Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 526-534 ◽  
Author(s):  
Augusto B. Federici ◽  
Pier M. Mannucci ◽  
Giancarlo Castaman ◽  
Luciano Baronciani ◽  
Paolo Bucciarelli ◽  
...  
Keyword(s):  
Platelet Count ◽  
Confidence Interval ◽  
Von Willebrand Disease ◽  
Stress Conditions ◽  
Severe Thrombocytopenia ◽  
Risk Of Bleeding ◽  
Platelet Receptor ◽  
Low Platelet Count ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Type 2B von Willebrand disease (VWD2B) is caused by an abnormal von Willebrand factor (VWF) with increased affinity for the platelet receptor glycoprotein Ib-α (GPIb-α) that may result in moderate to severe thrombocytopenia. We evaluated the prevalence and clinical and molecular predictors of thrombocytopenia in a cohort of 67 VWD2B patients from 38 unrelated families characterized by VWF mutations. Platelet count, mean platelet volume, and morphologic evaluations of blood smear were obtained at baseline and during physiologic (pregnancy) or pathologic (infections, surgeries) stress conditions. Thrombocytopenia was found in 20 patients (30%) at baseline and in 38 (57%) after stress conditions, whereas platelet counts were always normal in 16 patients (24%) from 5 families carrying the P1266L/Q or R1308L mutations. VWF in its GPIb-α–binding conformation (VWF–GPIb-α/BC) was higher than normal in all except the 16 cases without thrombocytopenia (values up to 6-fold higher than controls). The risk of bleeding was higher in patients with thrombocytopenia (adjusted hazard ratio = 4.57; 95% confidence interval, 1.17-17.90) and in those with the highest tertile of bleeding severity score (5.66; 95% confidence interval, 1.03-31.07). Prediction of possible thrombocytopenia in VWD2B by measuring VWF–GPIb-α/BC is important because a low platelet count is an independent risk factor for bleeding.

First Case of Platelet-Type Von Willebrand Disease (PT-VWD) Associated with Type 2B Von Willebrand Disease (2B VWD)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5313-5313
Author(s):  
Marie Dreyfus ◽  
Celine Desconclois ◽  
Corinne Guitton ◽  
Marie-Jeanne Baas ◽  
Helene Mandard ◽  
...  
Keyword(s):  
Platelet Count ◽  
Von Willebrand Disease ◽  
Biological Study ◽  
High Dose ◽  
Severe Thrombocytopenia ◽  
First Case ◽  
Platelet Receptor ◽  
Biological Phenotype ◽  
Neonatal Thrombocytopenia ◽  
Von Willebrand

Abstract Abstract 5313 Introduction VWD 2B and PT-VWD are rare diseases, due to mutations inducing a gain of function respectively of von Willebrand factor (VWF) and of its platelet receptor, Glycoprotein (GP)1bα Case history We report here the case of a young girl, born with an extensive purpura and a severe thrombocytopenia: platelet count: 16G/L. There was no associated biological nor clinical abnormality. A high dose of 1g/kg of immunoglobulin G infused on day 1 was unsuccessful, and a HPA-1a (−) platelet concentrate infusion led to a partial and transient increase of the platelet count up to 60G/L. Thrombocytopenia then resolved spontaneously. Biological study showed no sign of materno-fetal allo- or auto-immunity, parents were not consanguineous. The diagnosis of type 2B VWD was performed when she was 5 months old: VWF:RCo < 13 IU/dl, VWF:Ag 60 IU/dl, positive ristocetin induced platelet aggregation (RIPA) at a low ristocetin concentration (0.5 mg/ml). RIPA mixing studies were unconclusive. The same biological abnormalities were found in the father, whereas the mother had normal hemostasis tests. The biological phenotype also included a study of the multimeric VWF structure, showing a marked decrease in percentage of VWF high and intermediate molecular multimers. Genetic analysis performed on VWF gene showed the heterozygous p.Pro1266Leu missense mutation in the VWF A1 domain. This mutation ( o ) is only slightly deleterious, and induces usually a mild disease, without thrombocytopenia, even in stress situations, with normal VWF multimeric distribution; therefore, it could not explain the biological phenotype severity in this family. GPIBA was then analysed, and a candidate point mutation p.Met239Ile was evidenced. This mutation had not been described yet, but p.Met255Val had already been found in diagnosed cases of PT-VWD. Conclusion This case underlines the utmost importance to characterize precisely neonatal thrombocytopenia mechanism. Furthermore, it points out the difficulties to performing PT-VWD diagnosis, which incidence is most probably underestimated. In our case, it was the systematic and extensive biological workout performed in this case of isolated neonatal thrombocytopenia, without any obvious cause, which led to the diagnosis of a PT-VWD, inducing a severe biological phenotype, associated with type 2B VWD characterized by a mild expression. It is, to our knowledge, the first case described to date of such a morbid association. Disclosures: No relevant conflicts of interest to declare.

