Long-term objectives: To maintain inbred colonies of bleeder animals (von Willebrand disease dogs; hemophilia A and B dogs) as animal models of the corresponding human diseases; to study the genetics and pathophysiology of these diseases in animals and extend the studies as appropriate to the human counterpart; to characterize and utilize in diagnostic and physiologic studies Bothrops and Bitis venom factors that interact with the Factor VIII complex and blood platelets; to fractionate the plasma factor VIII complex and determine the comparative effectiveness of different fractions in correcting the several defects in the inherited bleeder disorders.
The specific aims of this proposal are a) to maintain and make available the inbred bleeder animals for study; b) to study the effect of various gene dosages of the vWF and hemophilia A genes on the manifestation of disease and their effect on the response to transfusions; c) to develop and study animal models of acquired bleeder disorders due to abnormalities in the factor VIII complex as von Willebrand syndrome or from the effects of the Bothrops or Bitis factors; and d) to investigate platelet aggregation and platelet adhesion as influenced by the factor VIII complex, the venom factors, and other variables. The methodologies for animal breeding will entail careful diagnosis as to phenotype of parent and offspring in relation the several markers of the factor VIII complet. Transfusion studies will entail plasma fractionation by standard technics (cryoprecipitation, salt precipitation, polyethylene glycol, etc.). Changes in the VIII markers (VIII:C, VIIIR:Ag, BT, etc) will be followed in the infused animals. Standard chromatographic, immunologic, and clotting and platelet bioassays will be used throughout.
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