The Activation of Prothrombin

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The goal of this project is to characterizethe physiology and pathology of the blood coagulation system in quantifiable terms. We have developed three approaches for these analyseswhich include: numerical models of the blood coagulation proteome, numerical recapitulations of the blood coagulation proteome using purified proteins, and studies of whole blood in vitro and flowing from microvascular wounds. We seek quantitatively transparent descriptions convergent with the biological/pathologic observations of medicine which can ultimately be useful for the diagnosis, prophylaxis and therapy of human thrombotic and lemorrhagic disease. In the renewal requested, we will evaluate, in the closed blood coagulation systems, the influence of additional components of the plasma proteome on the generation of thrombin and other constituents. Special emphasis will be focused on tissue factor from natural sources, protein S, and cellular contributions by platelets, monocytes and endothelial cells. We will apply our methods to open systems, initially using flow dynamics in two artificial systems, to investigate the binding and presentation of the components of the proteolytic coagulation complexes under conditions of shear ranging from venous to arterial. These experiments will be conducted using total internal reflectance fluorescence and a newly devised tool the Real Time Thrombosis Profiler. Experiments in flow will be quantitatively analyzed using biophysical techniques and evaluated using modern mathematical techniques used to describe flow dynamics. Flow reactions will be studied in systems ranging from artificial capillaries coated with synthetic . membrane films or endothelial cells, and ultimately to human vascular arterial and venous segments. The systems developed will be utilized to evaluate the influence of anticoagulants and antiplatelet agents on the coagulation response. We anticipate the latter studies will provide evidence for identifying control points and the qualities of new agents required for control of these points. Project 1 is integrated with each of the remaining five projects of this program project grant providing both intellectual material and physical support in the collaborative studies of coagulation and fibrinolysis in human biology. Relevance: Venous and arterial blood clots are major health problems in the United States associated with approximately one million deaths each year. Hemorrhagic diseases, especially hemophilia A and B are thankfully less frequent, but still major health issues for those affected. This project seeks to provide fundamental knowledge which will be useful to identify those at risk for thrombotic and bleeding diseases, and provide methods and information that can be useful in the diagnosis, prophylaxis and therapy of bleeding and clotting diseases. ^^