Studies with the Nanobody That Detects the Gain-of-Function of von Willebrand Factor in a Cohort of Patients with Type 2B von Willebrand Disease: Correlation with Platelet Count, VWF Multimers and Molecular Defects.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1011-1011 ◽  
Author(s):  
Augusto B. Federici ◽  
Luciano Baronciani ◽  
Maria T. Canciani ◽  
Barbara Moroni ◽  
Carlo Balduini ◽  
...  
Keyword(s):  
Platelet Count ◽  
Von Willebrand Factor ◽  
Antibody Fragment ◽  
Von Willebrand Disease ◽  
Stress Conditions ◽  
Giant Platelets ◽  
Additional Tool ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Type 2B von Willebrand disease (VWD) is an inherited bleeding disorder caused by abnormal von Willebrand factor (VWF) that displays increased affinity to the platelet glicoprotein 1b alpha (GpIba) and is due to a group of mutations clustered within VWF A1 domain. Such an enhanced 2BVWF-GpIba binding usually result in loss of large VWF multimers and moderate-mild thrombocytopenia. A llama-derived antibody fragment (AuVWFa11) recognizing the GpIba-binding conformation has been recently developed (Blood2005;106:3035). Aims and design of the study: to further explore the usefulness of AuVWFa11 in type 2B diagnosis, we have prospectively tested AuVWFa11 in our cohort of 16 patients previously characterized by platelet count, VWF multimers and mutations. Methods: Data of platelet count with mean platelet volume (MPV) and morphologic evaluation of the blood smear to search for giant platelets or aggregates were associated with the history of physiologic or pathologic stress conditions such as pregnancy, infections, surgery or use of DDAVP. All patients were diagnosed by ristocetin induced platelet agglutination (RIPA) in the Platelet Rich Plasma (PRP), ristocetin cofactor activity (VWF:RCo) with VWF antigen (VWF:Ag), multimeric structure of VWF. Mutations within VWF A1 domain were searched for and confirmed by sequencing exon 28. AuVWFa11 was tested in 40 normal individuals (expressed as % of active VWF in normal pool plasma =0.70±0.13) and in type 2B. Results: Data (mean ± SD) of the AuVWFa11 tested in the 16 patients with type 2B VWD are correlated with the main phenotypic data and genotype (Table1). Platelet count &lt; 140,000 was found at baseline in only 3/16 (%), but was observed after stress conditions in 12/16 cases (%); no reduced platelet counts was found in 4/16 patients (%) from two different families (R1308L, R1341Q). An increased MPV was found in 12 cases but giant platelet and aggregates in only 1 case. Activated VWF as tested by AuVWFa11 was positive in all but 3 (R1308L) cases, with values ranging from 2 to 6 times higher than normal controls: values &gt; 3 correlate with loss of large VWF multimers and mild-moderate thrombocytopenia. Conclusions: The AVWF11a can show activated VWF in most type 2B VWD patients, especially when 2B VWF mutants induce significant loss of large multimers and thrombocytopenia. Therefore AuVWF11a can be a useful additional tool in the diagnosis of type 2B VWD. Table 1 Mutation (n) RIPA (mg/ml) VWF.Ag (U/dL) Plat Count (×10^9/L) MPV (micron^3) Loss of HMW Mult AuVWFa11 (ratioNPP) R1306W (5) 0.65 40±9 165±39 10.3±2.3 YES 3.7±1.5 R1308C (3) 0.72 53±16 163±61 11.5±1.9 YES 3.3±2.3 R1308L (3) 0.50 48±13 341±104 8.1±3.1 NO 0.5±0.2 I1309V (1) 0.40 115 222 11.8 PARTIAL 2.1 V1316M (2) 0.50 32±7 119±30 9.2±2.4 YES 4.4±0.1 P1337L (1) 0.50 48 222 9.5 PARTIAL 1.3 R1341Q (1) 0.67 43 422 9.9 PARTIAL 2.9

