When the coagulation and fibrinolytic cascades are properly balanced the organism is protected from blood loss at the site of vascular injury and yet assured of vascular fluidity elsewhere. When they are not properly balanced, tendencies to bleed or thrombose and their concomitant pathologies exist. The overall objective is to obtain quantitative knowledge of the biochemical properties of the fibrinolytic cascade in order to better understand the regulation of the balance between fibrin deposition and removal. RESEARCH DESIGN AND METHODS. The first and third specific aims will be accomplished by measurements of state and transient kinetics.
The second aim will be accomplished by measuring fluorescence energy transfer.
The fourth aim will be accomplish, with Dr. Tracy, by investigating plasminogen activation and fibrinolysis, in the presence of platelets, plus or minus TAFIa. The fifth aim will be accomplished, in collaboration with Dr. Mann, by searching for perturbations of coagulation by TAFIa and identifying the specific targets of TAFIa in the coagulation cascade. The sixth aim will be accomplished by incorporating the experimental results obtained in aims (1)-(4) into the model which already exists. SIGNIFICANCE. These studies, along withe the others of the Program, should significantly advance our understanding of the regulation of coagulation and fibrinolysis., This information will help attenuate the consequences of pathologic disregulation of these processes such as bleeding, or heart attacks and strokes.
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