von Helmholtz was professor of physics at the University of Berlin, physicists from all over the world flocked to Berlin to study and do research with him. Among these were the German physicists Max Planck, Heinrich Kayser, Eugen Goldstein, Wilhelm Wien, and Heinrich Hertz, and Americans Henry Rowland, A. A. Michelson, and Michael Pupin. Examples of Helmholtz's scientific and personal interactions with these students and research associates show why he is justly considered the outstanding physics mentor of the 19th century. Both his ideas and his students played a major role in the development of physics in the late 19th and early 20th centuries.

  16. 7. Historic American Buildings Survey, Charles Von Urban, Photographer June ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. Historic American Buildings Survey, Charles Von Urban, Photographer June 23, 1936, INTERIOR-PARLOR SHOWING FIREPLACE, WINDOWN TRIM, AND CORNICE. - George Fordham House, 329 Cherry Street, New York County, NY

  17. John von Neumann's mathematical "Utopia" in quantum theory

    NASA Astrophysics Data System (ADS)

    Valente, Giovanni

    This paper surveys John von Neumann's work on the mathematical foundations of quantum theories in the light of Hilbert's Sixth Problem concerning the geometrical axiomatization of physics. We argue that in von Neumann's view geometry was so tied to logic that he ultimately developed a logical interpretation of quantum probabilities. That motivated his abandonment of Hilbert space in favor of von Neumann algebras, specifically the type II1 factors, as the proper limit of quantum mechanics in infinite dimensions. Finally, we present the reasons why his axiomatic program remained an "unsolved problem" in mathematical physics. A recent unpublished result by Huzimiro Araki, proving that no algebra with a tracial state defined on it, such as the type II1 factors, can support any (regular) representation of the canonical commutation relations, is also reviewed and its consequences for von Neumann's projects are discussed.

  18. Quantum theory and geometry: sixty years after von Neumann

    NASA Astrophysics Data System (ADS)

    Varadarajan, V. S.

    1993-10-01

    This paper is a brief review of some of the developments in the mathematical foundations of quantum mechanics that have taken place since the publication in 1932 of John von Neumann's celebrated treatise Mathematische Grundlagen der Quantenmechanik.

  19. Baron von Zach and the astronomy in Languedoc

    NASA Astrophysics Data System (ADS)

    Faidit, Jean-Michel

    The paper gives an overview of Franz Xaver von Zach's relations to the region of Languedoc in France and lists published and unpublished sources, among these letters to and from Zach kept in French archives.

  20. Dr. Wernher Von Braun examines a ruby crystal.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Wernher Von Braun (right), director of the Marshall Space Flight Center, and Dr. Eberhard Rees (left), deputy director, technical, examine a ruby crystal used in laser experiments in the Marshall Center's Space Sciences Laboratory.

  1. A proof of von Neumann's postulate in Quantum Mechanics

    SciTech Connect

    Conte, Elio

    2010-05-04

    A Clifford algebraic analysis is explained. It gives proof of von Neumann's postulate on quantum measurement. It is of basic significance to explain the problem of quantum wave function reduction in quantum mechanics.

  2. Alexander von Humboldt and the Origins of Landscape Archaeology.

    ERIC Educational Resources Information Center

    Mathewson, Kent

    1986-01-01

    Reviews the life, theories, and influence of Alexander von Humboldt, the early nineteenth century founder of modern geography. Maintains that Humboldt's novel approaches to the study of landscape antiquities have value for contemporary students in cultural and historical geography. (JDH)

  3. Computed tomography of the liver in von Gierke's disease.

    PubMed

    Biondetti, P R; Fiore, D; Muzzio, P C

    1980-10-01

    The computed tomography findings in the liver of a patient with von Gierke's disease are presented. Precontrast scans demonstrated diffuse decreased density throughout the liver. In the postcontrast scans, a focal right sided hyperdense area was visualized. PMID:6931833

  4. Director von Braun Presents General Medaris With Golf Bag

    NASA Technical Reports Server (NTRS)

    1959-01-01

    Marshall Space Flight Center Director Wernher von Braun presents General J.B. Medaris with a new golf bag. General Medaris, (left) was a Commander of the Army Ballistic Missile Agency (ABMA) in Redstone Arsenal, Alabama during 1955 to 1958.

  5. 33. HISTORIC VIEW OF WERNHER VON BRAUN LOOKS THROUGH THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    33. HISTORIC VIEW OF WERNHER VON BRAUN LOOKS THROUGH THE PERISCOPE FROM THE CONTROL ROOM AT TEST STAND NO. 1, PEENEMUENDE. - Marshall Space Flight Center, Redstone Rocket (Missile) Test Stand, Dodd Road, Huntsville, Madison County, AL

  6. 1. Historic American Buildings Survey David von Riesen, Photographer July ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Historic American Buildings Survey David von Riesen, Photographer July 1965 BARRACKS (West), Left - BARRACKS (East), Right (Combined into New Barn) - Fort Larned, Barracks (West), Larned, Pawnee County, KS

  7. 1. Historic American Buildings Survey David von Riesen, Photographer July ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Historic American Buildings Survey David von Riesen, Photographer July 1965 BARRACKS (West), Left - BARRACKS (East), Right (Combined into New Barn) - Fort Larned, Barracks (East), Larned, Pawnee County, KS

  8. Deficiency in mouse hyaluronidase 2: a new mechanism of chronic thrombotic microangiopathy.

    PubMed

    Onclinx, Cécile; Dogne, Sophie; Jadin, Laurence; Andris, Fabienne; Grandfils, Christian; Jouret, François; Mullier, François; Flamion, Bruno

    2015-08-01

    Hyaluronan is a major component of the extracellular matrix and glycocalyx. Its main somatic degrading enzymes are hyaluronidases 1 and 2, neither of which is active in the bloodstream. We generated hyaluronidase 2-deficient mice. These animals suffer from chronic, mild anemia and thrombocytopenia, in parallel with a 10-fold increase in plasma hyaluronan concentration. In this study we explored the mechanism of these hematologic anomalies. The decreased erythrocyte and platelet counts were attributed to peripheral consumption. The erythrocyte half-life was reduced from 25 to 8 days without signs of premature aging. Hyaluronidase 2-deficient platelets were functional. Major intrinsic defects in erythrocyte membrane or stability, as well as detrimental effects of high hyaluronan levels on erythrocytes, were ruled out in vitro. Normal erythrocytes transfused into hyaluronidase 2-deficient mice were quickly destroyed but neither splenectomy nor anti-C5 administration prevented chronic hemolysis. Schistocytes were present in blood smears from hyaluronidase 2-deficient mice at a level of 1% to 6%, while virtually absent in control mice. Hyaluronidase 2-deficient mice had increased markers of endothelial damage and microvascular fibrin deposition, without renal failure, accumulation of ultra-large multimers of von Willebrand factor, deficiency of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13 (ADAMTS13), or hypertension. There was no sign of structural damage in hepatic or splenic sinusoids, or in any other microvessels. We conclude that hyaluronidase 2 deficiency induces chronic thrombotic microangiopathy with hemolytic anemia in mice. The link between this uncommon condition and hyaluronidase 2 remains to be explored in humans. PMID:25934767

  9. Wernher von Braun with German Officers and Others

    NASA Technical Reports Server (NTRS)

    1942-01-01

    General Erich Fellgiebel, head of the German Army Information Service during World War II, congratulates members of the von Braun rocket team from Peenemunde for their October 3, 1942 A4 flight. Pictured front center is General Erich Fellgiebel. Shaking hands are General Walter Dornberger (left) and General Janssen, commanding officer of Peenemuende with Rudolph Hermarn to their right. Picture left to right in the back row are Wernher von Braun, Captain Stoelzel, Luftwaffe, and Dr. Gerhard Reisig.

  10. John von Neumann on Mathematical and Axiomatic Physics

    NASA Astrophysics Data System (ADS)

    Rédei, Miklós

    The aim of this paper is to recall and analyse von Neumann's position on mathematical and axiomatic physics. It will be argued that von Neumann demanded much less mathematical rigor in physics than commonly thought and that he followed an opportunistically interpreted soft axiomatic method in physics. The notion of opportunistic soft axiomatization is illustrated by recalling his work on the mathematical foundations of quantum mechanics.

  11. von Neumann entropy of N interacting pencils of radiation

    SciTech Connect

    Barakat, R. ); Brosseau, C. )

    1993-03-01

    The von Neumann entropy of N interacting pencils of radiation is analyzed by using their spectral density matrix. When the cross-spectral density is the same for all pairs of pencils, the entropy is evaluated in closed form as a function of Barakat's N-fold polarization measures. Some technical and historical remarks are made concerning the Planck-von Laue entropy of such pencils. 16 refs., 3 figs.

  12. Physik gestern und heute Von der Metallstange zum Hochenergielaser

    NASA Astrophysics Data System (ADS)

    Heering, Peter

    2002-05-01

    Im Mai 1752 wurde in Marly bei Paris auf Anregung des amerikanischen Forschers und Politikers Benjamin Franklin erstmals die elektrische Natur des Blitzes nachgewiesen. Damals beschrieb Franklin auch eine technische Vorrichtung, die als Schutz von Gebäuden vor Blitzschlägen dienen sollte: den Blitzableiter. Diese aus heutiger Sicht scheinbar triviale Vorrichtung wurde aber keineswegs unmittelbar akzeptiert. Und bis heute ist die Forschung zum Schutz von Einrichtungen vor Blitzschlägen nicht abgeschlossen.

  13. Neurological Management of Von Hippel-Lindau Disease.

    PubMed

    Hodgson, Trent S; Nielsen, Sarah M; Lesniak, Maciej S; Lukas, Rimas V

    2016-09-01

    Von Hippel-Lindau disease is a genetic condition due to mutation of the Von Hippel-Lindau gene, which leads to an increased risk in the development of hemangioblastomas of the brain and spinal cord. The pathophysiology of disease and its clinical manifestations, as they pertain to the general neurologist, are discussed. Therapeutic management of central nervous system hemangioblastomas ranging from neurosurgical resection, radiation therapy, and systemic therapies is reviewed. PMID:27564075

  14. Telecom 2-A (TC2A)

    NASA Technical Reports Server (NTRS)

    Dulac, J.; Latour, J.

    1991-01-01

    The DSN (Deep Space Network) mission support requirements for Telecom 2-A (TC2A) are summarized. The Telecom 2-A will provide high-speed data link applications, telephone, and television service between France and overseas territories. The mission objectives are outlined and the DSN support requirements are defined through the presentation of tables and narratives describing the spacecraft flight profile; DSN support coverage; frequency assignments; support parameters for telemetry, command and support systems; and tracking support responsibility.

