title: von Willebrand factor and animal models: contributions to gene therapy, thrombotic thrombocytopenic purpura, and coronary artery thrombosis.
abstract: Use of animal models of von Willebrand factor (vWF) deficiency, both inherited and induced, continues to advance the knowledge of vWF-related diseases. Three examples are reviewed in this article--von Willebrand's disease (vWD), thrombotic thrombocytopenic purpura, and coronary artery thrombosis. The success of gene transfer by liver and bone marrow transplantation in porcine vWD and canine hemophilia A, with a change in phenotype that establishes improved hemostasis, portends imminent testing of gene therapy in these models. With use of recombinant technology, the phenotype of hemophilia B fibroblasts has been transformed to normal, as evidenced by secretion of the normal hemostatically active protein. This result is a prelude to implantation in hemophilic animals. Thrombotic thrombocytopenic purpura is characterized by qualitative and quantitative alterations in vWF. A new animal model induced by the venom factor botrocetin, a cofactor of vWF, closely mimics the human syndrome. A proposed pathophysiologic mechanism for thrombotic thrombocytopenic purpura is outlined. The third contribution is recognition that occlusive coronary thrombosis is a vWF-dependent condition. Without vWF, as in porcine vWD or normal pigs treated with a monoclonal anti-vWF antibody, occlusive thrombi do not develop, even with luminal stenosis. The thrombogenicity of coronary atheromas, including those with fissures of the fibrous cap, is also vWF-dependent.
authors.affiliation: Department of Pathology, School of Medicine, University of North Carolina, Chapel Hill.
authors.forename: K M
authors.initials: KM
authors.lastname: Brinkhous
authors.forename: R L
authors.initials: RL
authors.lastname: Reddick
authors.forename: M S
authors.initials: MS
authors.lastname: Read
authors.forename: T C
authors.initials: TC
authors.lastname: Nichols
authors.forename: D A
authors.initials: DA
authors.lastname: Bellinger
authors.forename: T R
authors.initials: TR
authors.lastname: Griggs
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D003328:Coronary Thrombosis / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy; D008297:Male; D011697:Purpura, Thrombotic Thrombocytopenic / Q000503:physiopathology*; D051381:Rats; D013552:Swine; D014842:von Willebrand Diseases / Q000628:therapy*; D014841:von Willebrand Factor / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D014841:von Willebrand Factor