Type 2B von Willebrand Disease: Early Manifestation as Neonatal Thrombocytopenia

2021 ◽  
Vol 41 (06) ◽  
pp. 469-474
Author(s):  
David Kranzhöfer ◽  
Anna Pavlova ◽  
Hendryk Schneider ◽  
Peter Franck ◽  
Hannah Glonnegger ◽  
...  
Keyword(s):  
Platelet Count ◽  
Light Transmission ◽  
Venous Blood ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Von Willebrand Disease ◽  
Severe Thrombocytopenia ◽  
Neonatal Thrombocytopenia ◽  
Low Platelet Count ◽  
Von Willebrand

AbstractHere, we report about a preterm female newborn with a prolonged course of severe thrombocytopenia and hematomas. The family history was positive for von Willebrand disease type 2B (VWD 2B). Diagnosis of VWD 2B was identified analyzing von Willebrand factor (VWF) parameters (VWF:antigen, VWF:activity, VWF multimer analyses) and performing light transmission aggregometry (with half concentration of ristocetin). In addition, the diagnosis was confirmed by molecular genetic analysis: identification of a disease-causing missense mutation (Val1316Met) in the VWF gene associated with a severe course of VWD 2B, which had been previously reported. Treatment with a VWF-containing plasma concentrate was initiated. Because the combination of prematurity and very low platelet count is often associated with intracranial bleeding, at the beginning platelet concentrates were transfused. Fortunately, the patient did not develop serious bleeding episodes. Interestingly, the patient had a mutation in the VWF gene, which had been described to be associated with aggravation of thrombocytopenia especially in stressful situations. Therefore, we replaced venous blood withdrawals by capillary blood samplings when possible and, consequently, we observed an increase of the platelet count after this change in management. At the age of 2 months, the patient was discharged after stabilization of the platelet count without any bleeding signs and without a need of long-term medication.

TYPE IIB VON WILLEBRAND DISEASE WITH CHRONIC THROMBOCYTOPENIA : BENEFICIAL EFFECT OF CRYOPRECIPITATE SUPERNATANT INFUSION ON PLATELET COUNT AND BLEEDING

1987 ◽  
Author(s):  
A Derlon ◽  
A Le Querrec ◽  
E Lebrun ◽  
G Tobelem ◽  
M Thomas
Keyword(s):  
Platelet Count ◽  
Von Willebrand Factor ◽  
Fresh Frozen Plasma ◽  
Von Willebrand Disease ◽  
Severe Thrombocytopenia ◽  
Plasma Infusion ◽  
Fresh Frozen ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Frozen Plasma

As we previously described, plasma infusion increased platelet count (PC) in four patients with IIB von Willebrand disease with severe thrombocytopenia. In a sixty years old patient in the same family, with chronic thrombocytopenia (PC = 30 000/ml) associated to an absence of large von Willebrand Factor multi-mers (vWF) in plasma, we successfully treated :1° A gastrointestinal bleeding episode with fresh frozen plasma infusion (15ml/Kg/day).2° Three months later a severe epistaxis with cryoprecipi-tate supernatant (15ml/Kg/day).During these bleeding episodes, the efficiency of these two treatments on the PC could be ascertained according to the following figureWe observed after ten days of these two treatments the following biological effects : a normalisation of vWF cross immunoelectrophoresis, of ristocetin induced normal platelet aggregation by patient's plasma, and of patient's plasma vWF binding to control platelets.In conclusion a factor appears to be present in both fresh frozen plasma and cryoprecipitate supernatant which prevents the abnormal binding of von Willebrand Factor (in this IIB von Willebrand disease) to the patient's platelets.

Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4862-4869 ◽  
Author(s):  
Mia Golder ◽  
Cynthia M. Pruss ◽  
Carol Hegadorn ◽  
Jeffrey Mewburn ◽  
Kimberly Laverty ◽  
...  
Keyword(s):  
Ferric Chloride ◽  
Von Willebrand Disease ◽  
Expression Vectors ◽  
Severe Thrombocytopenia ◽  
Normal Platelet ◽  
Injury Model ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Type 2B von Willebrand disease (2B VWD) results from von Willebrand factor (VWF) A1 mutations that enhance VWF-GPIbα binding. These “gain of function” mutations lead to an increased affinity of the mutant VWF for platelets and the binding of mutant high-molecular-weight VWF multimers to platelets in vivo, resulting in an increase in clearance of both platelets and VWF. Three common 2B VWD mutations (R1306W, V1316M, and R1341Q) were independently introduced into the mouse Vwf cDNA sequence and the expression vectors delivered to 8- to 10-week-old C57Bl6 VWF−/− mice, using hydrodynamic injection. The resultant phenotype was examined, and a ferric chloride–induced injury model was used to examine the thrombogenic effect of the 2B VWD variants in mice. Reconstitution of only the plasma component of VWF resulted in the generation of the 2B VWD phenotype in mice. Variable thrombocytopenia was observed in mice expressing 2B VWF, mimicking the severity seen in 2B VWD patients: mice expressing the V1316M mutation showed the most severe thrombocytopenia. Ferric chloride–induced injury to cremaster arterioles showed a marked reduction in thrombus development and platelet adhesion in the presence of circulating 2B VWF. These defects were only partially rescued by normal platelet transfusions, thus emphasizing the key role of the abnormal plasma VWF environment in 2B VWD.

Alteration in GPIIb/IIIa Binding of VWD-Associated von Willebrand Factor Variants with C-Terminal Missense Mutations

2019 ◽  
Vol 119 (07) ◽  
pp. 1102-1111
Author(s):  
Gesa König ◽  
Tobias Obser ◽  
Olivier Marggraf ◽  
Sonja Schneppenheim ◽  
Ulrich Budde ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Active Form ◽  
Von Willebrand Disease ◽  
Hek293 Cells ◽  
Missense Mutations ◽  
Primary Hemostasis ◽  
Platelet Receptor ◽  
Adhesive Proteins ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractThe platelet receptor glycoprotein (GP) IIb/IIIa, formed by integrins αIIb and β3, plays an important role in platelet adhesion and aggregation. Its major binding site is the arginine-glycine-aspartic acid (RGD) sequence present in several adhesive proteins. Upon platelet activation, inside-out signaling activates the complex permitting binding to RGD motif containing proteins, such as von Willebrand factor (VWF). VWF is a large multidomain plasma GP essential to primary hemostasis, which can directly interact with platelets because it exhibits binding sites for GPIbα and GPIIb/IIIa in its A1 and C4 domain, respectively. A vast variety of VWF variants have been identified in which domain-specific mutations affect distinct functions of VWF but reduced GPIIb/IIIa binding has barely been studied so far. Here, we strived to investigate the influence of C domain mutations, which have been identified in patients diagnosed with von Willebrand disease (VWD), on VWF–GPIIb/IIIa interaction. To determine binding to membrane-incorporated GPIIb/IIIa in the absence of GPIbα, we developed and validated a cell-based binding assay which uses HEK293 cells stably expressing a constitutively active form of the GPIIb/IIIa receptor complex on their plasma membrane. By employing this assay, we measured GPIIb/IIIa binding of 14 VWF C domain mutants identified in VWD patients. Mutants p.Cys2257Arg, p.Gly2441Cys, p.Cys2477Tyr, and p.Pro2722Ala exhibited significantly reduced binding. Summarizing, we have developed a useful research tool to specifically investigate GPIIb/IIIa interaction with its protein binding partners and identified four VWF variants that exhibit impaired GPIIb/IIIa binding. At least in the homozygous state, this defect could contribute to the VWD phenotype.