  15. Charakterisierung von Sulfotransferasen im Gastrointestinaltrakt von Mensch und Ratte und Aktivierung von Promutagenen in V79-Zellen, die eine intestinale Form (1B1) des Menschen und der Ratte exprimieren

    NASA Astrophysics Data System (ADS)

    Teubner, Wera

    2001-05-01

    Die Ausstattung der gastrointestinalen Mukosa des Menschen und der Ratte mit Sulfotransferasen wurde mit Hilfe von Immunodetektion und Enzymaktivitätsmessungen untersucht. In Proben aus Colon und Rektum von 39 Personen wurden die Formen h1A1, h1A3 und h1B1 identifiziert, wobei in einer weiteren Probe, die als einzige von einem an Colitis Ulcerosa erkrankten Patienten stammte, keine Sulfotransferasen nachgewiesen werden konnten. Bei der Immunblot-Analyse war das Expressionsmuster der einzelnen Formen in allen Proben ähnlich. In wenigen Proben waren die relativen Signalintensitäten der h1A1 und der h1B1 um die Hälfte erniedrigt. Der Gehalt von SULT an zytosolischem Protein zeigte einen bis zu 8 - 10fachen Unterschied, er betrug jedoch bei zwei Dritteln der Proben zwischen 0,15 und 0,3 (h1A1 und h1A3) bzw. 0,6 und 0,8 Promille (h1B1). Die Variation konnte nicht auf Alter, Geschlecht oder Krankheitsbild der Patienten zurückgeführt werden. Auch der für die allelischen Varianten der h1A1 beschriebene Effekt auf die Enzymaktiviät bzw. Stabilität konnte in der Menge an immunreaktivem Protein nicht in diesem Ausma detektiert werden. Die Allelhäufigkeit von h1A1*R und h1A1*H war gegenüber der gesunden Bevölkerung nicht verändert. In den sieben Proben aus dem Dünndarm (Coecum, viermal Ileum, Jejunum) konnten zusätzlich die Formen h1E1 und h2A1 identifiziert werden. Ein möglicherweise der Form h1C1 entsprechendes Protein wurde im Magen detektiert. Im Vergleich zum Menschen war die Expression in der Ratte stärker auf die Leber konzentriert. Während beim Menschen in allen untersuchten Abschnitten Sulfotransferasen in Mengen detektiert wurden, die in zwei Fällen (h1B1 und h1A3) sogar den Gehalt in der Leber überstiegen, beschränkte sich die Expression in der Ratte auf im Vergleich zur Leber geringe Mengen im Magen und Dickdarm. Nachgewiesen wurden die r1B1, r1A1 sowie eine nicht identifizierte Form von 35kD, bei der es sich vermutlich um die r1C2 handelt. Im

  16. Periodontal manifestations of von Recklinghausen neuro fibromatosis.

    PubMed

    Shetty, Bhavya; Umesh, Y; Kranti, K; Seshan, Hema

    2013-03-01

    Neurofibroma is an uncommon benign tumor of the oral cavity derived from the cells that constitute the nerve sheath neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is the most common type of neurofibromatosis and accounts for about 90% of all cases. It is one of the most frequent human genetic diseases, with the prevalence of one case in 3,000 births. Neurofibroma is seen either as a solitary lesion or as part of the generalized syndrome of neurofibromatosis. The solitary form does not differ from the disseminated form or the multiple form of the disease, except that systemic and hereditary factors present in the disseminated form are absent in the solitary type. Oral cavity involvement by a solitary and peripheral plexiform neurofibroma in patients with no other signs of neurofibromatosis is uncommon. The expressivity of NF1 is extremely variable, with manifestations ranging from mild lesions to several complications and functional impairment. Oral manifestations can be found in almost 72% of NF1 patients. This is a case report of a 40-year-old lady with a history of multiple faint rounded densities in the skin, chest pain occasionally since 8 months and breathlessness since 1 year and swelling of the right side of the angle of the mandible with limited mouth opening. PMID:23869137

  17. The von Neumann Triple Point Paradox

    NASA Astrophysics Data System (ADS)

    Sanders, Richard; Tesdall, Allen M.

    We describe the problem of weak shock reflection off a wedge and discuss the triple point paradox that arises. When the shock is sufficiently weak and the wedge is thin, Mach reflection appears to be observed but is impossible according to what von Neumann originally showed in 1943. We summarize some recent numerical results for weak shock reflection problems for the unsteady transonic small disturbance equations, the nonlinear wave system, and the Euler equations. Rather than finding a standard but mathematically inadmissible Mach reflection with a shock triple point, the solutions contain a complex structure: there is a sequence of triple points and supersonic patches in a tiny region behind the leading triple point, with an expansion fan originating at each triple point. The sequence of patches may be infinite, and we refer to this structure as Guderley Mach reflection. The presence of the expansion fans at the triple points resolves the paradox. We describe some recent experimental evidence which is consistent with these numerical findings.

  18. Locally Compact Quantum Groups. A von Neumann Algebra Approach

    NASA Astrophysics Data System (ADS)

    Van Daele, Alfons

    2014-08-01

    In this paper, we give an alternative approach to the theory of locally compact quantum groups, as developed by Kustermans and Vaes. We start with a von Neumann algebra and a comultiplication on this von Neumann algebra. We assume that there exist faithful left and right Haar weights. Then we develop the theory within this von Neumann algebra setting. In [Math. Scand. 92 (2003), 68-92] locally compact quantum groups are also studied in the von Neumann algebraic context. This approach is independent of the original C^*-algebraic approach in the sense that the earlier results are not used. However, this paper is not really independent because for many proofs, the reader is referred to the original paper where the C^*-version is developed. In this paper, we give a completely self-contained approach. Moreover, at various points, we do things differently. We have a different treatment of the antipode. It is similar to the original treatment in [Ann. Sci. & #201;cole Norm. Sup. (4) 33 (2000), 837-934]. But together with the fact that we work in the von Neumann algebra framework, it allows us to use an idea from [Rev. Roumaine Math. Pures Appl. 21 (1976), 1411-1449] to obtain the uniqueness of the Haar weights in an early stage. We take advantage of this fact when deriving the other main results in the theory. We also give a slightly different approach to duality. Finally, we collect, in a systematic way, several important formulas. In an appendix, we indicate very briefly how the C^*-approach and the von Neumann algebra approach eventually yield the same objects. The passage from the von Neumann algebra setting to the C^*-algebra setting is more or less standard. For the other direction, we use a new method. It is based on the observation that the Haar weights on the C^*-algebra extend to weights on the double dual with central support and that all these supports are the same. Of course, we get the von Neumann algebra by cutting down the double dual with this unique

  19. Gamma Stability in Free Product von Neumann Algebras

    NASA Astrophysics Data System (ADS)

    Houdayer, Cyril

    2015-06-01

    Let be a free product of arbitrary von Neumann algebras endowed with faithful normal states. Assume that the centralizer is diffuse. We first show that any intermediate subalgebra which has nontrivial central sequences in M is necessarily equal to M 1. Then we obtain a general structural result for all the intermediate subalgebras with expectation. We deduce that any diffuse amenable von Neumann algebra can be concretely realized as a maximal amenable subalgebra with expectation inside a full nonamenable type III1 factor. This provides the first class of concrete maximal amenable subalgebras in the framework of type III factors. We finally strengthen all these results in the case of tracial free product von Neumann algebras.

  20. Renaturierung von subalpinen und alpinen Ökosystemen

    NASA Astrophysics Data System (ADS)

    Krautzer, B.; Klug, Brigitte

    Die große Vielfalt an alpinen und subalpinen Ökosystemen auf waldfreien Standorten stellt besonders hohe Anforderungen an Planung und Durchführung von Renaturierungsmaßnahmen. Zunehmende Meereshöhe, starke Hangneigungen und extreme klimatische Verhältnisse im Gebirge bedingen zudem seit jeher natürliche Erosionsprozesse. Die zahllosen menschlichen Aktivitäten der letzten Jahrzehnte, gepaart mit unzureichenden Begrünungsmaßnahmen, erhöhen dieses Risiko noch um ein Vielfaches: Geländekorrekturen im Zuge von Skipistenbauten, Almrevitalisierungen, Forst- und Almwegebauten, Maßnahmen zur Verbesserung der touristischen Infrastruktur oder Wildbach- und Lawinenverbauungen. Nur durch Verwendung von hochwertigem, dem Standort angepasstem Pflanzen-oder Saatgutmaterial in Kombination mit der passenden Begrünungstechnik kann dieser Bedrohung dauerhaft entgegengewirkt werden. Dabei sind folgende limitierende Faktoren besonders zu beachten.

  1. Gunther von Hagens' BODY WORLDS: selling beautiful education.

    PubMed

    Burns, Lawrence

    2007-04-01

    In the BODY WORLDS exhibitions currently touring the United States, Gunther von Hagens displays human cadavers preserved through plastination. Whole bodies are playfully posed and exposed to educate the public. However, the educational aims are ambiguous, and some aspects of the exhibit violate human dignity. In particular, the signature cards attached to the whole-body plastinates that bear the title, the signature of Gunther von Hagens, and the date of creation mark the plastinates as artwork and von Hagens as the artist in a gesture that strips the personal dignity from the donors. I conclude that the educational use of cadavers is compatible with respect for dignity if: 1) the utility of such use is great enough; 2) there are no other ways of achieving these ends; and 3) every effort is made to honor the dignity of the donors. PMID:17454986

  2. Georg von Békésy: visualization of hearing.

    PubMed

    Evans, Rand B

    2003-09-01

    Georg von Békésy received the Nobel Prize in 1961 for his research on the functioning of the auditory system. In psychoacoustics, Békésy both extended and perfected the lines of research begun by von Helmholtz in the 19th century. First in his native Hungary and later at Harvard, Békésy used novel and imaginative devices and methods to observe and model the functioning of the inner ear. He also explored the nature of sensory inhibition by which the nervous system sharpens sensory transitions. PMID:14584991

  3. Einblicke in die Dynamik von Quantensystemen: Elektrostatische Speicherringe

    NASA Astrophysics Data System (ADS)

    Welsch, Carsten P.

    2005-03-01

    Elektrostatische Speicherringe kombinieren die Vorteile elektrostatischer Fallen und klassischer magnetischer Speicherringe. Kompaktheit, gute Zugänglichkeit sämtlicher Elemente, hohe Flexibilität in der Wahl möglicher Experimente und die Eigenschaft, alle Teilchen unabhängig von ihrer Masse über einen weiten Geschwindigkeitsbereich zu speichern, bieten Zugang zu einem weiten experimentellen Spektrum. Insbesondere das Potenzial, das in neuartigen, energievariablen Maschinen in Kombination mit Elektronenkühlung, internen Targets und hochauflösenden Reaktionsmikroskopen steckt, verspricht hochinteressante Ergebnisse mit den unterschiedlichsten Teilchen - von exotischen Antiprotonen oder schweren radioaktiven Ionen bis hin zu einfachen und komplexen Molekülen oder Biosystemen.

  4. The Hochschild cohomology problem for von Neumann algebras

    PubMed Central

    Sinclair, Allan M.; Smith, Roger R.

