CONTROL OF BLOOD ACTIVATION DURING OPEN HEART SURGERY

体外循环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， 产生血管活性物质和微栓子，介导 与开放手术相关的出血、血栓和炎症并发症 心脏手术。这项提议的基本原理是为了防止这些血液 抑制血液关键元素功能的反应 体外循环期间的可逆性抑制剂。我们使用三种模式： 体外系统(SECC)，与其血液蛋白发生交叉反应的狒狒 针对人类抗原的抗体，以及患者。因为凝血酶形成 并在CPB期间在每个患者体内循环，尽管使用了肝素，一个目标是 这项建议是为了防止凝血酶的形成和循环 重组硬蜱抗凝肽或依诺菊酯针对 凝血因子Xa单独或联合凝血酶直接抑制物，r- 水飞蓟素或DUP 714(BZ-Phe-Phe-BoroArg氯甲基酮) 体外模型和狒狒模型。第二个目标是确定组织的作用 体外循环期间伤口和/或单核细胞表达的因子 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和外部的相对重要性 组织因子表达与内源性凝血途径的研究 因子VIIa的产生和接触系统激活的研究 新的、特定的中间体：激肽释放酶-2-巨球蛋白复合体，激动素- 游离激肽原与高、低分子激肽原指示物 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物或组织因子 抗体来阻断外在途径和一种新的有效多肽，Ecotin， 来阻断内在的途径。第四个目标是解决 关于循环中的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而胜任 血小板膜糖蛋白IIb/IIIa受体。此外，我们还将测试两个 协同、可逆的血小板抑制药联合应用于狒狒 在体外循环中实现“血小板麻醉”。这项建议利用了我们的 能够测量各种血液成分和反应 标记物用于了解体外循环中血液活化的机制。使用 有了这些知识，我们就可以利用我们的体外和狒狒模型来开发 调节出血的特定反应的抑制剂， 与体外循环相关的血栓和炎症并发症。

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.