POTENT INHIBITORS OF COAGULATION FACTOR XIIA

体外循环(CPB)在心胸外科的应用 与术后大出血和肺部疾病有关 血浆蛋白水解酶系统大量激活所致的损伤 体外循环。激肽释放酶的接触性激活- 激肽系统、内凝血、补体级联和 体外循环期间的纤溶均会导致体外循环后的过度 失血和炎症反应表现为肺 功能障碍。这项研究的目标是发现一种有效的 人凝血因子XIIa蛋白抑制物和血浆激肽释放酶 可用于防止在体外循环期间激活接触系统 以减少失血量，瘦化肺脏参数 功能障碍。蛋白质工程技术已被用于 鉴定库尼茨蛋白抑制物域(KPI)的变异体 有效的人类淀粉样β蛋白前体 XIIa、血浆激肽释放酶和纤溶酶的抑制物。在 本研究的第二阶段，高产重组 将建立表达系统以产生临床前 供应一种关键绩效指标变体。人类KPI变种将进行测试 在绵羊体外循环模型中 显著减少术后失血量和肺损伤。 拟议的商业应用一种有效的重组人蛋白 抑制因子XIIa、血浆激肽释放酶和纤溶酶 在需要的手术中预防性给药 体外循环减少术后输血量 并缩短恢复时间。

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.