Potent Inhibitors of Coagulation Factor XIIa

During cardiopulmonary bypass, plasma factor XII is converted to active XIIa by contact with the subypass circuit, initiating a process which results in massive activation of the plasma proteases ofProducts of contact activation include bradykinin from the kallikrein-kinin system and the neutrophikallikrein and complement factor C5a. Neutrophil activation can result in neutrophil-mediated lung ddysfunction, a significant cause of post-bypass morbidity. Our goal is to discover a potent proteinXIIa which can be used to prevent activation of the contact system during extracorporeal circulationpost-bypass pulmonary injury. Phagemid libraries which display variants of the Kunitz protease inhibhuman protease nexin-2/amyloid beta-protein precursor will be selected with immobilized human factorKPI mutants which inhibit human-factor XIIa with high potency. In the Phase II time period, a potentinhibitor will be tested in vivo for its ability to inhibit the contact activation system and reducedamage in an animal model of cardiopulmonary bypass.