Combined Nitric Oxide Release and Argatroban for Thromboresistant Coatings

结合一氧化氮释放和阿加曲班用于抗血栓涂层

• 批准号: 8580797
• 负责人: Robert H. Bartlett
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580797
• 关键词: Adherence; Adhesions; Allergic; Amination; Animal Model; Animal Testing; Anticoagulants; Anticoagulation; Antithrombins; Area; Argatroban; Artificial Organs; Binding; Biocompatible Materials; Biological Assay; Biological Preservation; Blood; Blood Circulation; Blood Platelets; Cardiopulmonary Bypass; Chemicals; Clinical; Coagulation Process; Complex; Complication; Data; Devices; Dialysis procedure; Effectiveness; Equilibrium; Evaluation; Extracorporeal Circulation; FDA approved; Fibrin; Fibrinogen; Goals; Hemodialysis; Hemofiltration; Hemorrhage; Heparin; Hour; In Vitro; Isocyanates; Link; Modeling; Modification; Nitric Oxide; Oryctolagus cuniculus; Patients; Plasma; Polymers; Polyurethanes; Preparation; Process; Property; Prosthesis; Research; Surface; Syndrome; Testing; Thrombin; Thrombocytopenia; Thrombus; Time; animal tissue; in vivo; inhibitor/antagonist; intravenous administration; prevent; public health relevance; research and development

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.

描述（由申请人提供）：每天通过人工器官进行数千次体外循环（CPB，血液透析，血液过滤，血浆电泳，ECMO）。需要进行全身抗凝，以防止装置内凝血导致主要并发症：出血。尽管几十年的研究发展的非血栓形成的表面，以消除需要全身抗凝仍然是一个难以捉摸的目标。在假体表面的凝血有两个组成部分：血小板粘附/活化和纤维蛋白原向纤维蛋白的转化。将抗凝血剂肝素与表面结合可阻止局部纤维蛋白的形成，但不能阻止血小板的粘附。我们已经开发了一氧化氮（NO）分泌表面，防止血小板粘附。我们目前正在开发联合肝素和NO聚合物表面，目的是消除对ECC系统抗凝的需要。虽然肝素/NO联合承诺是一个理想的非血栓表面，肝素也有缺点。肝素来源于动物组织，在凝血级联中的几个点起作用，不是直接的凝血酶抑制剂，并且依赖于血浆抗凝血酶（at）。肝素可导致过敏综合征称为肝素诱发的血小板减少症（HIT）。阿加曲班是一种直接凝血酶抑制剂，可阻止纤维蛋白的形成。阿加曲班是合成的，容易获得，FDA批准静脉注射给药，无过敏性。本研究将评估一氧化氮分泌与表面结合的阿加曲班作为ECC非血栓形成表面的结合。本研究的目的是开发和评估阿加曲班和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，一氧化氮释放涂层结合固定化凝血酶抑制剂阿加曲班，将允许ECC无需全身抗凝。