    1998-01-01

    In 1967, when Kadison and Ringrose began the development of continuous cohomology theory for operator algebras, they conjectured that the cohomology groups Hn(M, M), n ≥ 1, for a von Neumann algebra M, should all be zero. This conjecture, which has important structural implications for von Neumann algebras, has been solved affirmatively in the type I, II∞, and III cases, leaving open only the type II1 case. In this paper, we describe a positive solution when M is type II1 and has a Cartan subalgebra and a separable predual. PMID:9520373

  5. The hochschild cohomology problem for von neumann algebras.

    PubMed

    Sinclair, A M; Smith, R R

    1998-03-31

    In 1967, when Kadison and Ringrose began the development of continuous cohomology theory for operator algebras, they conjectured that the cohomology groups Hn(M, M), n >/= 1, for a von Neumann algebra M, should all be zero. This conjecture, which has important structural implications for von Neumann algebras, has been solved affirmatively in the type I, IIinfinity, and III cases, leaving open only the type II1 case. In this paper, we describe a positive solution when M is type II1 and has a Cartan subalgebra and a separable predual. PMID:9520373

  6. The smooth entropy formalism for von Neumann algebras

    NASA Astrophysics Data System (ADS)

    Berta, Mario; Furrer, Fabian; Scholz, Volkher B.

    2016-01-01

    We discuss information-theoretic concepts on infinite-dimensional quantum systems. In particular, we lift the smooth entropy formalism as introduced by Renner and collaborators for finite-dimensional systems to von Neumann algebras. For the smooth conditional min- and max-entropy, we recover similar characterizing properties and information-theoretic operational interpretations as in the finite-dimensional case. We generalize the entropic uncertainty relation with quantum side information of Tomamichel and Renner and discuss applications to quantum cryptography. In particular, we prove the possibility to perform privacy amplification and classical data compression with quantum side information modeled by a von Neumann algebra.

  7. An Accurate von Neumann's Law for Three-Dimensional Foams

    SciTech Connect

    Hilgenfeldt, Sascha; Kraynik, Andrew M.; Koehler, Stephan A.; Stone, Howard A.

    2001-03-19

    The diffusive coarsening of 2D soap froths is governed by von Neumann's law. A statistical version of this law for dry 3D foams has long been conjectured. A new derivation, based on a theorem by Minkowski, yields an explicit analytical von Neumann's law in 3D which is in very good agreement with detailed simulations and experiments. The average growth rate of a bubble with F faces is shown to be proportional to F{sup 1/2} for large F , in contrast to the conjectured linear dependence. Accounting for foam disorder in the model further improves the agreement with data.

  8. Anreicherung von Webinhalten mit Semantik - Microformats und RDFa

    NASA Astrophysics Data System (ADS)

    Hausenblas, Michael

    Semantik in Webinhalten wird heftig diskutiert. Teilweise wird es auch schon praktiziert. Dieser Beitrag geht auf semantisches HTML, Microformats und RDFa näher ein und zeigt anhand von praktischen Beispielen, wie und wo diese verwendet werden können.

  9. Wernher von Braun: Reflections on His Contributions to Space Exploration

    NASA Technical Reports Server (NTRS)

    Goldman, Arthur E.

    2012-01-01

    In 1950, Dr. Wernher von Braun and approximately 100 of his team members came to Huntsville, Alabama, to begin work with the Army on what would later become America's historic space program. He would later serve as the first director of the Marshall Space Flight Center and led the development of the Saturn V launch vehicle that launched seven crewed American mission to the moon, as well as America s first space station, Skylab. Von Braun is best known for his team s technical achievements. He realized his dream of exploring outer space by helping place humans on the moon. His engineering and managerial talent during the Apollo era had contributed to a technological revolution. He was by all accounts a good engineer, but he was only one among many. What set Von Braun apart were his charisma, his vision, and his leadership skills. He inspired loyalty and dedication in the people around him. He understood the importance of communicating his vision to his team, to political and business leaders and the public. Today, the Marshall Center continues his vision by pursuing engineering and scientific projects that will continue to open space to exploration. This presentation will discuss Von Braun's impact on Huntsville, the Marshall Center, the nation and the world and look at his contributions in context of where world space exploration is today.

  10. Von Kármán between Aachen and Pasadena

    NASA Astrophysics Data System (ADS)

    Krause, Egon; Kalkmann, Ulrich

    2013-05-01

    In the Introduction the reader is referred back to the academic ceremonials held after Theodore von Kármán's death in Aachen in May 1963. His work as the first director of the Aerodynamisches Institut (Institute of Aerodynamics) of the RWTH Aachen University of Technology from 1913 on and his initiative to re-establish international cooperation after World War I, resulting in the International Union of Theoretical and Applied Mechanics (IUTAM), are commented on. The following chapter describes von Kármán's relation to his former teacher Ludwig Prandtl. Some of von Kármán's scientific contributions during his time in Aachen are briefly reviewed. Thereafter, his first contacts to the California Institute of Technology are covered. Finally, the scientific and political circumstances, which led to von Kármán's decision to leave Germany in the early thirties, are elucidated in some detail. The English translation of the titles of the Aachen papers is given in Appendix I.

  11. F.X. von Zach and the Fifth Continent

    NASA Astrophysics Data System (ADS)

    Brosche, Peter

    2007-07-01

    In his journals which were devoted mainly to astronomy, Franz Xaver von Zach also presented geographical and geodetic information about Australia. Initially these accounts were in German, but towards the end of his life he wrote them in French for a more general audience.

  12. Dr. Wernher Von Braun with Congressman Gerald R. fod

    NASA Technical Reports Server (NTRS)

    1999-01-01

    On a visit to the Marshall Space Flight Center in April, 1964, Congressman Gerald R. Ford, Jr. Republican of Michigan, was warmly greeted by Dr. Wernher Von Braun, Marshall Space Flight Center director. Ford, along with two other congressmen, visited the center for a briefing on the Saturn program and for a tour of the facilities.

  13. Dr. Wernher Von Braun near the mobile launcher.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. George Mueller, NASA associate administrator for manned space flight, and Dr. Wernher Von Braun (right), director of the Marshall Space Flight Center, are seen near the mobile launcher carrying a 363 foot tall Saturn V space launch vehicle as the rocket is rolled from the vehicle assembly building at KSC for its three mile trip to the launch pad.

  14. Wilhelm von Humboldt's Idea of "Bildung" and Education.

    ERIC Educational Resources Information Center

    Stubbs, Elsina

    The importance of Wilhelm von Humboldt's work in educational philosophy is little known outside of Germany and even there he is more often criticized than praised. This is unfortunate because his contributions to education and other areas had an important impact on other philosophers of his period and are well worth considering today. In his main…

  15. Ernst von Glasersfeld's Radical Constructivism and Truth as Disclosure

    ERIC Educational Resources Information Center

    Joldersma, Clarence W.

    2011-01-01

    In this essay Clarence Joldersma explores radical constructivism through the work of its most well-known advocate, Ernst von Glasersfeld, who combines a sophisticated philosophical discussion of knowledge and truth with educational practices. Joldersma uses Joseph Rouse's work in philosophy of science to criticize the antirealism inherent in…

  16. Anaesthesia in Von Gierke's disease. Current approach to management.

    PubMed

    Bevan, J C

    1980-07-01

    A case report of a patient with Von Gierke's (glycogen storage disease Cori type (1)1 disease who required femoral osteotomy is presented. Current techniques of management of this condition which are likely to improve the outcome of general anaesthesia and surgery are discussed. PMID:6933867

  17. Dr. von Braun Touring the Johnson Space Center

    NASA Technical Reports Server (NTRS)

    1964-01-01

    This photograph is dated October 14, 1964, and shows Dr. von Braun, left, during a tour of the NASA Marned Spacecraft Center, now the Johnson Space Center. He is with Dr. J.P. Kuettner, center, from the Marshall Space Flight Center, and Warren J. North from the Manned Spacecraft Center.

  18. Dr. von Braun, Mayor Searcy, and General Medaris

    NASA Technical Reports Server (NTRS)

    1959-01-01

    Dr. Wernher von Braun, Director of the U.S. Army Ballistic Missile Agency's (ABMA) Development Operations Division, talks to Huntsville Mayor R. B. 'Speck' Searcy, center, and Army Ordnance Missile Command (ARMC) Major General John B. Medaris, right, during 'Moon Day' celebrations in downtown Huntsville, Alabama. (Courtesy of Huntsville/Madison County Public Library)

  19. Dr. von Braun with Governor Wallace and NASA Administrator Webb

    NASA Technical Reports Server (NTRS)

    1965-01-01

    Governor of Alabama George Wallace (left), NASA Administrator James Webb and Marshall Space Flight Center (MSFC) Director Dr. von Braun during a tour of MSFC on June 8, 1965. Governor Wallace and Dr. Webb were at MSFC to witness the first test firing of a Saturn V Booster, along with members of the Alabama legislature and press reporters.

  20. Dr. von Braun, Governor Wallace and NASA Administrator Webb

    NASA Technical Reports Server (NTRS)

    1965-01-01

    In this photograph are Alabama Governor George Wallace (left), Marshall Space Flight Center Dr. Wernher von Braun (Center) and NASA Administrator James Webb (right). Governor Wallace and Dr. Webb were at MSFC to witness the first test firing of a Saturn V Booster, along with members of the Alabama legislature and press reporters.

  1. Hans von Haberer: a forgotten pioneer in vascular surgery.

    PubMed

    Mönig, S P; Walter, M; Erasmi, H; Pichlmaier, H

    1997-03-01

    After carrying out the first free vein graft transplantation on an aneurysm of the axillary vein by Lexer in 1907, many attempts were made to reconstruct arterial injuries with direct vascular suture technique or vein graft transplants during the Balkan War (1912) and the First World War (1914-1918). Hans von Haberer gained wide experience in the reconstructive surgery of traumatic aneurysms at the Department of Surgery at the University of Innsbruck. During this period, he operated on a total of 201 vascular aneurysms, mainly using a direct circular vascular suture technique. In 1914, von Haberer described the first reconstruction of a carotid aneurysm. First experiences with vein bypasses were made, but not pursued in the following years. PMID:9181777

  2. Water Experiments Related To The "Von Karman Sodium" Dynamo Project

    NASA Astrophysics Data System (ADS)

    Marie, L.; Bourgoin, M.; Petrelis, F.; Roy, J.; Burguete, J.; Chiffaudel, A.; Daviaud, F.; Fauve, S.; Odier, P.; Pinton, J.-F.

    2002-07-01

    The purpose of the "Von Karman Sodium" (V.K.S.) experiment is to study the "Dynamo Effect," namely the spontaneous generation of magnetic field in a flow of electrically conducting fluid. The device has been built at CEA / Cadarache, in collaboration with CEA / Saclay, Ecole Normale Superieure de Lyon and Ecole Normale Superieure de Paris. It consists of a cylindrical vessel, filled with liquid Sodium, in which two coaxial rotating disks induce a Von-Karman type flow. Several experimental runs have taken place since June 2000. In order to optimize the V.K.S. set-up, a half-scale water prototype has also been built. It has allowed us to measure mean velocity profiles, as well as pressure fluctuations and mechanical power dissipation. We have observed that under certain circumstances the mean component of the turbulent flow can undergo a global bifurcation.

