Combined Nitric Oxide Release and Argatroban for Thromboresistant Coatings

描述(申请人提供)：通过人工器官对血液进行体外循环(ECC)每天进行数千次(CPB、血液透析、血液滤过、血浆凝胶、ECMO)。需要全身抗凝，以防止设备中的凝块导致主要并发症：出血。尽管经过几十年的研究，开发一种非血栓形成表面以消除全身抗凝的需要仍然是一个难以实现的目标。人工假体表面的凝血有两个组成部分：血小板黏附/激活和纤维蛋白原向纤维蛋白的转化。将抗凝剂肝素结合到表面可以防止局部纤维蛋白的形成，但不能防止血小板粘连。我们已经开发了一氧化氮(NO)分泌表面，可以防止血小板粘连。我们目前正在开发肝素和非聚合物的联合表面，目的是消除ECC中全身抗凝的需要。尽管肝素/NO组合有望成为一种理想的非血栓形成表面，但肝素也有缺点。肝素来源于动物组织，作用于凝血级联反应的多个点，不是直接的凝血酶抑制物，S依赖于血浆抗凝血酶(AT)。肝素可导致称为肝素诱导的血小板减少症(HIT)的过敏综合征。阿加曲班是一种直接的凝血酶抑制剂，可以防止纤维蛋白的形成。阿加曲班是人工合成的，很容易获得，FDA批准静脉给药，而且不会引起过敏。这项研究将评估NO分泌与表面结合的阿加曲班作为ECC的非血栓形成表面的结合。本研究的目的是建立和评价阿加曲班和NO对ECC血栓形成和血小板活性的联合作用。我们的中心假设是，NO释放涂层结合固定化凝血酶抑制剂阿加曲班，将允许ECC在没有全身抗凝的情况下发生。

DESCRIPTION (provided by applicant): Extracorporeal circulation (ECC) on blood through artificial organs is practiced thousands of times each day (CPB, hemodialysis, hemofiltration, plasma phoresis, ECMO). Systemic anticoagulation is required to prevent clotting in the devices resulting in the major complication: bleeding. Despite decades of research development of a nonthrombogenic surface to eliminate the need for systemic anticoagulation remains an elusive goal. Clotting as on prosthetic surfaces has two components: platelet adhesion/activation and conversion of fibrinogen to fibrin. Bonding the anticoagulant heparin to the surface prevents local fibrin formation but does not prevent platelet adhesion. We have developed nitric oxide (NO) secreting surfaces which prevent platelet adhesion. We are currently developing combined heparin and NO polymer surfaces with the goal of eliminating the need for systemic anticoagulation in ECC. Although heparin/NO combination promises to be an ideal nonthrombogenic surface, there are drawbacks to heparin. Heparin is derived from animal tissue, acts at several points in the coagulation cascade, is not a direct thrombin inhibitor, and s dependent on plasma antithrombin (AT). Heparin can result in the allergic syndrome called heparin induced thrombocytopenia (HIT). Argatroban is a direct thrombin inhibitor that prevents fibrin formation. Argatroban is synthetic, easily available and FDA approved for intravenous administration, and is nonallergenic. This research will evaluate the combination of NO secretion with surface bound argatroban as a nonthrombogenic surface for ECC. The objective of this research is to develop and evaluate the combined effect of argatroban and NO on thrombus formation and platelet activity in ECC. Our central hypothesis is that a NO release coating combined with immobilized thrombin inhibitor, argatroban, will allow ECC without systemic anticoagulation.