scholarly journals Acquired Deficiency of von Willebrand Factor-Cleaving Protease in a Patient With Thrombotic Thrombocytopenic Purpura

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2839-2846 ◽  
Author(s):  
Miha Furlan ◽  
Rodolfo Robles ◽  
Max Solenthaler ◽  
Bernhard Lämmle
Keyword(s):  
Platelet Count ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Protease Activity ◽  
Temporary Increase ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma of patients with thrombotic thrombocytopenic purpura (TTP) has been shown to contain unusually large von Willebrand factor (vWF) multimers that may cause platelet agglutination in vivo. Fresh frozen plasma infusions and plasma exchange represent the most efficient therapy of acute TTP. A specific protease responsible for cleavage of vWF multimers has been recently isolated from normal human plasma and was found to be deficient in four patients with chronic relapsing TTP. We examined the activity of the vWF-cleaving protease in plasma samples collected over a period of 400 days from a further patient with recurrent episodes of TTP who was treated by plasma exchange, plasma infusion, vincristine, corticosteroid therapy, and splenectomy. Complete deficiency of the vWF-cleaving protease was established during the first episode of TTP. The ensuing normalization of the platelet count was associated with the appearance of the protease activity. Three months after remission from the initial TTP event, the vWF-cleaving protease again disappeared and the platelet count gradually decreased. Relapses of severe thrombocytopenia occurred 7 and 11 months after the first acute episode of TTP. Deficient protease activity was associated with the presence in the patient plasma of an inhibitor that was found to be an IgG. Plasma exchange/infusion was followed by a temporary increase in the antibody titer, whereas treatment with vincristine led to a recovery of the platelet count without affecting the inhibitor concentration. Splenectomy and corticosteroid treatment resulted in disappearance of the autoantibody and normalization of the protease activity and of the platelet count. Our data suggest that the thrombocytopenia in this patient with TTP was associated with a lack of the vWF-cleaving protease activity depleted by an autoimmune mechanism. This case, together with our previously reported patients, leads us to conclude that acquired as well as constitutional deficiency of the vWF-cleaving protease may predispose to TTP.

Post-DDAVP Thrombocytopenia in Type 2B von Willebrand Disease Is not Associated with Platelet Consumption: Failure to Demonstrate Glycocalicin Increase or Platelet Activation

1999 ◽  
Vol 81 (02) ◽  
pp. 224-228 ◽  
Author(s):  
A. Steffan ◽  
E. Pontara ◽  
A. Zucchetto ◽  
C. Rossi ◽  
L. De Marco ◽  
...  
Keyword(s):  
Platelet Count ◽  
Platelet Activation ◽  
Surface Expression ◽  
Von Willebrand Disease ◽  
Platelet Surface ◽  
Platelet Counts ◽  
Normal Platelet ◽  
Thrombotic Complications ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThrombocytopenia is frequently reported in type 2B von Willebrand disease (vWD), and thought to be related to the abnormally high affinity of 2B von Willebrand factor (vWF) for platelet GPIb-IX. To gain an insight into the nature of this thrombocytopenia, we measured plasma glycocalicin (GC) levels (as a marker of platelet turnover), and platelet surface expression of the alpha granule protein P-selectin (as a marker of platelet activation) in 9 patients with type 2B vWD before, and in 4 patients also following the infusion of 1-desamino-8-d-arginine vasopressin (DDAVP). Three patients presented a persistent decrease of platelet counts in the resting condition. GC levels were within the normal range, regardless of the platelet counts, in all but one patient who presented, on the other hand, a normal platelet count. Moreover, platelets expressed normal amounts of P-selectin on their surface, regardless of platelet counts. These findings suggest that the thrombocytopenia observed in type 2B vWD is not due to platelet activation and subsequent consumption in circulation.Despite a significant, albeit transient, decrease in platelet count, DDAVP did not induce an increase in plasma GC levels, nor enhance P-selectin expression. These observations indicate that the acute post-DDAVP thrombocytopenia in type 2B vWD is not related to platelet activation and consumption. We advance that the post-DDAVP 2B vWF is hemostatically more active, and able to induce agglutination but not aggregation of circulating platelets. This would explain both the prompt recovery of basal platelet counts after the post-DDAVP decrease, and the lack of reported thrombotic complications in this disorder.Therefore, even though 2B vWF is characterized by an enhanced affinity for the platelet surface, its binding to platelet GPIb-IX in the soluble phase is not able to induce true platelet aggregation; vWF thus appears to be mainly an adhesive protein, rather than an aggregating agent.