  3. Lipid storage myopathy in von Gierke's disease: a case report.

    PubMed

    Yamaguchi, K; Santa, T; Inoue, K; Omae, T

    1978-09-01

    An 18-year-old girl with von Gierke's disease associated with a lipid storage myopathy is reported. The diagnosis of von Gierke's disease was made from decreased activity in glucose-6-phosphatase in the jejunal biopsy specimen. Neurologically she showed generalized hypotonia of the muscles, atrophy of bilateral proximal muscles of the lower extremities, weakness in neck flexors, deltoid and lumbar girdle muscles, and a positive Gower's sign. Muscle biopsy from flexor femoris muscle revealed fatty deposition in type 1 fibers and atrophy of type 2 fibers and the diagnosis of an accompanying lipid storage myopathy was made. This case also had a ventricular septal defect confirmed by right cardiac catheterization. PMID:213538

  4. Von Humboldt bis Einstein. Berlin als Weltzentrum der exakten Wissenschaften.

    NASA Astrophysics Data System (ADS)

    Meschkowski, H.

    Contents: 1. Die Anfänge. 2. Die Ära Dirichlet-Jacobi. 3. Der Ausbau der experimentellen Naturwissenschaften. 4. Alexander von Humboldt. 5. Berlin wird "Weltzentrum" der Mathematik. 6. Die Ära Helmholtz. 7. Neue Arbeitsweisen der Astronomie. 8. Chemie: Forschung und Industrie. 9. Max Planck. 10. Ins technische Zeitalter. 11. Zur Mathematik der zwanziger Jahre. 12. Albert Einstein. 13. Fortschritte der Grundlagenforschung. 14. Erwin Schrödinger: Physiker, Philosoph und Poet. 15. Zum Schluß.

  5. FROM THE HISTORY OF PHYSICS: John von Neumann

    NASA Astrophysics Data System (ADS)

    Monastyrskii, Mikhail I.

    2004-12-01

    This article is dedicated to John von Neumann, one of the most outstanding scholars of the 20th century. His life was short but bright, and his contribution to almost all branches of mathematics, as well as to physics, economics, biology, and astronomy was enormous. He constructed some of the first computers and he was among the key persons in the American atomic project. Development of his ideas will continue to play a vital part in various areas of pure and applied mathematics.

  6. Johann Baptist von Schweitzer: the queer Marx loved to hate.

    PubMed

    Kennedy, H

    1995-01-01

    Despite his conviction on a morals charge involving a boy, the early German Social Democrat Johann Baptist von Schweitzer went on to have a successful political career. His life furnishes the context to present remarks by his political opponents Marx and Engels, which reveal their deep-seated homophobia. It is pointed out that this has been glossed over by the translations of the recently published Marx/Engels Collected Works. Some remarks on boy-love and anarchism are appended. PMID:8666759

  7. Replacing energy by von Neumann entropy in quantum phase transitions

    SciTech Connect

    Kopp, Angela; Jia Xun; Chakravarty, Sudip . E-mail: sudip@physics.ucla.edu

    2007-06-15

    We propose that quantum phase transitions are generally accompanied by non-analyticities of the von Neumann (entanglement) entropy. In particular, the entropy is non-analytic at the Anderson transition, where it exhibits unusual fractal scaling. We also examine two dissipative quantum systems of considerable interest to the study of decoherence and find that non-analyticities occur if and only if the system undergoes a quantum phase transition.

  8. Baron von Zach's business relations with the Munich entrepreneur Joseph von Utzschneider (German Title: Geschäftsbeziehungen des Barons von Zach zu dem Münchner Unternehmer Joseph von Utzschneider)

    NASA Astrophysics Data System (ADS)

    Schneider, Ivo

    The relationship between the astronomer von Zach on the one side and the entrepreneur Joseph von Utzschneider and his partner Georg von Reichenbach on the other dates presumably from the year 1807 when Zach spent two months in Munich. Already in the same year Zach had ordered an instrument for himself and began to solicit business for the institute of Reichenbach, Utzschneider, and Liebherr, which was founded in 1804. One of the clients canvassed by Zach was the director of the observatory in Naples Zuccari. Zuccari had ordered the whole equipment for the new observatory from this institute in 1813. The instruments for Naples, which were completed in 1814, were sent accompanied by Reichenbach by land and sea to their destination where Reichenbach supervised their setup. At that time Reichenbach had separated from Utzschneider who kept the optical institute in Benediktbeuern with his new partner Joseph von Fraunhofer whereas Reichenbach became owner of the mathematical-mechanical institute in Munich. For personal and economical reasons Utzschneider began soon after to produce not only optical glass but also optical devices similar to those offered by Reichenbach. As soon as two institutes in Munich competed against each other on the market for sophisticated geodetical and astronomical instruments Zach sided with Utzschneider. Zach's main professional argument for this decision was that both competitors got the optical glass for their instruments from Utzschneider's optical institute in Benediktbeuern. This meant that Utzschneider had first choice and so the optical part of his instruments could be considered as better than that of Reichenbach`s instruments. Zach's role as an agent in Italy and France for the sale of products coming from Utzschneider's manufactories is highlighted by three of Zach's letters to Utzschneider from 1817 and 1818, two of which are reproduced here for the first time.

  9. Dr. Wernher Von Braun at the launch of Apollo 11.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Mission officials relax, all smiles, a few moments after the successful launch of the Apollo 11 spacecraft by Saturn V vehicle AS-506. Relieved of the tension of waiting through the countdown are (left to right) Charles W. Matthews, NASA deputy associate administrator for manned space flight; Dr. Wernher Von Braun, Director of the Marshall Space Flight Center; Dr. George E. Meuller, NASA associate administrator for manned spaceflight, and Lt. General Samuel C. Phillips, director of the Apollo program.

  10. Interpolatability distinguishes LOCC from separable von Neumann measurements

    SciTech Connect

    Childs, Andrew M.; Leung, Debbie; Mančinska, Laura; Ozols, Maris

    2013-11-15

    Local operations with classical communication (LOCC) and separable operations are two classes of quantum operations that play key roles in the study of quantum entanglement. Separable operations are strictly more powerful than LOCC, but no simple explanation of this phenomenon is known. We show that, in the case of von Neumann measurements, the ability to interpolate measurements is an operational principle that sets apart LOCC and separable operations.

  11. Von Gierke's disease adopts an orphan (and its partner).

    PubMed

    Cheng, Alan; Saltiel, Alan R

    2009-01-01

    The enzyme glucose-6-phosphatase is critical for maintaining fasting blood sugar levels by increasing hepatic glucose production. Its absence in patients with von Gierke's disease leads to severe hypoglycemia and abnormal accumulation of glycogen (glycogenosis) in the liver. New players that control the expression of glucose-6-phosphatase have been identified that may provide insight into this metabolic disorder, as well as type 2 diabetes. PMID:19224896

  12. Dr. von Braun in the Gemini Simulator at MSC

    NASA Technical Reports Server (NTRS)

    1964-01-01

    In this 1964 photograph, Marshall Space Flight Center (MSFC) Director Dr. Wernher von Braun (in commander's seat, background) tries out the Gemini Simulator at the Marned Spacecraft Center (now Johnson Space Center). Looking on from the pilot's seat is J.P. Kuettner, deputy director of MSFC Saturn Apollo Systems Office, and standing at left, Warren J. North, chief of Manned Spacecraft Center's (MSC) Flight Crew Support Division.

  13. Von Neumann's `No Hidden Variables' Proof: A Re-Appraisal

    NASA Astrophysics Data System (ADS)

    Bub, Jeffrey

    2010-10-01

    Since the analysis by John Bell in 1965, the consensus in the literature is that von Neumann’s ‘no hidden variables’ proof fails to exclude any significant class of hidden variables. Bell raised the question whether it could be shown that any hidden variable theory would have to be nonlocal, and in this sense ‘like Bohm’s theory.’ His seminal result provides a positive answer to the question. I argue that Bell’s analysis misconstrues von Neumann’s argument. What von Neumann proved was the impossibility of recovering the quantum probabilities from a hidden variable theory of dispersion free (deterministic) states in which the quantum observables are represented as the ‘beables’ of the theory, to use Bell’s term. That is, the quantum probabilities could not reflect the distribution of pre-measurement values of beables, but would have to be derived in some other way, e.g., as in Bohm’s theory, where the probabilities are an artefact of a dynamical process that is not in fact a measurement of any beable of the system.

  14. The British Interplanetary Society - Val Cleaver and Wernher von Braun

    NASA Astrophysics Data System (ADS)

    Willhite, I. P.

    This article is concerned with the early relationship between Wernher von Braun and the British Interplanetary Society (BIS). The BIS/Wernher von Braun/Val Cleaver correspondence files located here at the US Space & Rocket Center in Huntsville, Alabama are unparalleled. As one reads the stimulating comments between Cleaver and von Braun, the need to share their thoughts prevails. Following is an excerpt from one letter that whets ones appetite for more. 10 June 1951 Cleaver writes, “I'm so glad you enjoyed my last letter, and look forward to your promised further contribution to our discussion of the ethics of science in general and astronautics in particu- lar. As regards the one particular point on which you found yourself unable to hold your fire, I should say there are really two distinct issues at stake:. . .” This article attempts to represent the best of the letters as they goad each other on scientific principles, means to prevent wars, and other philosophic ideas.

  15. GRIN2A

    PubMed Central

    Turner, Samantha J.; Mayes, Angela K.; Verhoeven, Andrea; Mandelstam, Simone A.; Morgan, Angela T.

    2015-01-01

    Objective: To delineate the specific speech deficits in individuals with epilepsy-aphasia syndromes associated with mutations in the glutamate receptor subunit gene GRIN2A. Methods: We analyzed the speech phenotype associated with GRIN2A mutations in 11 individuals, aged 16 to 64 years, from 3 families. Standardized clinical speech assessments and perceptual analyses of conversational samples were conducted. Results: Individuals showed a characteristic phenotype of dysarthria and dyspraxia with lifelong impact on speech intelligibility in some. Speech was typified by imprecise articulation (11/11, 100%), impaired pitch (monopitch 10/11, 91%) and prosody (stress errors 7/11, 64%), and hypernasality (7/11, 64%). Oral motor impairments and poor performance on maximum vowel duration (8/11, 73%) and repetition of monosyllables (10/11, 91%) and trisyllables (7/11, 64%) supported conversational speech findings. The speech phenotype was present in one individual who did not have seizures. Conclusions: Distinctive features of dysarthria and dyspraxia are found in individuals with GRIN2A mutations, often in the setting of epilepsy-aphasia syndromes; dysarthria has not been previously recognized in these disorders. Of note, the speech phenotype may occur in the absence of a seizure disorder, reinforcing an important role for GRIN2A in motor speech function. Our findings highlight the need for precise clinical speech assessment and intervention in this group. By understanding the mechanisms involved in GRIN2A disorders, targeted therapy may be designed to improve chronic lifelong deficits in intelligibility. PMID:25596506

  16. Die Wirtschaftliche Bedeutung von Cyberphysical Systems aus der Sicht Eines Global Players

    NASA Astrophysics Data System (ADS)

    Beetz, Klaus

    Langfristiges und nachhaltiges Denken ist ein wichtiger Teil unserer Tradition. Nachhaltigkeit heißt für uns, in unseren Handlungen die Belange von Ökologie, Ökonomie und sozialer Verantwortung ausgewogen zu berücksichtigen.", sagte Peter Löscher, CEO von Siemens, im Januar 2010.

