scholarly journals von Willebrand factor propeptide: biology and clinical utility

Blood ◽  
2015 ◽  
Vol 126 (15) ◽  
pp. 1753-1761 ◽  
Author(s):  
Sandra L. Haberichter
Keyword(s):  
Von Willebrand Factor ◽  
Clinical Utility ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
True Type ◽  
And Function ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Von Willebrand Factor Propeptide

Abstract von Willebrand factor (VWF) is a large multimeric glycoprotein that mediates the attachment of platelets to damaged endothelium and also serves as the carrier protein for coagulation factor VIII (FVIII), protecting it from proteolytic degradation. Quantitative or qualitative defects in VWF result in von Willebrand disease (VWD), a common inherited bleeding disorder. VWF is synthesized with a very large propeptide (VWFpp) that is critical for intracellular processing of VWF. VWFpp actively participates in the process of VWF multimerization and is essential for trafficking of VWF to the regulated storage pathway. Mutations identified within VWFpp in VWD patients are associated with altered VWF structure and function. The assay of plasma VWFpp has clinical utility in assessing acute and chronic vascular perturbation associated with diseases such as thrombotic thrombocytopenic purpura, sepsis, and diabetes among others. VWFpp assay also has clear utility in the diagnosis of VWD subtypes, particularly in discriminating true type 3 subjects from type 1C (reduced plasma survival of VWF), which is clinically important and has implications for therapeutic treatment.

Clinical cases of using coagulation factor VIII with von Willebrand factor in parturient women with type III von Willebrand disease

2020 ◽  
Author(s):  
И.В. Куртов ◽  
Е.С. Фатенкова ◽  
Н.А. Юдина ◽  
А.М. Осадчук ◽  
И.Л. Давыдкин
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Coagulation Factor Viii ◽  
Vitro Fertilization ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Болезнь Виллебранда (БВ) может представлять определенные трудности у рожениц с данной патологией. Приведены 2 клинических примера использования у женщин с БВ фактора VIII свертывания крови с фактором Виллебранда, показана эффективность и безопасность их применения. У одной пациентки было также показано использование фактора свертывания крови VIII с фактором Виллебранда во время экстракорпорального оплодотворения. Von Willebrand disease presents a certain hemostatic problem among parturients. This article shows the effectiveness and safety of using coagulation factor VIII with von Willebrand factor for the prevention of bleeding in childbirth in 2 patients with type 3 von Willebrand disease. In one patient, the use of coagulation factor VIII with von Willebrand factor during in vitro fertilization was also shown.

scholarly journals von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease

Blood ◽  
2015 ◽  
Vol 125 (19) ◽  
pp. 3006-3013 ◽  
Author(s):  
Yvonne V. Sanders ◽  
Dafna Groeneveld ◽  
Karina Meijer ◽  
Karin Fijnvandraat ◽  
Marjon H. Cnossen ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Key Points ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Severe Type ◽  
Von Willebrand Factor Propeptide

Key Points VWFpp discriminates between type 3 VWD patients and severe type 1 VWD patients with very low VWF levels. The pathophysiological mechanisms of all types of VWD can be defined by the combined ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag.

Von Willebrand disease and Weibel-Palade bodies

2010 ◽  
Vol 30 (03) ◽  
pp. 150-155 ◽  
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.

Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease

2021 ◽  
Vol 47 (02) ◽  
pp. 192-200
Author(s):  
James S. O'Donnell
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Risk ◽  
Von Willebrand Disease ◽  
Personalized Treatment ◽  
Treatment Plans ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractThe biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

scholarly journals Phage Display Broadly Identifies Inhibitor-reactive Regions in von Willebrand Factor

2021 ◽  
Author(s):  
Andrew Yee ◽  
Manhong Dai ◽  
Stacy E. Croteau ◽  
Jordan A. Shavit ◽  
Steven W. Pipe ◽  
...  
Keyword(s):  
Phage Display ◽  
Von Willebrand Factor ◽  
Gene Deletion ◽  
Von Willebrand Disease ◽  
Response To Treatment ◽  
Phage Library ◽  
Incomplete Removal ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryBackgroundCorrection of von Willebrand factor (VWF) deficiency with replacement products containing VWF can lead to the development of anti-VWF alloantibodies (i.e., VWF inhibitors) in patients with severe von Willebrand disease (VWD).ObjectiveLocate inhibitor-reactive regions within VWF using phage display.MethodsWe screened a phage library displaying random, overlapping fragments covering the full length VWF protein sequence for binding to a commercial anti-VWF antibody or to immunoglobulins from three type 3 VWD patients who developed VWF inhibitors in response to treatment with plasma-derived VWF. Immunoreactive phage clones were identified and quantified by next generation DNA sequencing (NGS).ResultsNGS markedly increased the number of phage analyzed for locating immunoreactive regions within VWF following a single round of selection and identified regions not recognized in previous reports using standard phage display methods. Extending this approach to characterize VWF inhibitors from three type 3 VWD patients (including two siblings homozygous for the same VWF gene deletion) revealed patterns of immunoreactivity distinct from the commercial antibody and between unrelated patients, though with notable areas of overlap. Alloantibody reactivity against the VWF propeptide is consistent with incomplete removal of the propeptide from plasma-derived VWF replacement products.ConclusionThese results demonstrate the utility of phage display and NGS to characterize diverse anti-VWF antibody reactivities.