scholarly journals Type 2B von Willebrand Disease: A Matter of Plasma Plus Platelet Abnormality

2016 ◽  
Vol 42 (05) ◽  
pp. 478-482 ◽  
Author(s):  
Giancarlo Castaman ◽  
Augusto Federici
Keyword(s):  
Autosomal Dominant ◽  
Platelet Rich Plasma ◽  
Von Willebrand Disease ◽  
Variable Degree ◽  
Gene Encoding ◽  
Platelet Receptor ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Type 2B von Willebrand disease (VWD2B) is a rare, autosomal-dominant inherited bleeding disorder, characterized by an enhanced ristocetin-induced platelet aggregation in platelet-rich plasma and often with variable degree of thrombocytopenia and loss of high-molecular-weight multimers von Willebrand factor (VWF). All these phenomena are caused by a mutant VWF, normally synthesized and assembled by endothelial cells, but with heightened affinity binding to the platelet receptor glycoprotein Ib-α (GpIb-α). When this abnormal VWF is released into the circulation and under specific clinical circumstances, in vivo platelet clumping is observed. Mutations, invariably clustered in exon 28 of the VWF gene encoding for the VWF A1 domain involved in VWF binding to GpIb-α, are responsible for VWD2B phenotype. Clinical and laboratory phenotype appears strongly related to the type of VWF-causative mutations. However, recent evidences suggest that a true platelet defect is also present in this type, with several morphological and functional abnormalities being detected in a subset of VWD2B patients.

O-linked glycosylation of von Willebrand factor modulates the interaction with platelet receptor glycoprotein Ib under static and shear stress conditions

Blood ◽  
2012 ◽  
Vol 120 (1) ◽  
pp. 214-222 ◽  
Author(s):  
Agata A. Nowak ◽  
Kevin Canis ◽  
Anne Riddell ◽  
Michael A. Laffan ◽  
Thomas A. J. McKinnon
Keyword(s):  
Shear Stress ◽  
Binding Sites ◽  
Stress Conditions ◽  
Collagen Binding ◽  
Platelet Receptor ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Double Cluster

AbstractWe have examined the effect of the O-linked glycan (OLG) structures of VWF on its interaction with the platelet receptor glycoprotein Ibα. The 10 OLGs were mutated individually and as clusters (Clus) on either and both sides of the A1 domain: Clus1 (N-terminal side), Clus2 (C-terminal side), and double cluster (DC), in both full-length-VWF and in a VWF construct spanning D′ to A3 domains. Mutations did not alter VWF secretion by HEK293T cells, multimeric structure, or static collagen binding. The T1255A, Clus1, and DC variants caused increased ristocetin-mediated GPIbα binding to VWF. Platelet translocation rate on OLG mutants was increased because of reduced numbers of GPIbα binding sites but without effect on bond lifetime. In contrast, OLG mutants mediated increased platelet capture on collagen under high shear stress that was associated with increased adhesion of these variants to the collagen under flow. These findings suggest that removal of OLGs increases the flexibility of the hinge linker region between the D3 and A1 domain, facilitating VWF unfolding by shear stress, thereby enhancing its ability to bind collagen and capture platelets. These data demonstrate an important functional role of VWF OLGs under shear stress conditions.

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