This is a proposal for continuation of a Program project Grant to study both fundamental and clinical aspects of coagulation, focusing especially on fibrinogen, fibrin and fibrinolytic therapy. The long-term objectives are to better understand fundamental questions and to translate this information from the laboratory to the bedside in order to improve the diagnosis and management of thrombotic disease.
Specific aims of basic studies are to elucidate the structure/function relationship of fibrinogen and the macromolecular organization of the alpha-polymer in crosslinked fibrin and its plasmic derivatives, the mechanisms and consequences of fibrin interaction with endothelial cells, the interaction of fibrinogen with thrombin and dynamic evolution into a fibrin polymer following this interaction, the identification of functional domains of a recombinant hybrid prethrombin/trypsin enzyme, the expression of fibrinogen in megakaryocytes and hepatocytes and the mechanisms of its genetic control, especially regrading the synthesis of variants of the fibrinogen gamma chain, the effects of soluble fibrin polymers on blood viscosity and the physical structure of thrombi as defined by magnetic resonance imaging. Clinical studies will compare new thrombolytic agents and regimens in coronary artery syndromes and in deep vein thrombosis, test new prophylactic approaches for preventing deep vein thrombosis after orthopedic procedures, assess the diagnostic potential of magnetic resonance imaging for evolving thrombi, and apply changes in blood parameters of fibrinogen and fibrinolysis and a new assay under development) for unique alpha-polymer degradation products as related to clinical events of vascular occlusion, vascular reperfusion and bleeding, The five research projects will be supported by three Core facilities, devoted to administration, tissue culture and monoclonal antibody production and clinical services related to patient observations, coagulation assays and data analysis. In addition to a primary goal of new fundamental observations made by scientists working individually and in concert, the program emphasizes a balance between the expertise of fundamental and clinical scientists working independently and in concert with each other, and in the bidirectional flow of ideas and data between the laboratory bench and the hospital bed.
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