ALTERNATIVE TO HEPARIN ANTICOAGULATION

描述（由申请人提供）：在体外循环或其他需要体外循环的手术中，抗凝血是预防凝血和/或血栓栓塞所必需的。通常，抗凝是通过施用肝素实现的，并通过用鱼精蛋白中和肝素来逆转。这两种手术都可能有潜在的病理后果。已知患者亚群对鱼精蛋白敏感，肝素本身已被证明在接受心脏直视手术的患者亚群中引起血小板减少症。这是一项完善和发展替代肝素-鱼精蛋白策略的建议。一种新的装置，称为凝血因子过滤器（CFF）已经开发出来，将结合和短暂去除循环血液中的凝血因子。去除凝血因子的血液在体外循环中既不会形成凝块，也不会形成血栓栓子，从而达到与肝素相同的效果。停止手术后，低凝血逐渐恢复正常，或输自体血或血浆可加速恢复，立即恢复正常止血。初步I期研究证实了CFF方法的安全性和有效性。本II期提案的目标包括：优化CFF，优化系统的表征和性能，并验证CFF能够在动物模型中在体外循环期间安全地实现适当的“抗凝”。对于有源矩阵，将研究连接体和基板。对于等离子体-基质接触系统，将选择最佳的柱形结构，并设计高流量等离子体分离器。最佳的CFF系统将被表征为确定所需的“抗凝”水平，以消除ECC期间的血栓形成。最后，将使用猪CPB模型来测试CFF方法在旁路期间血液“抗凝”的安全性和有效性。这将包括在手术期间和动物长期生存期间仔细评估血液学和心血管参数，以确保CFF方法是有效和安全的。

DESCRIPTION (provided by applicant): Anticoagulation of blood is necessary for prevention of clotting and/or thromboembolism during cardiopulmonary bypass or other procedures that require extracorporeal circulation. Conventionally, anticoagulation is achieved by administering heparin and reversed by neutralizing heparin with protamine. Both of these procedures may have potential pathological consequences. A subpopulation of patients is known to be sensitive to protamine, and heparin itself has been shown to cause thrombocytopenia in a subpopulation of patients undergoing open heart surgery. This is proposal to refine and develop an alternative to the heparin-protamine strategy. A novel device, termed clotting factor filter (CFF) has been developed that will bind and transiently remove clotting factors from circulating blood. Blood from which clotting factors have been removed would neither form clots nor thromboemboli during extracorporeal circulation, thus achieving the same effect as intended with heparin. Hypocoagulable blood gradually returns to normal state when the procedure is stopped, or recovery can be accelerated and normal hemostasis restored immediately by transfusion of autologous blood or plasma. Preliminary Phase I studies have confirmed the safety and efficacy of CFF approach. The objective of this Phase II proposal include: optimization of the CFF, characterization and performance of the optimized system, and verification that the CFF is able to effect appropriate 'anticoagulation' safely during cardiopulmonary bypass in an animal model. For the active matrix, linkers and base substrates will be investigated. For the plasma-matrix contact system, optimal column geometry will be selected, and a high-flow plasma separator will be designed. The optimal CFF system will be characterized to ascertain required level of 'anticoagulation' that will eliminate thrombosis during ECC. Finally, a porcine CPB model will be utilized to test the safety and efficacy of the CFF approach for 'anticoagulation' of blood during bypass. This will include careful assessment of hematologic and cardiovascular parameters during the procedure and during long term survival of the animal to assure that CFF approach is efficacious and safe.