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

J Rayes, MJ Hollestelle, P Legendre… - Blood, The Journal …, 2010 - ashpublications.org
J Rayes, MJ Hollestelle, P Legendre, I Marx, PG de Groot, OD Christophe, PJ Lenting…
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
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.
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