  17. The Fate of Western Civilization: G. H. von Wright's Reflections on Science, Technology, and Global Society

    ERIC Educational Resources Information Center

    Heikkero, Topi

    2004-01-01

    This article introduces the central ideas of G. H. von Wright's cultural philosophy concerning the techno-scientific form of life. Georg Henrik von Wright (1916-2003) was best known for his achievements in the field of modal logic and for his association with Ludwig Wittgenstein. However, his work also included a critical analysis of science and…

  18. An Alternative Perspective on von Winterfeldt et al.'s (1997) Test of Consequence Monotonicity

    ERIC Educational Resources Information Center

    Ho, Moon-Ho R.; Regenwetter, Michel; Niederee, Reinhard; Heyer, Dieter

    2005-01-01

    D. von Winterfeldt, N.-K. Chung, R. D. Luce, and Y. Cho (see record 1997-03378-008) provided several tests for consequence monotonicity of choice or judgment, using certainty equivalents of gambles. The authors reaxiomatized consequence monotonicity in a probabilistic framework and reanalyzed von Winterfeldt et al.'s main experiment via a…

  19. Reevaluation of McCulloch-Pitts-von Neumann's clock.

    PubMed

    Ohta, Hiroyuki

    2015-01-01

    In neuroscience research, a firing pattern expression, called a firing snapshot, defined by firing counts of multiple neurons in discrete time-bin is frequently used. However, the firing pattern expression over multiple neurons requires synchronization commonly known as a "central clock" in computation circuits to externally control or observe multi-neuron firing. Since it is not appropriate to hypothesize the central clock in the brain, we have to reconsider the synchronization assumption. We found the historical origins of central clock synchronization in the works of McCulloch, Pitts and von Neumann and propose an alternative perspective to study neural processing without the central clock. In the "First draft of a report on the EDVAC" known as the first proposal of store-program type computer, von Neumann incorporated McCulloch and Pitts' arbitrary assumption of constant synaptic delay into the logical circuit modeling. He introduced a constant pulse delay stabilized by a central clock to synchronize multiple pulse lines. This constant delay carried over to automaton theory by von Neumann and then theoretical neuroscience as an integral part of distributed representation and firing pattern analysis. Instead, we propose a rethinking of neuronal processing by focusing on a variable synaptic delay. We review neuron-type dependent differences and point out that the maximum inter-stimulus interval which can affect the last stimulus response is longer than the minimum inter-spike interval, indicating the possibility of asynchronous input summation without a firing rate level clock. This fundamental baseline contributes to the investigation of time consuming processes: e.g., the compression of appositional synaptic inputs with duration into a single firing. PMID:25458264

  20. [On the centennial of Ernst von Bergmann's death].

    PubMed

    Czymek, R; Düsel, W

    2007-03-01

    "dear aunt lina. i do not know any big letters yet, but i want to thank you in small letters for the beautiful pens. say hello to grandpa and to everybody. yours truly, ernst." These are the first surviving written words of Ernst von Bergmann. Between them and his last words about his suspected colon cancer on 25 March 1907 ("I diagnosed this 5 years ago, and now it has come to pass.") lie many years in a vigorous life characterised by untiring activity and creativity, self-discipline, and care for patients and his family. They were years of enormous success in surgery and private happiness but also of professional setbacks and tragic family loss. Ernst von Bergmann became a leading German surgeon not only because of his surgical and scientific achievements, particularly in the fields of asepsis and war surgery, but also due to his exemplary character, reliability, engaging personality, and commitment to medical training in various medical societies. Of these, the German Society of Surgery is most indebted to him. After assuming a chair in surgery in 1882, he continued to play a leading role in this society, not least as its five-time president from 1888 to 1890 and in 1896 and 1900. A worthy successor to Bernhard von Langenbeck, he was a full professor at the Berlin University Hospital for 25 years. He also taught at the Medical and Surgical Academy for the Military after being appointed there by Emperor Wilhelm I on 16 November 1882. This position was important to him and corresponded to his patriotic views. PMID:17287931

  1. von Baer's law for the ages: lost and found principles of developmental evolution.

    PubMed

    Abzhanov, Arhat

    2013-12-01

    In 1828, Karl Ernst von Baer formulated a series of empirically defined rules, which became widely known as the 'Law of Development' or 'von Baer's law of embryology'. This was one the most significant attempts to define the principles that connected morphological complexity and embryonic development. Understanding this relation is central to both evolutionary biology and developmental genetics. Von Baer's ideas have been both a source of inspiration to generations of biologists and a target of continuous criticism over many years. With advances in multiple fields, including paleontology, cladistics, phylogenetics, genomics, and cell and developmental biology, it is now possible to examine carefully the significance of von Baer's law and its predictions. In this review, I argue that, 185 years after von Baer's law was first formulated, its main concepts after proper refurbishing remain surprisingly relevant in revealing the fundamentals of the evolution-development connection, and suggest that their explanation should become the focus of renewed research. PMID:24120296

  2. Karl ernst von Baer's 'Uber Entwickelungsgeschichte der Thiere II' and its unpublished drawings.

    PubMed

    Tammiksaar, Erki; Brauckmann, Sabine

    2004-01-01

    In 1828 Karl Ernst von Baer (1792-1876) published his seminal Uber Entwickelungsgeschichte der Thiere. Beobachtung und Reflexion. In the preface he announced that a second volume with one copper plate would be finished 'in a few weeks'. However, it took nine years until the unfinished second volume was released, with four copperplates. In his 'Autobiography', von Baer did not clarify the reasons why he did not finish his research program of comparative embryology. The paper attempts to elucidate them, furnished by archival documents and von Baer's unpublished embryological drawings. Our sketch of a few figures will show that (1) von Baer searched for 'analogies' (homologies) as a unifying principle and (2) explained the mechanisms of embryogenesis by physiological reasoning (electromagnetism). The main objective is to show that technical problems in illustrating and conceptual difficulties impeded von Baer's ambitious research program. PMID:16302690

  3. Klassifikation von Standardebenen in der 2D-Echokardiographie mittels 2D-3D-Bildregistrierung

    NASA Astrophysics Data System (ADS)

    Bergmeir, Christoph; Subramanian, Navneeth

    Zum Zweck der Entwicklung eines Systems, das einen unerfahrenen Anwender von Ultraschall (US) zur Aufnahme relevanter anatomischer Strukturen leitet, untersuchen wir die Machbarkeit von 2D-US zu 3D-CT Registrierung. Wir verwenden US-Aufnahmen von Standardebenen des Herzens, welche zu einem 3D-CT-Modell registriert werden. Unser Algorithmus unterzieht sowohl die US-Bilder als auch den CT-Datensatz Vorverarbeitungsschritten, welche die Daten durch Segmentierung auf wesentliche Informationen in Form von Labein für Muskel und Blut reduzieren. Anschließend werden diese Label zur Registrierung mittels der Match-Cardinality-Metrik genutzt. Durch mehrmaliges Registrieren mit verschiedenen Initialisierungen ermitteln wir die im US-Bild sichtbare Standardebene. Wir evaluierten die Methode auf sieben US-Bildern von Standardebenen. Fünf davon wurden korrekt zugeordnet.

  4. Otto von Guericke and 17th century cosmology

    NASA Astrophysics Data System (ADS)

    Knobloch, Eberhard

    Otto von Guericke's scientific method was based on reason and experimental science. His cosmology was embedded in theology and can be interpreted as a refutation of Descartes' worldview. He used Nicolaus Cusanus' theory of quantities in order to characterize space. The notion of space has to be distinguished from that of world or heaven. Forces play a crucial role in this respect described by Athanasius Kircher in his "Celestial Journey". Guericke read this work very diligently. In spite of some obvious similarities between Guericke's and Newton's scientific aims and methods there are crucial differences between the scientific convictions and results of these scholars.

  5. Karl Ernst von Baer (1792-1876) and evolution.

    PubMed

    Brauckmann, Sabine

    2012-01-01

    The research program of Karl Ernst von Baer (1792-1876) intended to enhance the comparative approach of animal classification by demonstrating vertebrate affinities (homology). Baer visualized his ideas on development and evolution with an unpublished figure of a branching tree. To buttress his reflections on how species-specific embryogenesis produces a branching tree, he worked out a cladogram-like chart, depicting the ontogeny and phylogeny of vertebrate embryos. For Baer, changes in development were responsible for changes in phenotype. I will offer a new interpretation of Baer's ideas about evolution showing that he believed in the transformation of species and announced such views publicly. PMID:23319342

  6. Asymmetric biclustering with constrained von Mises-Fisher models

    NASA Astrophysics Data System (ADS)

    Watanabe, Kazuho; Wu, Hsiang-Yun; Takahashi, Shigeo; Fujishiro, Issei

    2016-03-01

    As a probability distribution on the high-dimensional sphere, the von Mises-Fisher (vMF) distribution is widely used for directional statistics and data analysis methods based on correlation. We consider a constrained vMF distribution for block modeling, which provides a probabilistic model of an asymmetric biclustering method that uses correlation as the similarity measure of data features. We derive the variational Bayesian inference algorithm for the mixture of the constrained vMF distributions. It is applied to a multivariate data visualization method implemented with enhanced parallel coordinate plots.

  7. von Hippel-Lindau Disease: Review of Genetics and Imaging.

    PubMed

    Shanbhogue, Krishna Prasad; Hoch, Michael; Fatterpaker, Girish; Chandarana, Hersh

    2016-05-01

    von Hippel-Lindau (VHL) disease is an autosomal-dominant, hereditary, multisystem neoplasia syndrome with increased susceptibility to several benign and malignant tumors. VHL occurs in about 1 in 36,000 live births and is associated with germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. VHL disease exhibits diverse genotype and phenotype correlations, exhibits variable intrafamilial and interfamilial expressivity, and can manifest with benign and malignant tumors of the central nervous system, kidneys, adrenals, pancreas, and reproductive organs. Imaging and management of this entity are therefore multidisciplinary. An overview of VHL disease is presented. PMID:27153780

  8. Kernschmelze Der nachhaltige Einfluss von Nuklearwaffen auf Politik und Wirtschaft

    NASA Astrophysics Data System (ADS)

    Greiner, Bernd

    "Was sollen wir von einer Kultur halten, der die Ethik stets als wesentliches Element des menschlichen Lebens galt, die aber - außer in fachlicher oder spieltheoretischer Terminologie - nicht in der Lage war, über die Möglichkeit zu sprechen, nahezu alle Menschen zu töten?" Der Fragesteller gehört zu den berühmtesten Physikern des 20. Jahrhunderts und zu den nach wie vor Umstrittensten. über ihn wurde in den 1960er Jahren ein international viel beachtetes Theaterstück geschrieben, vor wenigen Jahren gar eine Oper.

