We propose to study thrombus formation and dissolution in baboons using well characterized quantitative models relevant to man. This proposal represents the integrated interaction among five projects, an animal core, and a hybridoma core. The program components are based in the Department of Basic and Clinical Research, and collaborate with two scientists located in the Department of Immunology at Scripps Clinic and Research Foundation and three outside laboratories. The overall objective of the proposed research is to examine quantitatively and in vivo the relative sensitivity, time course, extent, interaction, therapeutic interruption by pharmacologic agents and monoclonal antibodies of activation processes affecting vascular endothelium, platelets, coagulation cascade and thrombolysis. In Project I, Dr. S. R. Hanson addresses the development and characterization of quantitative models of thrombosis in the baboon that are designed to simulate clinical thrombogenesis. Using these models of thrombosis Project II (Dr. L. A. Harker) evaluates quantitatively antithrombotic strategies involving the three classes of antithrombotic agents - anticoagulant, platelet-modifying and fibrinolytic. Project III (Dr. L. A. Harker) tests the hypothesis that thrombolytic therapy in acute stroke salvages neurologic function without risk of intracranial bleeding. In Project IV, Dr. Z. M. Ruggeri explores the mechanisms of von Willebrand factor and fibrinogen interaction with platelets in the process of thrombosis in vivo. Project V (Dr. T. S. Zimmerman) defines the role of Factor VIII:C in coagulation and platelet mechanisms of thrombosis. A wide ranging technical expertise and collaboration is represented. Since the non-human primate will be used for the experimental thrombosis model work, the results and immunologic probes will be applied directly to patient studies.
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