title: 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.
authors.affiliation: Inserm U770 and Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Rayes
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Hollestelle
authors.forename: Paulette
authors.initials: P
authors.lastname: Legendre
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marx
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.forename: Olivier D
authors.initials: OD
authors.lastname: Christophe
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lenting
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D014841:von Willebrand Factor; D012310:Ristocetin; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein