scholarly journals Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease

Blood ◽  
2015 ◽  
Vol 126 (2) ◽  
pp. 262-269 ◽  
Author(s):  
Junmei Chen ◽  
Jesse D. Hinckley ◽  
Sandra Haberichter ◽  
Paula Jacobi ◽  
Robert Montgomery ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Phenotypic Variability ◽  
Von Willebrand Disease ◽  
Variable Expressivity ◽  
Key Points ◽  
Variable Content ◽  
Von Willebrand ◽  
Willebrand Factor

Key Points VWD is characterized by variable expressivity, even within families with the same VWF mutation. The content of mutant monomers in the final multimeric structure may explain the observed variability.

Unraveling the Influence of Common von Willebrand factor variants on von Willebrand Disease Phenotype: An Exploratory Study on the Molecular and Clinical Profile of von Willebrand Disease in Spain Cohort

2020 ◽  
Vol 120 (03) ◽  
pp. 437-448
Author(s):  
Nina Borràs ◽  
Iris Garcia-Martínez ◽  
Javier Batlle ◽  
Almudena Pérez-Rodríguez ◽  
Rafael Parra ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Phenotypic Variability ◽  
Substantial Effect ◽  
Von Willebrand Disease ◽  
Clinical Profile ◽  
Single Nucleotide Variants ◽  
Hereditary Factors ◽  
Bleeding Score ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractThe clinical diagnosis of von Willebrand disease (VWD), particularly type 1, can be complex because several genetic and environmental factors affect von Willebrand factor (VWF) plasma levels. An estimated 60% of the phenotypic variation is attributable to hereditary factors, with the ABO blood group locus being the most influential. However, recent studies provide strong evidence that nonsynonymous single nucleotide variants (SNVs) contribute to VWF and factor VIII phenotypic variability in healthy individuals. This study aims to investigate the role of common VWF SNVs on VWD phenotype by analyzing data from 219 unrelated patients included in the “Molecular and Clinical Profile of von Willebrand Disease in Spain project.” To that end, generalized linear mixed-effects regression models were fitted, and additive and epistatic analyses, and haplotype studies were performed, considering five VWD-related measures (bleeding score, VWF:Ag, VWF:RCo, factor VIII:C, and VWF:CB). According to these analyses, homozygotes: for p.Thr789Ala(C) would be expected to show 39% higher VWF:Ag levels; p.Thr1381Ala(C), 27% lower VWF:Ag levels; and p.Gln852Arg(C), 52% lower VWF:RCo levels. Homozygotes for both p.Thr789Ala(C) and p.Gln852Arg(T) were predicted to show 185% higher VWF:CB activity, and carriers of two copies of the p.Thr1381Ala(T)/p.Gln852Arg(T) haplotype would present a 100% increase in VWF:RCo activity. These results indicate a substantial effect of common VWF variation on VWD phenotype. Although additional studies are needed to determine the true magnitude of the effects of SNVs on VWF, these findings provide new evidence regarding the contribution of common variants to VWD, which should be taken into account to enhance the accuracy of the diagnosis and classification of this condition. ClinicalTrials.gov identifier: NCT02869074.

Analysis of the storage and secretion of von Willebrand factor in blood outgrowth endothelial cells derived from patients with von Willebrand disease

Blood ◽  
2013 ◽  
Vol 121 (14) ◽  
pp. 2762-2772 ◽  
Author(s):  
Jiong-Wei Wang ◽  
Eveline A. M. Bouwens ◽  
Maria Carolina Pintao ◽  
Jan Voorberg ◽  
Huma Safdar ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Key Points ◽  
Phenotypic Features ◽  
String Formation ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Multiple Patients

Key Points Isolation of BOECs from multiple patients with VWD is feasible, and the study of BOECs helps explain the pathogenic complexity of VWD. Abnormalities in WPB biogenesis and exocytosis and defects in VWF string formation correlate with the phenotypic features of patients with VWD.

scholarly journals Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism

Blood ◽  
2016 ◽  
Vol 128 (4) ◽  
pp. 584-593 ◽  
Author(s):  
Lindsey Hawke ◽  
Mackenzie L. Bowman ◽  
Man-Chiu Poon ◽  
Mary-Frances Scully ◽  
Georges-Etienne Rivard ◽  
...  
Keyword(s):  
Shear Stress ◽  
Alternative Splicing ◽  
Von Willebrand Factor ◽  
Normal Population ◽  
Von Willebrand Disease ◽  
Aberrant Splicing ◽  
Key Points ◽  
Von Willebrand ◽  
Willebrand Factor

Key Points Aberrant splicing is an underrecognized mechanism causing VWD and is affected by shear stress. Alternative splicing of endothelial VWF occurs in the normal population.

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.

