POTENT INHIBITORS OF COAGULATION FACTOR XIIA

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The use of cardiopulmonary bypass (CPB) in cardiothoracic surgery is associated with significant postoperative bleeding and pulmonary injury due to massive activation of plasma protease systems during extracorporeal circulation. Contact activation of the kallikrein- kinin system, intrinsic coagulation, the complement cascade and fibrinolysis during CPB all contribute to excessive post-bypass blood loss and an inflammatory response manifested by pulmonary dysfunction. The goal of this research is to discover a potent protein inhibitor of human factor XIIa and plasma kallikrein which can be used to prevent activation of the contact system during CPB in order to reduce blood loss and attenuate parameters of pulmonary dysfunction. Protein engineering techniques have been used to identify variants of the Kunitz protease inhibitor domain (KPI) of the human amyloid beta-protein precursor which are potent inhibitors of factor XIIa, plasma kallikrein and plasmin. In the Phase II portion of this research, a high yield recombinant expression system will be established to generate preclinical supplies of one KPI variant. The human KPI variant will be tested in a sheep model of cardiopulmonary bypass for its ability to significantly reduce post-operative blood loss and lung injury. PROPOSED COMMERCIAL APPLICATIONS A potent recombinant human protein inhibitor of factor XIIa, plasma kallikrein and plasmin would be administered prophylactically during surgeries requiring cardiopulmonary bypass to reduce postoperative blood transfusions and improve recovery times.