A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: An elusive phenotype and a difficult diagnosis

Alessandra Casonato; Francesca Sartorello; Elena Pontara; Lisa Gallinaro; Antonella Bertomoro; Maria Grazia Cattini; Viviana Daidone; Maryta Szukowska; Antonio Pagnan

doi:10.1160/TH07-05-0347

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(06): 1182-1187
DOI: 10.1160/TH07-05-0347

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: An elusive phenotype and a difficult diagnosis

Alessandra Casonato

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Francesca Sartorello

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Elena Pontara

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Lisa Gallinaro

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Antonella Bertomoro

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Maria Grazia Cattini

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Viviana Daidone

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Maryta Szukowska

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

,

Antonio Pagnan

¹University of Padua, Medical School, Department of Medical and Surgical Sciences, Second Chair of Internal Medicine, Padua, Italy

› Author Affiliations

Abstract

Summary

Mutations in the A1 domain of von Willebrand factor (VWF) may be associated with gain of function in theVWF-platelet GPIb interaction and consumption of largeVWF multimers, as seen in type 2B von Willebrand disease (VWD). We report a new VWF abnormality associated with greater VWF-GPIb interaction in the presence of all VWF multimers. The index case is a woman with a lifelong history of bleeding, found hyperresponsive to ristocetin with spontaneous platelet aggregation (SPA). She had normal factor VIII,VWF:Ag,VWF:RCo and VWF:CB levels, normal VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios, and a full panel of plasma and platelet VWF multimers. A missense mutation (4115T>G) was found in exon 28 of theVWF gene, which replaced a isoleucine with a serine at position 1372 of pre-pro-VWF (I1372S) at heterozygous level. Recombinant VWF carrying the I1372S mutation and showing a normal VWF multimer organisation was capable of inducing SPA on normal plateletrich plasma (unlike wild-type VWF), as well as a hyper-response to ristocetin in the same platelets (0.6 mg/ml ristocetin vs. 1.2 of wild-type VWF). The new I1372S VWF mutation, characterised by SPA and hyper-responsiveness to ristocetin thus has some of the features of type 2B VWD, but not the lack of large VWF multimers, so we defined this variant as type 2B-likeVWD. Why I1372SVWF is associated with bleeding symptoms, despite normalVWF levels and multimer organisation,remains to be seen.

Keywords

von Willebrand factor - von Willebrand disease - type 2B VWD - VWF mutations - spontaneous platelet aggregation

Full Text

References

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