title: Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions.
abstract: Type 2B von Willebrand disease (2B VWD) results from von Willebrand factor (VWF) A1 mutations that enhance VWF-GPIbalpha binding. These "gain of function" mutations lead to an increased affinity of the mutant VWF for platelets and the binding of mutant high-molecular-weight VWF multimers to platelets in vivo, resulting in an increase in clearance of both platelets and VWF. Three common 2B VWD mutations (R1306W, V1316M, and R1341Q) were independently introduced into the mouse Vwf cDNA sequence and the expression vectors delivered to 8- to 10-week-old C57Bl6 VWF(-/-) mice, using hydrodynamic injection. The resultant phenotype was examined, and a ferric chloride-induced injury model was used to examine the thrombogenic effect of the 2B VWD variants in mice. Reconstitution of only the plasma component of VWF resulted in the generation of the 2B VWD phenotype in mice. Variable thrombocytopenia was observed in mice expressing 2B VWF, mimicking the severity seen in 2B VWD patients: mice expressing the V1316M mutation showed the most severe thrombocytopenia. Ferric chloride-induced injury to cremaster arterioles showed a marked reduction in thrombus development and platelet adhesion in the presence of circulating 2B VWF. These defects were only partially rescued by normal platelet transfusions, thus emphasizing the key role of the abnormal plasma VWF environment in 2B VWD.
authors.affiliation: Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University Cancer Research Institute, Queen's University, Kingston, ON, Canada.
authors.forename: Mia
authors.initials: M
authors.lastname: Golder
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Pruss
authors.forename: Carol
authors.initials: C
authors.lastname: Hegadorn
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Mewburn
authors.forename: Kimberly
authors.initials: K
authors.lastname: Laverty
authors.forename: Kate
authors.initials: K
authors.lastname: Sponagle
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002712:Chlorides / Q000633:toxicity; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000633:toxicity; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009676:Noxae / Q000633:toxicity; D010973:Platelet Adhesiveness; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D056728:von Willebrand Disease, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D039421:Integrin alpha2; D009676:Noxae; D014841:von Willebrand Factor; C024555:ferric chloride