Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B.

Abstract:

:Von Willebrand disease (VWD)-type 2B originates from a gain-of-function mutation in von Willebrand factor (VWF), resulting in enhanced platelet binding. Clinical manifestations include increased bleeding tendency, loss of large multimers, thrombocytopenia, and circulating platelet aggregates. We developed a mouse model to study phenotypic consequences of VWD-type 2B mutations in murine VWF: mVWF/R1306Q and mVWF/V1316M. Both mutations allow normal multimerization but are associated with enhanced ristocetin-induced platelet aggregation, typical for VWD-type 2B. In vivo expression resulted in thrombocytopenia and circulating aggregates, both of which were more pronounced for mVWF/V1316M. Furthermore, both mutants did not support correction of bleeding time or arterial vessel occlusion in a thrombosis model. They further displayed a 2- to 3-fold reduced half-life and induced a 3- to 6-fold increase in number of giant platelets compared with wild-type VWF. Loss of large multimers was observed in 50% of the mice. The role of ADAMTS13 was investigated by expressing both mutants in VWF/ADAMTS13 double-deficient mice. ADAMTS13 deficiency resulted in more and larger circulating platelet aggregates for both mutants, whereas the full multimer range remained present in all mice. Thus, we established a mouse model for VWD-type 2B and found that phenotype depends on mutation and ADAMTS13.

journal_name

Blood

journal_title

Blood

authors

Rayes J,Hollestelle MJ,Legendre P,Marx I,de Groot PG,Christophe OD,Lenting PJ,Denis CV

doi

10.1182/blood-2009-11-254193

subject

Has Abstract

pub_date

2010-06-10 00:00:00

pages

4870-7

issue

23

eissn

0006-4971

issn

1528-0020

pii

blood-2009-11-254193

journal_volume

115

pub_type

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