Ventricular Assist Devices: Bleeding/Thrombosis &Therapy

心室辅助装置：出血/血栓形成

• 批准号: 6892945
• 负责人: ANN MARIE SCHMIDT
• 金额: $ 42.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892945
• 关键词: activation product; auxiliary heart prosthesis; biomaterial interface interaction; blood disorder chemotherapy; cardiovascular disorder therapy; cardiovascular infection; clinical trial phase II; clotting factor; combination therapy; congestive heart failure; coronary bypass; coronary occlusion /thrombosis; data collection methodology /evaluation; drug screening /evaluation; heart function; hemorrhage; heparin; human subject; human therapy evaluation; medical implant science; platelet activation; postoperative complications; protamines; swine; therapy adverse effect

The landmark report of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group demonstrated that the use of a left ventricular assist device (VAD) in patients with advanced heart failure resulted in a significantly meaningful survival benefit and an improved quality of life compared with medically-treated subjects with similarly advanced heart failure. Yet, despite the increased survival benefit, subject with VADs displayed increased frequency of serious adverse events, including bleeding, infection and device malfunction. Unlike subjects with medically-managed CHF, subjects with VADs require cardiopulmonary bypass (CPB) for device insertion. Cardiopulmonary bypass (CPB) initiates activation of the intrinsic and extrinsic pathways of the prothrombotic response. The intrinsic pathway of coagulation is rapidly recruited secondary to blood flow across the artificial bypass circuit. In parallel, the extrinsic pathway of coagulation is activated by the tremendous amounts of tissue factor released from the surgical wound, such as sternotomy and pericardiotomy. These two pathways synergize in CPB to amplify thrombin generation. In addition, activation of platelets and complement cascades sustains the host response. In settings such as coronary artery bypass grafting or valve replacement, upon reversal of heparin and restoration of blood flow across natural endothelial surfaces, gradual resolution of the prothrombotic stimulus ensues. However, in subjects undergoing CPB for ventricular assist devices (VAD) placement, we postulate that CPB-triggered activation of coagulation fails to resolve, as VAD-host interaction sustains activation of prothrombotic mechanisms. We propose that unless effective equilibrium is achieved between prothrombotic and antithrombotic forces in the VAD milieu, imbalance leads to untoward bleeding and/or procoagulant diatheses. Subjects with VADs display an increased incidence of bleeding complications, both at the time of VAD placement, and, at later times after implantation. Aim 1: To fully characterize the time course of activation of prothrombotic pathways in animals undergoing CPB and VAD implantation. Aim 2: To test novel antagonists of the Intrinsic Pathway of coagulation in CPB and VAD placement in canine and porcine models, and to monitor the response to CPB/VAD placement in human subjects. Aim 3: To perform Phase II trials in human subjects with advanced heart failure undergoing CPB and VAD placement with Intrinsic Pathway antagonists.

具有里程碑意义的报告对治疗充血性心力衰竭（重新竞赛）研究的机械援助的随机评估小组表明，在心力衰竭患者中使用左心室辅助装置（VAD）的使用，与具有类似心脏衰竭的医学治疗的受试者相比，具有明显有意义的生存率和改善的生存质量，并改善了生活质量。然而，尽管生存率提高，但VAD的受试者显示出严重不良事件的频率增加，包括出血，感染和装置故障。与具有医学管理的CHF的受试者不同，具有VAD的受试者需要心肺旁路（CPB）进行设备插入。心肺旁路（CPB）启动了血栓形成反应的内在和外在途径的激活。凝血的固有途径迅速募集到人造旁路电路上的血流。同时，通过手术伤口释放的大量组织因子激活了凝结的外在途径， 例如胸骨切开术和心包切开术。这两种途径在CPB中协同作用，以扩大凝血酶生成。此外，血小板的激活和补体级联反应维持宿主反应。在诸如冠状动脉搭桥术或瓣膜替换之类的环境中，肝素逆转并恢复了自然内皮表面的血液流动，随后逐渐消除了血栓性刺激。但是，在接受CPB的心室辅助设备（VAD）放置的受试者中，我们假设CPB触发的凝结激活无法解决，因为VAD-HOST相互作用维持了促血栓性机制的激活。我们建议，除非在VAD环境中实现癌症和抗血栓形成力之间达到有效的平衡，否则不平衡会导致不愉快的出血和/或Procagulant Giantheses。 VADS的受试者在VAD放置时以及植入后的后期出现出血并发症的发生率增加。 目标1：充分表征动物促血栓形成途径的激活时间过程 接受CPB和VAD植入。 AIM 2：测试CPB和VAD位置中凝结凝结固有途径的新型拮抗剂，并监测人类受试者中对CPB/VAD放置的响应。 AIM 3：在患有CPB的晚期心力衰竭和具有内在途径拮抗剂的VAD位置的人类受试者中进行II期试验。