CONTROL OF BLOOD ACTIVATION DURING OPEN HEART SURGERY

心脏直视手术期间血液活化的控制

• 批准号: 2655242
• 负责人: L HENRY EDMUNDS
• 金额: $ 38.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2655242
• 关键词: activation product; anticoagulants; antithrombins; baboons; blood coagulation; clinical research; coagulation factor VII; coagulation factor X; coagulation factor XII; extracorporeal circulation; gene expression; heart /lung bypass; hirudins; human subject; integrins; kallikreins; kininogens; molecular weight; monoclonal antibody; monocyte; platelet activation; platelet aggregation; thrombocytopenia; thromboplastin; thrombosis

Blood contact with biomaterials during cardiopulmonary bypass(CPB) activates at least five plasma protein systems and five blood cells that produce the vasoactive substances and microemboli that mediate the bleeding, thrombotic and inflammatory complications associated with open heart surgery. The rationale of this proposal is to prevent these blood reactions by inhibiting the function of key blood elements using reversible inhibitors during the period of CPB. We use three models: an in vitro system (SECC), baboons, whose blood proteins cross-react with antibodies against human antigens, and patients. Because thrombin forms and circulates during CPB in every patient despite heparin, one goal of this proposal is to prevent formation and circulation of thrombin with recombinant tick anticoagulant peptide or enoxaprin directed against factor Xa alone or in combination with direct inhibitors of thrombin, r- hirudin or DuP 714 (Bz-Phe-Phe BoroArg chloromethyl ketone) in our in vitro and baboon models. A second goal is to determine the role of tissue factor expressed in the wound and/or in monocytes during CPB in stimulating thrombin formation via the extrinsic coagulation pathway. A third goal is to determine the relative importance of the extrinsic and intrinsic coagulation pathways by studies of tissue factor expression and factor VIIa generation and by studies of contact system activation using new, specific intermediates: kallikrein--2-macroglobulin complex, kinin- free kininogen and indicators of high and low molecular weight kininogen cleavage in patients. To reduce factor Xa formation, we will use recombinant tissue factor pathway inhibitor (r-TFPI) or tissue factor antibody to block the extrinsic pathway and a new potent peptide, ecotin, to block the intrinsic pathway. A fourth goal is to resolve the controversy as to whether or not circulating platelets are functionally competent by using sensitive antibodies against different conformations of the platelet GPIIb/IIIa receptor. Additionally, we will test two synergistic, reversible platelet inhibitors in combination in the baboon to achieve "platelet anesthesia" during CPB. This proposal utilizes our ability to measure a wide variety of blood constituents and reaction markers to understand the mechanisms of blood activation during CPB. With this knowledge, we can use our in vitro and baboon models to develop inhibitors of selected, specific reactions that mediate the bleeding, thrombotic and inflammatory complications associated with CPB.

心肺旁路（CPB）期间的生物材料接触与生物材料接触 激活至少五个血浆蛋白系统和五个血细胞 产生介导的血管活性物质和微栓塞 与开放有关的出血，血栓和炎症并发症 心脏手术。该提议的理由是防止这些血液 通过抑制使用关键血液元素的功能的反应 CPB期间可逆抑制剂。我们使用三种型号： 体外系统（SECC），狒狒，其血蛋白与 针对人类抗原和患者的抗体。因为凝血酶形成 尽管肝素，但在每位患者的CPB期间循环，一个目标是 该建议是为了防止与 重组tick tick抗凝肽或依诺氏肽针对 XA因子单独或与凝血酶直接抑制剂R-结合 我们的IN 体外模型。第二个目标是确定组织的作用 在CPB中的伤口和/或单核细胞中表达的因子 通过外部凝结途径刺激凝血酶形成。一个 第三个目标是确定外部和外部目标的相对重要性 通过研究组织因子表达和 VIIA因子生成并通过使用接触系统激活的研究 新的，特定的中间体：kallikrein-2-2-摩克洛蛋白复合蛋白，Kinin- 高分子和低分子量算力的游离动力学和指标 患者的裂解。为了减少因子XA的形成，我们将使用 重组组织因子途径抑制剂（R-TFPI）或组织因子 阻断外部途径和新的有效肽Ecotin的抗体 阻止内在途径。第四个目标是解决 关于循环血小板是否功能的争议 通过使用敏感抗体来胜任不同的构象 血小板GPIIB/IIIA受体的。 此外，我们将测试两个 狒狒合并的协同，可逆的血小板抑制剂 在CPB期间实现“血小板麻醉”。该提议利用了我们的 能够测量各种血液成分和反应 了解CPB期间血液激活机制的标记。和 这些知识，我们可以使用我们的体外和狒狒模型来发展 介导出血的选定的特定反应的抑制剂， 与CPB相关的血栓形成和炎症并发症。