Spontaneous pyohaemothorax in a teenager with von Willebrand disease: a case report and review of literature

2021 ◽  
Vol 14 (8) ◽  
pp. e241613
Author(s):  
Vaishnavi Divya Nagarajan ◽  
Asha Shenoi ◽  
Lucy Burgess ◽  
Vlad C Radulescu
Keyword(s):  
Case Report ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Surgical Drainage ◽  
Review Of Literature ◽  
History Of ◽  
Factor Concentrate ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

An 18-year-old man with a history of type 3 von Willebrand disease (VWD) presented with a spontaneous pyohaemothorax. Type 3 VWD may present with both mucocutaneous and deep-seated bleeds, such as visceral haemorrhages, intracranial bleeds and haemarthrosis. There have been very few cases described in children of spontaneous pyohaemothorax. Management of this patient was challenging due to risks of bleeding following surgical drainage, requiring constant replacement with von Willebrand factor concentrate, while monitoring factor VIII levels to balance the risks of thrombosis.

von Willebrand factor alloantibodies in type 3 von Willebrand disease

2020 ◽  
Vol 31 (1) ◽  
pp. 77-79
Author(s):  
Barbara Faganel Kotnik ◽  
Karin Strandberg ◽  
Maruša Debeljak ◽  
Lidija Kitanovski ◽  
Janez Jazbec ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Reduced Von Willebrand Factor Secretion Is Associated with Loss of Weibel-Palade Formation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 541-541
Author(s):  
Giancarlo Castaman ◽  
Sofia Helene Giacomelli ◽  
Paula M. Jacobi ◽  
Tobias Obser ◽  
Reinhard Schneppenheim ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Von Willebrand Disease ◽  
Hek293 Cells ◽  
Wild Type ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 541 Background. Von Willebrand Disease (VWD) is caused by mutations in von Willebrand factor (VWF) that have different pathophysiologic effect in causing low plasma VWF levels. Type 1 VWD includes patients with quantitative plasma VWF deficiency with normal VWF structure and function. Aim of the study. We report three different novel type 1 VWF mutations (A1716P, C2190Y and R2663C) which although located in different VWF domains are associated with reduced secretion and lack of formation of Weibel-Palade body-like granules. Methods. Transient expression of recombinant mutant full-length VWF in 293 EBNA cells was performed and secretion, collagen binding, and GpIb binding assessed in comparison to wild-type VWF. Furthermore, expression was also examined in HEK293 cells that form Weibel-Palade body (WPB)-like granules when transfected with wt VWF. Results. The multimer analysis of plasma VWF was compatible with type 1 VWD. The results of 3 different expression experiments showed a slightly reduced VWF synthesis and drastically impaired secretion into the medium with homozygous expression. In HEK293 cells, homozygous A1716P and C2190Y VWF variants failed to form WPB-like granules, while R2663C was capable of forming granules, but had fewer cells with granules and more with ER-localized VWF. Heterozygous expression of A1716P and C2160Y VWF variants had a negative impact on wild-type VWF and WPB-like granules were observed in transfected cells. Conclusions. Our results demonstrate that homozygous and heterozygous quantitative VWF deficiency caused by missense VWF mutations can be associated with inability to form endothelial Weibel-Palade-like granules and mutations in different VWF domains can affect the formation of these organelles. Disclosures: No relevant conflicts of interest to declare.

Expression and characterization of von Willebrand factor dimerization defects in different types of von Willebrand disease

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 2059-2066 ◽  
Author(s):  
Reinhard Schneppenheim ◽  
Ulrich Budde ◽  
Tobias Obser ◽  
Jacqueline Brassard ◽  
Kerstin Mainusch ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Recombinant Expression ◽  
Von Willebrand Disease ◽  
Disulfide Bonding ◽  
Amino Terminal ◽  
Carboxy Terminal ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Dimerization defects of von Willebrand factor (vWF) protomers underlie von Willebrand disease (vWD) type 2A, subtype IID (vWD 2A/IID), and corresponding mutations have been identified at the 3′ end of the vWF gene in exon 52. This study identified and expressed 2 additional mutations in this region, a homozygous defect in a patient with vWD type 3 (C2754W) and a heterozygous frameshift mutation (8566delC) in a patient with vWD type 2A, subtype IIE. Both mutations involve cysteine residues that we propose are possibly essential for dimerization. To prove this hypothesis, transient recombinant expression of each of the 2 mutations introduced in the carboxy-terminal vWF fragment II and in the complete vWF complementary DNA, respectively, were carried out in COS-7 cells and compared with expression of vWD 2A/IID mutation C2773R and the wild-type (WT) sequence in COS-7 cells. Recombinant WT vWF fragment II assembled correctly into a dimer, whereas recombinant mutant fragments were monomeric. Homozygous expression of recombinant mutant full-length vWF resulted in additional dimers, probably through disulfide bonding at the amino-terminal multimerization site, whereas recombinant WT vWF correctly assembled into multimers. Coexpression of recombinant mutant and recombinant WT vWF reproduced the multimer patterns observed in heterozygous individuals. Our results suggest that a common defect of vWF biosynthesis—lack of vWF dimerization—may cause diverse types and subtypes of vWD. We also confirmed previous studies that found that disulfide bonding at the vWF amino-terminal is independent of dimerization at the vWF carboxy-terminal.

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