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.

体外循环 (CPB) 期间血液与生物材料的接触 激活至少五个血浆蛋白系统和五个血细胞 产生介导血管活性物质和微栓子 与开放性相关的出血、血栓和炎症并发症 心脏手术。该提案的基本原理是为了防止这些血液 通过抑制关键血液元素的功能来抑制反应 CPB 期间可逆抑制剂。我们使用三个模型： 体外系统（SECC），狒狒，其血液蛋白与 针对人类抗原的抗体和患者。因为凝血酶形成 尽管有肝素，但在 CPB 期间仍会在每位患者中循环，这是治疗的目标之一 该提案旨在防止凝血酶的形成和循环 重组蜱抗凝肽或依诺普林针对 单独使用因子 Xa 或与凝血酶、r-直接抑制剂联合使用 水蛭素或 DuP 714（Bz-Phe-Phe BoroArg 氯甲基酮）在我们的 体外和狒狒模型。第二个目标是确定组织的作用 CPB 期间伤口和/或单核细胞中表达的因子 通过外源性凝血途径刺激凝血酶的形成。一个 第三个目标是确定外部因素和外部因素的相对重要性。 通过研究组织因子表达和内源性凝血途径 因子 VIIa 的产生和接触系统激活的研究 新的特定中间体：激肽释放酶--2-巨球蛋白复合物、激肽- 游离激肽原和高、低分子量激肽原指示剂 患者的乳沟。为了减少 Xa 因子的形成，我们将使用 重组组织因子途径抑制剂 (r-TFPI) 或组织因子 阻断外在途径的抗体和一种新的有效肽，大肠杆菌素， 阻断内在途径。第四个目标是解决 关于循环血小板是否具有功能性的争议 通过使用针对不同构象的敏感抗体来胜任 血小板 GPIIb/IIIa 受体。 此外，我们将测试两个 狒狒体内联合使用协同、可逆的血小板抑制剂 在CPB过程中实现“血小板麻醉”。该提案利用了我们的 能够测量多种血液成分和反应 标记物以了解 CPB 期间血液活化的机制。和 这些知识，我们可以使用我们的体外模型和狒狒模型来开发 介导出血的选定的特定反应的抑制剂， 与 CPB 相关的血栓和炎症并发症。