  9. Quantum Dynamics in Phase Space using Projected von Neumann Bases.

    PubMed

    Machnes, Shai; Assémat, Elie; Larsson, Henrik R; Tannor, David J

    2016-05-19

    We describe the mathematical underpinnings of the biorthogonal von Neumann method for quantum mechanical simulations (PvB). In particular, we present a detailed discussion of the important issue of nonorthogonal projection onto subspaces of biorthogonal bases, and how this differs from orthogonal projection. We present various representations of the Schrödinger equation in the reduced basis and discuss their relative merits. We conclude with illustrative examples and a discussion of the outlook and challenges ahead for the PvB representation. PMID:26977715

  10. Charakterisierung von Sulfotransferasen im Gastrointestinaltrakt von Mensch und Ratte und Aktivierung von Promutagenen in V79-Zellen, die eine intestinale Form (1B1) des Menschen und der Ratte exprimieren

    NASA Astrophysics Data System (ADS)

    Teubner, Wera

    2001-05-01

    Die Ausstattung der gastrointestinalen Mukosa des Menschen und der Ratte mit Sulfotransferasen wurde mit Hilfe von Immunodetektion und Enzymaktivitätsmessungen untersucht. In Proben aus Colon und Rektum von 39 Personen wurden die Formen h1A1, h1A3 und h1B1 identifiziert, wobei in einer weiteren Probe, die als einzige von einem an Colitis Ulcerosa erkrankten Patienten stammte, keine Sulfotransferasen nachgewiesen werden konnten. Bei der Immunblot-Analyse war das Expressionsmuster der einzelnen Formen in allen Proben ähnlich. In wenigen Proben waren die relativen Signalintensitäten der h1A1 und der h1B1 um die Hälfte erniedrigt. Der Gehalt von SULT an zytosolischem Protein zeigte einen bis zu 8 - 10fachen Unterschied, er betrug jedoch bei zwei Dritteln der Proben zwischen 0,15 und 0,3 (h1A1 und h1A3) bzw. 0,6 und 0,8 Promille (h1B1). Die Variation konnte nicht auf Alter, Geschlecht oder Krankheitsbild der Patienten zurückgeführt werden. Auch der für die allelischen Varianten der h1A1 beschriebene Effekt auf die Enzymaktiviät bzw. Stabilität konnte in der Menge an immunreaktivem Protein nicht in diesem Ausma detektiert werden. Die Allelhäufigkeit von h1A1*R und h1A1*H war gegenüber der gesunden Bevölkerung nicht verändert. In den sieben Proben aus dem Dünndarm (Coecum, viermal Ileum, Jejunum) konnten zusätzlich die Formen h1E1 und h2A1 identifiziert werden. Ein möglicherweise der Form h1C1 entsprechendes Protein wurde im Magen detektiert. Im Vergleich zum Menschen war die Expression in der Ratte stärker auf die Leber konzentriert. Während beim Menschen in allen untersuchten Abschnitten Sulfotransferasen in Mengen detektiert wurden, die in zwei Fällen (h1B1 und h1A3) sogar den Gehalt in der Leber überstiegen, beschränkte sich die Expression in der Ratte auf im Vergleich zur Leber geringe Mengen im Magen und Dickdarm. Nachgewiesen wurden die r1B1, r1A1 sowie eine nicht identifizierte Form von 35kD, bei der es sich vermutlich um die r1C2 handelt. Im

  11. The von Hippel–Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice

    PubMed Central

    Hickey, Michele M.; Richardson, Theresa; Wang, Tao; Mosqueira, Matias; Arguiri, Evguenia; Yu, Hongwei; Yu, Qian-Chun; Solomides, Charalambos C.; Morrisey, Edward E.; Khurana, Tejvir S.; Christofidou-Solomidou, Melpo; Simon, M. Celeste

    2010-01-01

    Mutation of the von Hippel–Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2α activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2α in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2α and suggest potential treatments for Chuvash patients. PMID:20197624

  12. The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice.

    PubMed

    Hickey, Michele M; Richardson, Theresa; Wang, Tao; Mosqueira, Matias; Arguiri, Evguenia; Yu, Hongwei; Yu, Qian-Chun; Solomides, Charalambos C; Morrisey, Edward E; Khurana, Tejvir S; Christofidou-Solomidou, Melpo; Simon, M Celeste

    2010-03-01

    Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2alpha activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2alpha in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2alpha and suggest potential treatments for Chuvash patients. PMID:20197624

  13. The von Neumann model of measurement in quantum mechanics

    SciTech Connect

    Mello, Pier A.

    2014-01-08

    We describe how to obtain information on a quantum-mechanical system by coupling it to a probe and detecting some property of the latter, using a model introduced by von Neumann, which describes the interaction of the system proper with the probe in a dynamical way. We first discuss single measurements, where the system proper is coupled to one probe with arbitrary coupling strength. The goal is to obtain information on the system detecting the probe position. We find the reduced density operator of the system, and show how Lüders rule emerges as the limiting case of strong coupling. The von Neumann model is then generalized to two probes that interact successively with the system proper. Now we find information on the system by detecting the position-position and momentum-position correlations of the two probes. The so-called 'Wigner's formula' emerges in the strong-coupling limit, while 'Kirkwood's quasi-probability distribution' is found as the weak-coupling limit of the above formalism. We show that successive measurements can be used to develop a state-reconstruction scheme. Finally, we find a generalized transform of the state and the observables based on the notion of successive measurements.

  14. Renaturierung von Ökosystemen in urban-industriellen Landschaften

    NASA Astrophysics Data System (ADS)

    Rebele, Franz

    Die Urbanisierung ist ein weltweit stattfindender Prozess mit weitreichenden Auswirkungen auf Mensch und Natur. In Mitteleuropa leben heute etwa 80% aller Bewohner in Städten. Urban-industrielle Landschaften gehören deshalb zur unmittelbaren Lebensumwelt der meisten Menschen. Allein in Deutschland wird heute täglich eine Fläche von 120 ha neu für Siedlungs- und Verkehrszwecke in Anspruch genommen. Zu den Siedlungs- und Verkehrsflächen zählen Gebäude-und gebäudebezogene Freiflächen, Verkehrsflächen, Erholungsflächen und Friedhöfe sowie Betriebsflächen für Industrie und Gewerbe. Nicht enthalten sind Tagebauflächen zum Abbau von Bodenschätzen (Kapitel 13). In Deutschland liegt der Anteil der Siedlungs- und Verkehrsflächen an der Gesamtfläche derzeit bei ca. 13%, in Österreich bei 5 % und in der Schweiz bei knapp 7 %. Charakteristisch für die heutige Entwicklung in Mitteleuropa ist, dass die Prozesse der Urbanisierung und der Flächeninanspruchnahme für Siedlung und Verkehr nicht ursächlich mit einem Bevölkerungswachstum verbunden sind, d. h. dass Freiflächen auch bei stagnierender oder in manchen Regionen sogar bei sinkender Einwohnerzahl bebaut werden.

  15. [Richard von Volkmann, one career of orthopaedic surgeon and poet].

    PubMed

    Bumbasirević, M; Lesić, A; Sudjić, V; Zagorac, S

    2010-01-01

    Richard von Volkman was one of the most famous and important surgeons in the 19th century. He pioneered antiseptic procedures and was especially known for his achivements in orthopedic surgery. Von Volkmann was born in Leipzig, Germany and attended medical schools in Giessen, Halle, and Berlin. Starting in 1867, he worked as a professor of surgery at the University of Halle, also leading its surgical clinic. He was active as a surgeon during Seven Weeks' War with Austria in 1866 and the Franco-Prussian war 1870/1871, in the latter as consulting Generalarzt. He was important in the introduction of antiseptic wound treatment in Germany, and through it to the United States of America. Two observations in orthopaedic surgery bear his name to these days: Volkmans contracture and Heuter-Volkmans low. Volkmann also wrote poetry under the name Richard Leander and his book entitled "Dreams by French Firesides" which still has a place in literature. He died of paralysis due to a chronic spinal disease, following a prolonged illness, in the Binswanger institution in Jena in 1889, at the top of his careere. PMID:20954309

  16. Von Braun Rocket Team at Fort Bliss, Texas

    NASA Technical Reports Server (NTRS)

    1940-01-01

    The German Rocket Team, also known as the Von Braun Rocket Team, poses for a group photograph at Fort Bliss, Texas. After World War II ended in 1945, Dr. Wernher von Braun led some 120 of his Peenemuende Colleagues, who developed the V-2 rocket for the German military during the War, to the United Sttes under a contract to the U.S. Army Corps as part of Operation Paperclip. During the following five years the team worked on high altitude firings of the captured V-2 rockets at the White Sands Missile Range in New Mexico, and a guided missile development unit at Fort Bliss, Texas. In April 1950, the group was transferred to the Army Ballistic Missile Agency (ABMA) at Redstone Arsenal in Huntsville, Alabama, and continued to work on the development of the guided missiles for the U.S. Army until transferring to a newly established field center of the National Aeronautic and Space Administration (NASA), George C. Marshall Space Flight Center (MSFC).

  17. Superfluid high REynolds von Kármán experiment.

    PubMed

    Rousset, B; Bonnay, P; Diribarne, P; Girard, A; Poncet, J M; Herbert, E; Salort, J; Baudet, C; Castaing, B; Chevillard, L; Daviaud, F; Dubrulle, B; Gagne, Y; Gibert, M; Hébral, B; Lehner, Th; Roche, P-E; Saint-Michel, B; Bon Mardion, M

    2014-10-01

    The Superfluid High REynolds von Kármán experiment facility exploits the capacities of a high cooling power refrigerator (400 W at 1.8 K) for a large dimension von Kármán flow (inner diameter 0.78 m), which can work with gaseous or subcooled liquid (He-I or He-II) from room temperature down to 1.6 K. The flow is produced between two counter-rotating or co-rotating disks. The large size of the experiment allows exploration of ultra high Reynolds numbers based on Taylor microscale and rms velocity [S. B. Pope, Turbulent Flows (Cambridge University Press, 2000)] (Rλ > 10000) or resolution of the dissipative scale for lower Re. This article presents the design and first performance of this apparatus. Measurements carried out in the first runs of the facility address the global flow behavior: calorimetric measurement of the dissipation, torque and velocity measurements on the two turbines. Moreover first local measurements (micro-Pitot, hot wire,…) have been installed and are presented. PMID:25362417

  18. Attractors and Long Time Behavior of von Karman Thermoelastic Plates

    SciTech Connect

    Chueshov, Igor Lasiecka, Irena

    2008-10-15

    This paper undertakes a study of asymptotic behavior of solutions corresponding to von Karman thermoelastic plates. A distinct feature of the work is that the model considered has no added dissipation-particularly mechanical dissipation typically added to plate equation when long time-behavior is considered. Thus, the model consists of undamped oscillatory plate equation strongly coupled with heat equation. Nevertheless we are able to show that the ultimate (asymptotic) behavior of the von Karman evolution is described by finite dimensional global attractor. In addition, the obtained estimate for the dimension and the size of the attractor are independent of the rotational inertia parameter {gamma} and heat/thermal capacity {kappa}, where the former is known to change the character of dynamics from hyperbolic ({gamma}>0) to parabolic like ({gamma}=0). Other properties of attractors such as additional smoothness and upper-semicontinuity with respect to parameters {gamma} and {kappa} are also established. The main ingredients of the proofs are (i) sharp regularity of Airy's stress function, and (ii) newly developed (Chueshov and Lasiecka in Memoirs of AMS, in press) 'compensated' compactness methods applicable to non-compact dynamics.

