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

Authors

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

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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