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: 8692758
• 负责人: Robert H. Bartlett
• 金额: $ 18.85万
• 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/8692758
• 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血液体外循环（ECC）数千次（CPB、血液透析、血液滤过、血浆泳动、ECMO）。需要全身抗凝以防止装置中出现凝血，从而导致主要并发症：出血。尽管经过数十年的研究，开发出一种非血栓表面以消除全身抗凝的需要仍然是一个难以实现的目标。假体表面上的凝血有两个组成部分：血小板粘附/激活和纤维蛋白原转化为纤维蛋白。将抗凝剂肝素结合到表面可以防止局部纤维蛋白形成，但不能防止血小板粘附。我们开发出一氧化氮 (NO) 分泌表面，可防止血小板粘附。我们目前正在开发肝素和 NO 聚合物组合表面，目的是消除 ECC 中全身抗凝的需要。尽管肝素/NO 组合有望成为理想的非血栓形成表面，但肝素也有缺点。肝素源自动物组织，在凝血级联中的多个点起作用，不是直接的凝血酶抑制剂，并且依赖于血浆抗凝血酶（AT）。肝素可导致称为肝素诱导血小板减少症 (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 批准用于静脉注射，并且不致敏。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，NO 释放涂层与固定化凝血酶抑制剂阿加曲班相结合，将允许 ECC 无需全身抗凝。

项目成果

The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation.

将直接凝血酶抑制剂固定在聚氨酯上，作为体外循环的非血栓形成表面涂层。

• DOI: 10.1039/c5tb02419f
• 发表时间: 2016-04-07
• 期刊: Journal of materials chemistry. B
• 作者: Yu J;Brisbois E;Handa H;Annich G;Meyerhoff M;Bartlett R;Major T
• 通讯作者: Major T