  19. Superfluid high REynolds von Kármán experiment

    NASA Astrophysics Data System (ADS)

    Rousset, B.; Bonnay, P.; Diribarne, P.; Girard, A.; Poncet, J. M.; Herbert, E.; Salort, J.; Baudet, C.; Castaing, B.; Chevillard, L.; Daviaud, F.; Dubrulle, B.; Gagne, Y.; Gibert, M.; Hébral, B.; Lehner, Th.; Roche, P.-E.; Saint-Michel, B.; Bon Mardion, M.

    2014-10-01

    The Superfluid High REynolds von Kármán experiment facility exploits the capacities of a high cooling power refrigerator (400 W at 1.8 K) for a large dimension von Kármán flow (inner diameter 0.78 m), which can work with gaseous or subcooled liquid (He-I or He-II) from room temperature down to 1.6 K. The flow is produced between two counter-rotating or co-rotating disks. The large size of the experiment allows exploration of ultra high Reynolds numbers based on Taylor microscale and rms velocity [S. B. Pope, Turbulent Flows (Cambridge University Press, 2000)] (Rλ > 10000) or resolution of the dissipative scale for lower Re. This article presents the design and first performance of this apparatus. Measurements carried out in the first runs of the facility address the global flow behavior: calorimetric measurement of the dissipation, torque and velocity measurements on the two turbines. Moreover first local measurements (micro-Pitot, hot wire,…) have been installed and are presented.

  20. On conjugate families and Jeffreys priors for von Mises–Fisher distributions

    PubMed Central

    Hornik, Kurt; Grün, Bettina

    2013-01-01

    This paper discusses characteristics of standard conjugate priors and their induced posteriors in Bayesian inference for von Mises–Fisher distributions, using either the canonical natural exponential family or the more commonly employed polar coordinate parameterizations. We analyze when standard conjugate priors as well as posteriors are proper, and investigate the Jeffreys prior for the von Mises–Fisher family. Finally, we characterize the proper distributions in the standard conjugate family of the (matrix-valued) von Mises–Fisher distributions on Stiefel manifolds. PMID:23805026

  1. Ein stochastisches Modell zur Beschreibung von Signalen in digitalen Schaltungen basierend auf quadratischer Optimierung

    NASA Astrophysics Data System (ADS)

    Kleeberger, V. B.; Maier, P.; Schlichtmann, U.

    2013-07-01

    Die kontinuierlich fortschreitende Miniaturisierung in integrierten Schaltungen führt zu einem erhöhten Modellierungsbedarf verschiedenster Effekte, wie z.B. Alterung oder Stromverbrauch. Diese hängen von den auftretenden Signalen innerhalb der Schaltung ab, wodurch deren statistische Modellierung ein zentrales Problem darstellt. Dieser Beitrag stellt eine neue Methode zur stochastischen Signalmodellierung basierend auf quadratischer Optimierung vor. Die Methode wird mit Hilfe von realen Daten mit existierenden Ansätzen verglichen. Die Testergebnisse zeigen hierbei im vorgestellten Modell einen Genauigkeitszuwachs von bis zu einem Faktor 10 im Vergleich zu bereits existierenden Modellen.

  2. Two different anesthetic managements of a patient with von Gierke's disease.

    PubMed

    Huang, I-Ren; Jean, Wei-Horng; Lu, Cheng-Wei; Wu, Chia-Chan; Lin, Tzu-Yu; Chuang, Yueh-Hsun; Sun, Wei-Zen

    2006-03-01

    Von Gierke's disease, a form of glycogen storage disturbance, is a rare metabolic disorder with important implications for anesthesiologists. It is caused by the lack of the glucose-6-phosphatase, which is necessary for the liver to convert glycogen to glucose. To avoid severe hypoglycemia, it is crucial to keep oral feeding at intervals 2-3 hr for maintaining a normal blood sugar level. The metabolic derangements of von Gierke's disease may result in serious complications in patients undergoing surgery and anesthesia. We report the anesthetic managements of a patient with von Gierke's disease in two operations with different encounters. PMID:16623410

  3. Die Bedeutung der Volumen- und Oberflächeneigenschaften von Biomaterialien für die Adsorption von Proteinen und nachfolgende zelluläre Reaktionen

    NASA Astrophysics Data System (ADS)

    Groth, Thomas

    2003-04-01

    Es ist schon seit längerer Zeit bekannt, dass nach Kontakt des Biomaterials mit der biologischen Umgebung bei Implantation oder extrakorporaler Wechselwirkung zunächst Proteine aus dem umgebenden Milieu adsorbiert werden, wobei die Oberflächeneigenschaften des Materials die Zusammensetzung der Proteinschicht und die Konformation der darin enthaltenden Proteine determinieren. Die nachfolgende Wechselwirkung von Zellen mit dem Material wird deshalb i.d.R. von der Adsorbatschicht vermittelt. Der Einfluss der Oberflächen auf die Zusammensetzung und Konformation der Proteine und die nachfolgende Wechselwirkung mit Zellen ist von besonderem Interesse, da einerseits eine Aussage über die Anwendbarkeit ermöglicht wird, andererseits Erkenntnisse über diese Zusammenhänge für die Entwicklung neuer Materialien mit verbesserter Biokompatibilität genutzt werden können. In der vorliegenden Habilitationsschrift wurde deshalb der Einfluss der Zusammensetzung von Polymeren bzw. von deren Oberflächeneigenschaften auf die Adsorption von Proteinen, den Aktivitätszustand der plasmatischen Gerinnung und die Adhäsion von Zellen untersucht. Dabei wurden auch Möglichkeiten zur Beeinflussung dieser Vorgänge über eine Veränderung der Volumenzusammensetzung oder durch Oberflächenmodifikationen von Biomaterialien vorgestellt. Erkenntnisse aus diesen Arbeiten konnten für die Entwicklung von Membranen für Biohybrid-Organe genutzt werden. The implantation of biomaterials or the contact of blood with extracorporal devices leads to the rapid adsorption of proteins from the surrounding biological fluids. The surface properties of materials determine the composition of the adsorption layer and the conformation of adsorbed proteins. Hence, the subsequent interaction of cells with biomaterials is dependent on the adsorption layer of proteins. The detailed knowledge on the role of surface properties in protein adsorption and cellular interactions is a useful means to learn about the

  4. The von Restorff effect in rats (Rattus norvegicus).

    PubMed

    Reed, P; Richards, A

    1996-06-01

    Two experiments examined the functional equivalence of memory in the rat (Rattus norvegicus) with memory in humans for serially presented items. Memory was assayed with an 8-arm radial maze, in which rats were allowed access to 5 arms of the maze and were then removed. Following a retention interval of 16 min, the rats were replaced in the maze and allowed to retrieve pellets from the 3 unvisited arms. The errors in reentering previously visited arms were noted. Both primacy and recency effects were found as with humans. Presenting a stimulus change after entry to 1 of the maze arms improved recall for that arm relative to when no change occurred. This effect was found using both handling and tone cues, and irrespective of whether the change consisted of presentation or nonpresentation of the cue. These results suggest that rats are subject to a von Restorff-like effect similar to that in humans. PMID:8681532

  5. Stochastic resonance in a generalized Von Foerster population growth model

    SciTech Connect

    Lumi, N.; Mankin, R.

    2014-11-12

    The stochastic dynamics of a population growth model, similar to the Von Foerster model for human population, is studied. The influence of fluctuating environment on the carrying capacity is modeled as a multiplicative dichotomous noise. It is established that an interplay between nonlinearity and environmental fluctuations can cause single unidirectional discontinuous transitions of the mean population size versus the noise amplitude, i.e., an increase of noise amplitude can induce a jump from a state with a moderate number of individuals to that with a very large number, while by decreasing the noise amplitude an opposite transition cannot be effected. An analytical expression of the mean escape time for such transitions is found. Particularly, it is shown that the mean transition time exhibits a strong minimum at intermediate values of noise correlation time, i.e., the phenomenon of stochastic resonance occurs. Applications of the results in ecology are also discussed.

  6. Ludwig von Bertalanffy's organismic view on the theory of evolution.

    PubMed

    Drack, Manfred

    2015-03-01

    Ludwig von Bertalanffy was a key figure in the advancement of theoretical biology. His early considerations already led him to recognize the necessity of considering the organism as a system, as an organization of parts and processes. He termed the resulting research program organismic biology, which he extended to all basic questions of biology and almost all areas of biology, hence also to the theory of evolution. This article begins by outlining the rather unknown (because often written in German) research of Bertalanffy in the field of theoretical biology. The basics of the organismic approach are then described. This is followed by Bertalanffy's considerations on the theory of evolution, in which he used methods from theoretical biology and then introduced his own, organismic, view on evolution, leading to the demand for finding laws of evolution. Finally, his view on the concept of homology is presented. PMID:25727202

  7. von Neumann entropy associated with the haldane exclusion statistics

    SciTech Connect

    Rajagopal, A.K. )

    1995-02-13

    We obtain the von Neumann entropy per state of the Haldane exclusion statistics with parameter [ital g] in terms of the mean occupation number [bar n][l brace][ital w]ln[ital w][minus](1+[ital w])ln(1+[ital w])[r brace], where [ital w]=(1[minus][bar n]). This reduces correctly to the well known expressions in the limiting cases of Bose ([ital g]=0) and Fermi ([ital g]=1) statistics. We have derived the second and third order fluctuations in the occupation numbers for arbitrary [ital g]. An elegant general duality relationship between the [ital w] factor associated with the particle and that associated with the hole at the reciprocal [ital g] is deduced along with the attendant relationship between the two respective entropies.

  8. Franz Xaver von Zach and Giovanni Battista Amici

    NASA Astrophysics Data System (ADS)

    Meschiari, Alberto

    The address explores the five-year relationship between Franz Xaver von Zach and the Italian instrument maker Giovanni Battista Amici (Modena 1786 - Florence 1863) from the time of their first meeting at Amici's workshop in Modena on 8 September 1820. Zach was particularly impressed by Amici's prismatic reflecting sector and helped him to obtain the optical glass required for its construction from Fraunhofer in Munich. With his "Correspondance astronomique", Zach was one of Amici's main publishers. In the space of four years he published seven of his scientific letters, discussing and commenting on them with extensive notes. The correspondence between Amici and Zach, kept at the Estense Library in Modena and covering a period of just under three years from July 1822 to May 1825, has been published by A. Meschiari in Nuncius, 1-2002.

