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）：每天通过人造器官对血液循环（ECC）进行数千次（CPB，血液透析，血液滤过，血浆Phoresis，ECMO）。需要进行全身抗凝治疗以防止在设备中凝结，从而导致主要并发症：出血。尽管进行了数十年的非组织性表面研究开发以消除对全身性抗凝需求的需求，这仍然是一个难以捉摸的目标。凝结与假体表面有两个组成部分：血小板粘附/激活和纤维蛋白原转化为纤维蛋白。将抗凝肝素粘合到表面可防止局部纤维蛋白形成，但不能阻止血小板粘附。我们已经开发了一氧化氮（NO）分泌表面，以防止血小板粘附。我们目前正在开发肝素组合，没有聚合物表面，目的是消除在ECC中进行全身抗凝的需求。尽管肝素/NO组合有望成为理想的非紧密表面，但肝素存在缺点。肝素源自动物组织，在凝血级联反应中的多个点起作用，不是直接的凝血酶抑制剂，并且依赖于血浆抗凝血酶（AT）。肝素可能导致称为肝素诱导血小板减少症（HIT）的过敏综合征。 Argatroban是一种直接的凝血酶抑制剂，可防止纤维蛋白形成。 Argatroban是合成的，易于获得，并且批准了用于静脉内给药的FDA，并且是非过敏性的。这项研究将评估NO分泌与表面结合的Argatroban作为ECC的非组织性表面的组合。这项研究的目的是开发和评估Argatroban和NO对ECC中血栓形成和血小板活性的综合作用。我们的中心假设是，与固定的凝血酶抑制剂Argatroban结合使用的无释放涂层将允许ECC无系统性抗凝。