The 2021 von Willebrand disease guidelines: Clarity and controversy

SummarySince 1978 an annual multicentric survey regarding the epidemiology of patients suffering of haemophilia is performed with support of haemophilia treating centres of any size. Again the actual compilation is resting upon a broad database returning to over 30 years of inquiry well representing both the actual and retrospective status of mortality. Prompted was exclusively information about patients with haemophilia A, B and von Willebrand disease. In particular anonymous data concerning the last 12 months about number of treated patients, type and severity of illness, HIV-status and detailed information about causes of death was inquired. This data was merged with existing data and analyzed statistically. In the 2007/2008 survey, a total

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Platelet Activation and Aggregation Induced by Recombinant von Willebrand Factors Reproducing Four Type 2B von Willebrand Disease Missense Mutations

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614241 ◽

1998 ◽

Vol 79 (01) ◽

pp. 211-216 ◽

Cited By ~ 13

Author(s):

Lysiane Hilbert ◽

Claudine Mazurier ◽

Christophe de Romeuf

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Von Willebrand Disease ◽

Platelet Glycoprotein ◽

Missense Mutations ◽

Inhibit Platelet Aggregation ◽

Wild Type ◽

A1 Domain ◽

Von Willebrand ◽

Willebrand Factor

SummaryType 2B of von Willebrand disease (vWD) refers to qualitative variants with increased affinity of von Willebrand factor (vWF) for platelet glycoprotein Ib (GPIb). All the mutations responsible for type 2B vWD have been located in the A1 domain of vWF. In this study, various recombinant von Willebrand factors (rvWF) reproducing four type 2B vWD missense mutations were compared to wild-type rvWF (WT-rvWF) for their spontaneous binding to platelets and their capacity to induce platelet activation and aggregation. Our data show that the multimeric pattern of each mutated rvWF is similar to that of WT-rvWF but the extent of spontaneous binding and the capacity to induce platelet activation and aggregation are more important for the R543Q and V553M mutations than for the L697V and A698V mutations. Both the binding of mutated rvWFs to platelets and platelet aggregation induced by type 2B rvWFs are inhibited by monoclonal anti-GPIb and anti-vWF antibodies, inhibitors of vWF binding to platelets in the presence of ristocetin, as well as by aurin tricarboxylic acid. On the other hand, EDTA and a monoclonal antibody directed against GPIIb/IIIa only inhibit platelet aggregation. Furthermore, the incubation of type 2B rvWFs with platelets, under stirring conditions, results in the decrease in high molecular weight vWF multimers in solution, the extent of which appears correlated with that of plasma vWF from type 2B vWD patients harboring the corresponding missense mutation. This study supports that the binding of different mutated type 2B vWFs onto platelet GPIb induces various degrees of platelet activation and aggregation and thus suggests that the phenotypic heterogeneity of type 2B vWD may be related to the nature and/or location of the causative point mutation.

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A New (K1518E) Candidate Mutation Detected by Universal Heteroduplex Generator Analysis in a Patient with Type 2A (Phenotype IIA) von Willebrand Disease

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614208 ◽

1998 ◽

Vol 79 (01) ◽

pp. 240-240 ◽

Cited By ~ 2

Author(s):

Bimal Theophilus ◽

Frank Hill ◽

Peter Rose ◽

Doris Culpan ◽

Jeffery Bidwell ◽

...

Keyword(s):

Von Willebrand Disease ◽

Candidate Mutation ◽

Von Willebrand

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Response to DDAVP in children with von Willebrand disease type 2

Hämostaseologie ◽

10.1055/s-0037-1617014 ◽

2009 ◽

Vol 29 (02) ◽

pp. 143-148 ◽

Cited By ~ 3

Author(s):

U. Budde ◽

K. Beutel ◽

W.-A. Hassenpflug ◽

H. Hauch ◽

T. Obser ◽

...

Keyword(s):

Disease Type ◽

Von Willebrand Disease ◽

Molecular Defect ◽

Variable Response ◽

Functional Parameters ◽

Functional Defect ◽

Biologic Response ◽

High Level ◽

Von Willebrand

SummaryWe have prospectively evaluated the biologic response to desmopressin (DDAVP) in 28 children with type 2 von Willebrand disease (VWD) in correlation with the phenotype and the molecular defect of VWF. The diagnosis of VWD type 2 was mainly based on VWF functional parameters and/or an aberrant VWF multimer pattern. Seventeen different mutations were identified (6 of them novel). No response with respect to the functional parameters VWF:RCo and/or VWF:CB was seen in patients with severe abnormality of the VWF multimer pattern. One patient with VWD type 2A phenotype IIC Miami did not respond with respect to VWF:CB, but showed a good response of VWF:Ag and FVIII:C as expected. Interestingly he showed a persistently high level of VWF:Ag and FVIII:C up to 4 hours after DDAVP infusion. Patients with minor alterations of multimer structure and particular mutations responded well to DDAVP, whereas patients with normal multimer structure but a defect in platelet dependent functional parameters did not respond with VWF:RCo. Conclusion: Children with VWD type 2 show a variable response to desmopressin depending on the mutation that correlates with the functional defect and the presence or absence as well as the half-life of large VWF multimers. Our data emphasize the usefulness of DDAVP testing even in patients with VWD type 2, possibly with the exception of VWD type 2B.

