von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure.

Holmberg, Lars; Dent, Judith A.; Schneppenheim, Reinhard; Budde, Ulrich; Ware, I Jerry; Ruggeri, Zaverio M.

doi:10.1172/jci116443

Cited by 81 publications

(68 citation statements)

References 54 publications

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“…This variant, P1266L, is associated with increased aggregation in the presence of low-dose ristocetin. 40,41 However, the absence of thrombocytopenia and normal distribution of VWF multimers are noteworthy distinctions between the P1266L variant and patients with other type 2B-associated mutations, such that one must wonder whether the results with ristocetin are of physiologic importance in this variant as well.…”

Section: Discussionmentioning

confidence: 99%

Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor

Flood

Gill

Morateck

et al. 2010

Blood

160

177

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The diagnosis of von Willebrand disease relies on abnormalities in specific tests of von Willebrand factor (VWF), including VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo). When examining healthy controls enrolled in the T. S. Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease, we, like others, found a lower mean VWF:RCo compared with VWF:Ag in African American controls and therefore sought a genetic cause for these differences. For the African American controls, the presence of 3 exon 28 single nucleotide polymorphisms (SNPs), I1380V, N1435S, and D1472H, was associated with a significantly lower VWF:RCo/VWF:Ag ratio, whereas the presence of D1472H alone was associated with a decreased ratio in both African American and Caucasian controls. Multivariate analysis comparing race, SNP status, and VWF:RCo/VWF:Ag ratio confirmed that only the presence of D1472H was significant. No difference was seen in VWF binding to collagen, regardless of SNP status. Similarly, no difference in activity was seen using a GPIb complex-binding assay that is independent of ristocetin. Because the VWF:RCo assay depends on ristocetin binding to VWF, mutations (and polymorphisms) in VWF may affect the measurement of “VWF activity” by this assay and may not reflect a functional defect or true hemorrhagic risk.

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Section: Discussionmentioning

confidence: 99%

Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor

Flood

Gill

Morateck

et al. 2010

Blood

160

177

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“…were reported in two families by Holmberg et al (18) and in one family by Zhang et al (22). Although multiple substitutions are rare, they seem to be very frequent in this region of the vWF gene.…”

mentioning

confidence: 86%

“…As we described before (6), the type I phenotype of the second family under study is caused by compound heterozygosity for a "silent allele" and the allele containing the substitutions Pro503 --Leu and Val516 --+Ile. The Pro503 -* Leu mutation has been described as the cause of enhanced platelet reactivity to ristocetin in type I New York (18). The majority of mutations described in vWD occur at CpG dinucleotides, which are hot spots for mutations (5 4i, pseudogene sequence.…”

mentioning

confidence: 99%

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

Eikenboom

Vink

Briët

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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“…At least 14 distinct mutations have been characterized in patients with VWD type 2B (136,140,141); one is a single amino acid insertion and the remainder are single amino acid substitutions (136). These cluster in a discrete region on the A1 domain (Figure 9), and appear to mark the location of a regulatory site that normally inhibits the binding of domain A1 to platelet GPIb (Figure 4).…”

Section: Classification and Molecular Defects In Vwdmentioning

confidence: 99%

Biochemistry and Genetics of Von Willebrand Factor

Sadler

1998

Annu. Rev. Biochem.

1,249

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Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical ≈250 kDa subunits into disulfide-linked multimers that may be >20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clincial symptoms and the response to therapy. CONTENTS

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von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure.

Cited by 81 publications

References 54 publications

Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor

Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor

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

Biochemistry and Genetics of Von Willebrand Factor

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