  9. Stochastic resonance in a generalized Von Foerster population growth model

    NASA Astrophysics Data System (ADS)

    Lumi, N.; Mankin, R.

    2014-11-01

    The stochastic dynamics of a population growth model, similar to the Von Foerster model for human population, is studied. The influence of fluctuating environment on the carrying capacity is modeled as a multiplicative dichotomous noise. It is established that an interplay between nonlinearity and environmental fluctuations can cause single unidirectional discontinuous transitions of the mean population size versus the noise amplitude, i.e., an increase of noise amplitude can induce a jump from a state with a moderate number of individuals to that with a very large number, while by decreasing the noise amplitude an opposite transition cannot be effected. An analytical expression of the mean escape time for such transitions is found. Particularly, it is shown that the mean transition time exhibits a strong minimum at intermediate values of noise correlation time, i.e., the phenomenon of stochastic resonance occurs. Applications of the results in ecology are also discussed.

  10. Dr. von Braun Standing by Five F-1 Engines

    NASA Technical Reports Server (NTRS)

    2004-01-01

    A pioneer of America's space program, Dr. von Braun stands by the five F-1 engines of the Saturn V launch vehicle. This Saturn V vehicle is an actual test vehicle which has been displayed at the U.S. Space Rocket Center in Huntsville, Alabama. Designed and developed by Rocketdyne under the direction of the Marshall Space Flight Center, a cluster of five F-1 engines was mounted on the Saturn V S-IC (first) stage. The engines measured 19-feet tall by 12.5-feet at the nozzle exit and burned 15 tons of liquid oxygen and kerosene each second to produce 7,500,000 pounds of thrust. The S-IC stage is the first stage, or booster, of a 364-foot long rocket that ultimately took astronauts to the Moon.

  11. Von Glaserfeld`s Radical Constructivism: A Critical Review

    NASA Astrophysics Data System (ADS)

    Hardy, Michael D.

    We explore Ernst von Glaserfelds radical constructivism, its criticisms, and our own thoughts on what it promises for the reform of science and mathematics teaching. Our investigation reveals that many criticisms of radical constructivism are unwarranted; nevertheless, in its current cognitivist form radical constructivism may be insufficient to empower teachers to overcome objectivist cultural traditions. Teachers need to be empowered with rich understandings of philosophies of science and mathematics that endorse relativist epistemologies; for without such they are unlikely to be prepared to reconstruct their pedagogical practices. More importantly, however, is a need for a powerful social epistemology to serve as a referent for regenerating the culture of science education. We recommend blending radical constructivism with Habermas theory of communicative action to provide science teachers with a moral imperative for adopting a constructivist epistemology.

  12. Alexander von Humboldt's perceptions of colonial Spanish America.

    PubMed

    Rebok, Sandra

    2009-01-01

    This study presents an in-depth analysis of Alexander von Humboldt's descriptions and critical comments on the colonial society of the different regions he visited during his well-known expedition through the Americas (1799-1804). The criticisms of colonialism that he expressed, reflecting his personal convictions, have already been the focal point of many studies, but Humboldt also was able to offer a more differentiated assessment through comparisons of regional and local traditions and developments. This essay focuses on his personal diaries, which offer many interesting comments on colonial societies. These considerations and impressions made during the expedition are of particular scholarly value since they were not subject to censorship of any kind. PMID:19852391

  13. Voluntarism in early psychology: the case of Hermann von Helmholtz.

    PubMed

    De Kock, Liesbet

    2014-05-01

    The failure to recognize the programmatic similarity between (post-)Kantian German philosophy and early psychology has impoverished psychology's historical self-understanding to a great extent. This article aims to contribute to recent efforts to overcome the gaps in the historiography of contemporary psychology, which are the result of an empiricist bias. To this end, we present an analysis of the way in which Hermann von Helmholtz's theory of perception resonates with Johann Gottlieb Fichte's Ego-doctrine. It will be argued that this indebtedness is particularly clear when focusing on the foundation of the differential awareness of subject and object in perception. In doing so, the widespread reception of Helmholtz's work as proto-positivist or strictly empiricist is challenged, in favor of the claim that important elements of his theorizing can only be understood properly against the background of Fichte's Ego-doctrine. PMID:24818740

  14. A Powerful Friendship: Theodore von Karman and Hugh L. Dryden

    NASA Technical Reports Server (NTRS)

    Gorn, Michael

    2003-01-01

    During their long personal friendship and professional association, Theodore von Karman (1882-1963) and Hugh L. Dryden (1898-1965) exercised a pivotal if somewhat elusive influence over American aeronautics and spaceflight. Both decisive figures in organizing scientists and engineers at home and abroad, both men of undisputed eminence in their technical fields, their range of contacts in government, academia, the armed forces, industry, and professional societies spanned the globe to an extent unparalleled then as now. Moreover, because they coordinated their activities closely, their combined influence far exceeded the sum of each one s individual contributions. This paper illustrates their personal origins as well as the foundations of their friendship, how their relationship became a professional alliance, and their joint impact on the world of aeronautics and astronautics during the twentieth century.

  15. Dynamics of Diffusion Flames in von Karman Swirling Flows Studied

    NASA Technical Reports Server (NTRS)

    Nayagam, Vedha; Williams, Forman A.

    2002-01-01

    Von Karman swirling flow is generated by the viscous pumping action of a solid disk spinning in a quiescent fluid media. When this spinning disk is ignited in an oxidizing environment, a flat diffusion flame is established adjacent to the disk, embedded in the boundary layer (see the preceding illustration). For this geometry, the conservation equations reduce to a system of ordinary differential equations, enabling researchers to carry out detailed theoretical models to study the effects of varying strain on the dynamics of diffusion flames. Experimentally, the spinning disk burner provides an ideal configuration to precisely control the strain rates over a wide range. Our original motivation at the NASA Glenn Research Center to study these flames arose from a need to understand the flammability characteristics of solid fuels in microgravity where slow, subbuoyant flows can exist, producing very small strain rates. In a recent work (ref. 1), we showed that the flammability boundaries are wider and the minimum oxygen index (below which flames cannot be sustained) is lower for the von Karman flow configuration in comparison to a stagnation-point flow. Adding a small forced convection to the swirling flow pushes the flame into regions of higher strain and, thereby, decreases the range of flammable strain rates. Experiments using downward facing, polymethylmethacrylate (PMMA) disks spinning in air revealed that, close to the extinction boundaries, the flat diffusion flame breaks up into rotating spiral flames (refs. 2 and 3). Remarkably, the dynamics of these spiral flame edges exhibit a number of similarities to spirals observed in biological systems, such as the electric pulses in cardiac muscles and the aggregation of slime-mold amoeba. The tail of the spiral rotates rigidly while the tip executes a compound, meandering motion sometimes observed in Belousov-Zhabotinskii reactions.

  16. John von Neumann and Klaus Fuchs: an Unlikely Collaboration

    NASA Astrophysics Data System (ADS)

    Bernstein, Jeremy

    2010-03-01

    I discuss the origin of the idea of making a fusion (hydrogen) bomb and the physics involved in it, and then turn to the design proposed for one by the unlikely collaborators John von Neumann and Klaus Fuchs in a patent application they filed at Los Alamos in May 1946, which Fuchs passed on to the Russians in March 1948, and which with substantial modifications was tested on the island of Eberiru on the Eniwetok atoll in the South Pacific on May 8, 1951. This test showed that the fusion of deuterium and tritium nuclei could be ignited, but that the ignition would not propagate because the heat produced was rapidly radiated away. Meanwhile, Stanislaw Ulam and C.J. Everett had shown that Edward Teller’s Classical Super could not work, and at the end of December 1950, Ulam had conceived the idea of super compression, using the energy of a fission bomb to compress the fusion fuel to such a high density that it would be opaque to the radiation produced. Once Teller understood this, he invented a greatly improved, new method of compression using radiation, which then became the heart of the Ulam-Teller bomb design, which was tested, also in the South Pacific, on November 1, 1952. The Russians have freely acknowledged that Fuchs gave them the fission bomb, but they have insisted that no one gave them the fusion bomb, which grew out of design involving a fission bomb surrounded by alternating layers of fusion and fission fuels, and which they tested on November 22, 1955. Part of the irony of this story is that neither the American nor the Russian hydrogen-bomb programs made any use of the brilliant design that von Neumann and Fuchs had conceived as early as 1946, which could have changed the entire course of development of both programs.

  17. Molecular cloning and characterization of the von Hippel-Lindau-like protein.

    PubMed

    Qi, Heng; Gervais, Michelle L; Li, Wei; DeCaprio, James A; Challis, John R G; Ohh, Michael

    2004-01-01

    von Hippel-Lindau (VHL) tumor suppressor protein-inactivated in VHL disease and sporadic kidney cancer-is a component of an E3 ubiquitin ligase complex that selectively ubiquitinates the alpha subunit of the hypoxia-inducible factor (HIF) transcription factor for subsequent destruction by the 26S proteasome. Here, we report the identification and characterization of the first VHL homologue, VHL-like protein (VLP), located on chromosome 1q21.2. A 676-bp partial cDNA encoding a 139-amino acid protein that is 78% similar to VHL was isolated by reverse transcription-PCR from human brain cerebellum and several cancer cell lines. The expression of VLP transcript is most abundant in the placenta. Like VHL, VLP contains a beta domain capable of binding HIFalpha. However, unlike VHL, it does not contain a recognizable alpha domain, which is required for nucleating the multiprotein E3 ubiquitin ligase complex. The increased expression of VLP in the presence of VHL attenuated the ubiquitination of HIFalpha and led to the accumulation of downstream HIF target genes. These results taken together indicate that VLP functions as a dominant-negative VHL to serve as a protector of HIFalpha. PMID:14757845

  18. A project to publish the collected correspondence of Baron Franz Xaver von Zach

    NASA Astrophysics Data System (ADS)

    Cunningham, Clifford J.

    The complete extant correspondence of Baron von Zach will be edited and published by the author, beginning in 2004, the 250th anniversary of his birth. Volume 1 of this work, featuring his correspondence with Jan Sniadecki, has been published.

  19. Dr. Wernher Von Braun leads a tour of the S-IC checkout area.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Eberhard Rees, Charles Schultze, James Webb, Elmer Staats, Comptroller General of the United States, and Dr. Wernher Von Braun tour the S-IC checkout area in the Marshall Space Flight Center quality lab.

  20. APOLLO 14 DR. WERNHER VON BRAUN WATCHES FROM FIRING ROOM 2

    NASA Technical Reports Server (NTRS)

    1971-01-01

    Dr. Wernher von Braun, the NASA Deputy Associate Administrator for Future Programs, uses binoculars to monitor data on closed- circuit television screens in Firing Room 2 of the Launch Control Center during final Apollo 14 launch preparations today.