Getting at the Variable Expressivity of Von Willebrand Disease

2001 ◽  
Vol 86 (07) ◽  
pp. 144-148 ◽  
Author(s):  
Gallia Levy ◽  
David Ginsburg
Keyword(s):  
General Population ◽  
Von Willebrand Factor ◽  
Genetic Factors ◽  
Von Willebrand Disease ◽  
Incomplete Penetrance ◽  
Large Component ◽  
Future Directions ◽  
Variable Expressivity ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryVon Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by abnormalities of von Willebrand factor (VWF). VWF levels vary widely in the general population, and this variation is likely to be a major factor accounting for the incomplete penetrance and variable expressivity of VWD. In addition, variation in VWF level may play an important role in determining the risk of venous thrombosis. A large component of the variation in VWF level in the general population has been shown to be attributable to genetic factors. This review will focus on the current understanding of the genetic causes for variation in VWF level, and will highlight future directions for getting at the variable expressivity of von Willebrand disease.

scholarly journals von Willebrand factor is dimerized by protein disulfide isomerase

Blood ◽  
2016 ◽  
Vol 127 (9) ◽  
pp. 1183-1191 ◽  
Author(s):  
Svenja Lippok ◽  
Katra Kolšek ◽  
Achim Löf ◽  
Dennis Eggert ◽  
Willem Vanderlinden ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Protein Disulfide Isomerase ◽  
Bond Formation ◽  
Von Willebrand Disease ◽  
Dimerization Domain ◽  
Disulfide Isomerase ◽  
Key Points ◽  
Von Willebrand ◽  
Protein Disulfide ◽  
Willebrand Factor

Key Points The protein disulfide isomerase is involved in VWF dimerization by initiating disulfide bond formation at cysteines 2771 and 2773. von Willebrand disease-associated mutations in the dimerization domain of von Willebrand factor disturb processing by the protein disulfide isomerase.

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

1992 ◽  
Vol 68 (04) ◽  
pp. 464-469 ◽  
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.

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

1993 ◽  
Vol 69 (02) ◽  
pp. 173-176 ◽  
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.

Characterization of Partial Gene Deletions in Type III von Willebrand Disease with Alloantibody Inhibitors

1994 ◽  
Vol 72 (02) ◽  
pp. 180-185 ◽  
Author(s):  
David J Mancuso ◽  
Elodee A Tuley ◽  
Ricardo Castillo ◽  
Norma de Bosch ◽  
Pler M Mannucci ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Pcr Analysis ◽  
Gene Deletions ◽  
Factor Gene ◽  
Type Iii ◽  
Large Deletions ◽  
Von Willebrand ◽  
Willebrand Factor

Summaryvon Willebrand factor gene deletions were characterized in four patients with severe type III von Willebrand disease and alloantibodies to von Willebrand factor. A PCR-based strategy was used to characterize the boundaries of the deletions. Identical 30 kb von Willebrand factor gene deletions which include exons 33 through 38 were identified in two siblings of one family by this method. A small 5 base pair insertion (CCTGG) was sequenced at the deletion breakpoint. PCR analysis was used to detect the deletion in three generations of the family, including two family members who are heterozygous for the deletion. In a second family, two type III vWD patients, who are distant cousins, share an -56 kb deletion of exons 22 through 43. The identification and characterization of large vWF gene deletions in these type III vWD patients provides further support for the association between large deletions in both von Willebrand factor alleles and the development of inhibitory alloantibodies.

Autoantibody Selectively Inhibits Binding of von Willebrand Factor to Glycoprotein Ib. Recognition Site Is Located in the A1 Loop of von Willebrand Factor

1997 ◽  
Vol 77 (04) ◽  
pp. 760-766 ◽  
Author(s):  
Hiroshi Mohri ◽  
Etsuko Yamazaki ◽  
Zekou Suzuki ◽  
Toshikuni Takano ◽  
Shumpei Yokota ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Significant Inhibition ◽  
Von Willebrand Disease ◽  
Recognition Site ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Virtual Absence ◽  
Heavy Chains ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryA 20-year-old man with severe von Willebrand disease recently presented a progressive bleeding tendency, characterized recurrent subcutaneous hemorrhages and cerebral hemorrhage. Mixing and infusion studies suggested the presence of an inhibitor directed against vWF:RCo activity of von Willebrand factor (vWF) without significant inhibition of the FVIII:C. The inhibitor was identified as an antibody of IgG class. The inhibitor inhibited the interaction of vWF in the presence of ristocetin and that of asialo-vWF with GPIb while it partially blocked botrocetin-mediated interaction of vWF to GPIb. The inhibitor reacted with native vWF, the 39/34kDa fragment (amino acids [aa] 480/ 481-718) and the recombinant vWF fragment (MalE-rvWF508-704), but not with Fragment III-T2 (heavy chains, aa 273-511; light chains, aa 674-728). A synthetic peptide (aa 514-542) did not inhibit vWF-inhibitor complex formation. We conclude that this is the first autoantibody of class IgG from human origin that recognizes the sequence in the A1 loop of vWF, resulting in a virtual absence of functional vWF and a concomitant severe bleeding tendency although recognition site is different from the residues 514-542 which is crucial for vWF-GPIb interaction.

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