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Screening for haemorrhagic disorders in paediatric patients by means of a questionnaire

Hämostaseologie ◽

10.1055/s-0037-1621503 ◽

2009 ◽

Vol 29 (S 01) ◽

pp. S87-S89 ◽

Cited By ~ 4

Author(s):

I. Music ◽

M. Novak ◽

B. Acham-Roschitz ◽

W. Muntean

Keyword(s):

Predictive Value ◽

Laboratory Diagnosis ◽

Von Willebrand Disease ◽

Control Group ◽

Older Children ◽

Mild Disease ◽

History Of ◽

Von Willebrand ◽

Specific Symptoms ◽

Infants And Young Children

SummaryAim: In children, screening for haemorrhagic disorders is further complicated by the fact that infants and young children with mild disease in many cases most likely will not have a significant history of easy bruising or bleeding making the efficacy of a questionnaire even more questionable. Patients, methods: We compared the questionnaires of a group of 88 children in whom a haemorrhagic disorder was ruled out by rigorous laboratory investigation to a group of 38 children with mild von Willebrand disease (VWD). Questionnaires about child, mother and father were obtained prior to the laboratory diagnosis on the occasion of routine preoperative screening. Results: 23/38 children with mild VWD showed at least one positive question in the questionnaire, while 21/88 without laboratory signs showed at least one positive question. There was a trend to more specific symptoms in older children. Three or more positive questions were found only in VWD patients, but only in a few of the control group. The question about menstrual bleeding in mothers did not differ significantly. Sensitivity of the questionnaire for a hemostatic disorder was 0.60, while specifity was 0.76. The negative predictive value was 0.82, but the positive predictive value was only 0.52. Conclusions: Our small study shows, that a questionnaire yields good results to exclude a haemostatic disorder, but is not a sensitive tool to identify such a disorder.

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Von Willebrand disease and Weibel-Palade bodies

Hämostaseologie ◽

10.1055/s-0037-1619048 ◽

2010 ◽

Vol 30 (03) ◽

pp. 150-155 ◽

Cited By ~ 9

Author(s):

J. W. Wang ◽

J. Eikenboom

Keyword(s):

Platelet Adhesion ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Inflammatory Factors ◽

Limited Data ◽

Storage Organelle ◽

And Function ◽

Von Willebrand ◽

Willebrand Factor

SummaryVon Willebrand factor (VWF) is a pivotal haemostatic protein mediating platelet adhesion to injured endothelium and carrying coagulation factor VIII (FVIII) in the circulation to protect it from premature clearance. Apart from the roles in haemostasis, VWF drives the formation of the endothelial cell specific Weibel-Palade bodies (WPBs), which serve as a regulated storage of VWF and other thrombotic and inflammatory factors. Defects in VWF could lead to the bleeding disorder von Willebrand disease (VWD).Extensive studies have shown that several mutations identified in VWD patients cause an intracellular retention of VWF. However, the effects of such mutations on the formation and function of its storage organelle are largely unknown. This review gives an overview on the role of VWF in WPB biogenesis and summarizes the limited data on the WPBs formed by VWD-causing mutant VWF.

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The Interaction of Botrocetin with Normal or Variant von Willebrand Factor (Types IIA and IIB) and Its Inhibition by Monoclonal Antibodies that Block Receptor Binding

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646298 ◽

1992 ◽

Vol 68 (04) ◽

pp. 464-469 ◽

Cited By ~ 9

Author(s):

Y Fujimura ◽

S Miyata ◽

S Nishida ◽

S Miura ◽

M Kaneda ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Von Willebrand Factor ◽

Binding Activity ◽

Von Willebrand Disease ◽

Platelet Glycoprotein ◽

Normal Individuals ◽

Rag 1 ◽

The One ◽

Von Willebrand ◽

Willebrand Factor

SummaryWe have recently shown the existence of two distinct forms of botrocetin (one-chain and two-chain), and demonstrated that the two-chain species is approximately 30 times more active than the one-chain in promoting von Willebrand factor (vWF) binding to platelet glycoprotein (GP) Ib. The N-terminal sequence of two-chain botrocetin is highly homologous to sea-urchin Echinoidin and other Ca2+-dependent lectins (Fujimura et al., Biochemistry 1991; 30: 1957–64).Present data indicate that purified two-chain botrocetin binds to vWF from plasmas of patients with type IIA or IIB von Willebrand disease and its interaction is indistinguishable from that with vWF from normal individuals. However, an “activated complex” formed between botrocetin and IIB vWF expresses an enhanced biological activity for binding to GP Ib whereas the complex with IIA vWF has a decreased binding activity. Among several anti-vWF monoclonal antibodies (MoAbs) which inhibit ristocetin-induced platelet aggregation and/or vWF binding to GPIb, only two MoAbs (NMC-4 and RFF-VIII RAG:1) abolished direct binding between purified botrocetin and vWF. This suggests that they recognize an epitope(s) on the vWF molecule in close proximity to the botrocetin binding site.

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A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650564 ◽

1996 ◽

Vol 76 (02) ◽

pp. 253-257 ◽

Cited By ~ 14

Author(s):

Takeshi Hagiwara ◽

Hiroshi Inaba ◽

Shinichi Yoshida ◽

Keiko Nagaizumi ◽

Morio Arai ◽

...

Keyword(s):

Missense Mutation ◽

Novel Mutation ◽

Point Mutations ◽

Japanese Patients ◽

Von Willebrand Disease ◽

Homozygous Mutation ◽

Missense Mutations ◽

Reaction Products ◽

Type 3 ◽

Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

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The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651575 ◽

1993 ◽

Vol 69 (02) ◽

pp. 173-176 ◽

Cited By ~ 5

Author(s):

Anna M Randi ◽

Elisabetta Sacchi ◽

Gian Carlo Castaman ◽

Francesco Rodeghiero ◽

Pier Mannuccio Mannucci

Keyword(s):

Von Willebrand Factor ◽

Autosomal Dominant ◽

Genetic Defect ◽

Von Willebrand Disease ◽

Type I ◽

Bleeding Tendency ◽

Factor Gene ◽

Low Levels ◽

Von Willebrand ◽

Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

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