Combined Nitric Oxide Release and Argatroban for Thromboresistant Coatings

描述（由申请人提供）：每天通过人工器官对血液进行数千次体外循环（ECC）（CPB、血液透析、血液滤过、血浆电泳、ECMO）。需要全身抗凝治疗，以防止器械内凝血，从而导致主要并发症：出血。尽管经过数十年的研究，开发出一种无血栓形成的表面以消除对全身抗凝的需要仍然是一个难以实现的目标。假体表面的凝血有两个组成部分：血小板粘附/活化和纤维蛋白原转化为纤维蛋白。将抗凝剂肝素结合到表面防止局部纤维蛋白形成，但不防止血小板粘附。我们已经开发了一氧化氮（NO）分泌表面，防止血小板粘附。我们目前正在开发肝素和NO聚合物表面的组合，目的是消除ECC中对全身抗凝的需要。尽管肝素/NO组合有望成为理想的非血栓形成表面，但肝素也存在缺点。肝素来源于动物组织，作用于凝血级联反应中的几个点，不是直接的凝血酶抑制剂，并且依赖于血浆抗凝血酶（AT）。肝素可导致称为肝素诱导性血小板减少症（HIT）的过敏综合征。阿加曲班是一种直接凝血酶抑制剂，可防止纤维蛋白形成。阿加曲班是合成的，容易获得并且FDA批准用于静脉内施用，并且是非过敏性的。本研究将评估NO分泌与表面结合阿加曲班的组合作为ECC的非血栓形成表面。本研究的目的是开发和评估阿加曲班和NO对ECC中血栓形成和血小板活性的联合作用。我们的中心假设是，一氧化氮释放涂层结合固定凝血酶抑制剂，阿加曲班，将允许ECC没有全身抗凝。

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.