POTENT INHIBITORS OF COAGULATION FACTOR XIIA

体外循环在心胸外科手术中的应用 与严重的术后出血和肺部感染有关。 由于血浆蛋白酶系统的大量激活而造成的损伤 体外循环接触激活激肽释放酶- 激肽系统，内源性凝血，补体级联反应， 体外循环期间的纤溶都有助于过度的转流后 失血和肺部炎症反应 功能障碍这项研究的目的是发现一种有效的 人因子XIIa和血浆激肽释放酶的蛋白抑制剂， 可用于防止CPB期间接触系统激活 为了减少失血和减弱肺动脉参数， 功能障碍蛋白质工程技术已被用于 确定的Kunitz蛋白酶抑制剂结构域（KPI）的变体， 人淀粉样β蛋白前体， 因子XIIa、血浆激肽释放酶和纤溶酶的抑制剂。在 本研究的第二阶段部分， 将建立表达系统，以产生临床前 一个KPI变量的供应。将测试人类KPI变体 在绵羊心肺转流模型中， 显著减少术后失血和肺损伤。 一种有效的重组人蛋白 因子XIIa、血浆激肽释放酶和纤溶酶抑制剂将被 在手术中进行药物治疗， 体外循环减少术后输血 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.