Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B.
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.
Rayes
Julie
J
Inserm U770 and Université Paris-Sud, Le Kremlin-Bicêtre, France.
Hollestelle
Martine J
MJ
Legendre
Paulette
P
Marx
Isabelle
I
de Groot
Philip G
PG
Christophe
Olivier D
OD
Lenting
Peter J
PJ
Denis
Cécile V
CV
D000071120:ADAMTS13 Protein; D019943:Amino Acid Substitution; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism*; D004195:Disease Models, Animal; D006207:Half-Life; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D055503:Protein Multimerization; D012310:Ristocetin / Q000009:adverse effects / Q000494:pharmacology; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D056728:von Willebrand Disease, Type 2 / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D014841:von Willebrand Factor; D012310:Ristocetin; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein