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: 2854230
• 负责人: L HENRY EDMUNDS
• 金额: $ 42.3万
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2854230
• 关键词: activation product; baboons; blood coagulation; blood proteins; coagulation factor IX; coagulation factor X; complement pathway; cyclic AMP; cyclic GMP; enzyme complex; enzyme inhibitors; extracorporeal circulation; heart /lung bypass; human tissue; immunocytochemistry; leukocyte activation /transformation; monocyte; neutrophil; phosphodiesterase inhibitors; platelet activation; postoperative complications; protein binding; synthetic peptide; thromboplastin; thrombosis

Blood contact with the wound and biomaterials of the cardiopulmonary bypass (CPB) system activates five plasma protein systems and five blood cells to produce cytotoxins and vasoactive chemicals and enzymes that mediate the bleeding, thrombotic and inflammatory complications of open heart surgery (OHS). The rationale of this proposal is that under- standing mechanisms of blood protein and cellular reactions during CPB and OHS identifies specific enzyme and activated cellular targets for temporary inhibition during the period of CPB. A specific hypotheses for selection of potential inhibitors is based on this knowledge of mechanisms. We use simulated extracorporeal circulation (SECC) for initial testing of potential inhibitors chosen from analysis of biochemical properties. The in vitro perfusion circuit consists of a 0.4M2 spiral coil membrane oxygenator, roller pump and reservoir bag to recirculate fresh heparinized human blood for 2-6 hours usually at 37 degrees C. We also use a baboon model that is being modified to include a subcutaneous tunnel to simulate a wound. The baboon is chosen since approximately 90 percent of human antibodies cross-react with baboon proteins and cells; thus the model that both robust and efficient. Previous work by ourselves and others have demonstrated the rationale of this approach in the use of fibrinolytics and proposed use of eptibatide for protecting platelets (see Progress Report). This project focuses on suppressing formation of the prothrombinase complex, complement activation and activation of neutrophils, monocytes and platelets. One goal is to inhibit thrombin formation. Prior studies indicate that inhibiting formation of the prothrombinase complex is necessary. We plan to study a tight binding new inhibitor of factor Xa, a factor IXai inhibitor and recombinant tissue factor pathway inhibitor individually and in combination. Suppression of neutrophil and monocyte activation focuses on cyclic AMP, cyclic GMP and specific phosphodiesterase inhibitors (PDEs). We will also study inhibition of neutrophil and monocyte Mac-1 receptor binding using synthesized peptides in an effort to inhibit cellular activation. Lastly we plan to study two potential inhibitors of complement activation that prevent cleavage of C3 by different means. Because blood reactions during CPB and OHS are often mutually interdependent, we plan to study combinations of inhibitors that we believe will act synergistically.

与心肺旁路（CPB）系统的伤口和生物材料接触，激活了五个血浆蛋白系统和五个血细胞，以产生介导开放式心脏手术的出血，血栓形成和炎症并发症（OHS）的细胞毒素和血管活性化学物质和酶。 该提议的理由是，在CPB和OHS期间，血液蛋白和细胞反应的缺乏抑制机制鉴定了特定的酶和活化的细胞靶标，以在CPB期间临时抑制。 选择潜在抑制剂的特定假设是基于这种机制的知识。我们使用模拟的体外循环（SECC）来初步测试从生化特性分析中选择的潜在抑制剂。体外灌注电路由0.4m2螺旋线圈膜氧化剂，滚筒泵和储层袋组成，以再循环新鲜的肝素化人体血液2-6小时，通常在37摄氏度下。我们还使用狒狒模型，该模型被修饰以包括皮下隧道来模拟伤口。 选择狒狒，因为大约90％的人类抗体与狒狒蛋白质和细胞交叉反应。因此，既有强大又有效的模型。我们自己和其他人的先前工作证明了这种方法在使用纤维蛋白剂和拟议使用Eptibatide保护血小板方面的理由（请参阅进度报告）。 该项目着重于抑制凝血酶酶复合物的形成，中性粒细胞，单核细胞和血小板的补体激活和激活。 一个目标是抑制凝血酶形成。 先前的研究表明，抑制凝血酶酶复合物的形成是必要的。 我们计划研究一个因子Xa的紧密结合新抑制剂，这是IXAI抑制剂和重组组织因子途径抑制剂抑制剂单独和组合的因子。 中性粒细胞和单核细胞活化的抑制重点是环状AMP，环状GMP和特定的磷酸二酯酶抑制剂（PDES）。 我们还将使用合成肽研究抑制中性粒细胞和单核细胞MAC-1受体结合，以抑制细胞活化。 最后，我们计划研究两个潜在的补体激活抑制剂，以防止通过不同方式裂解C3。 由于CPB和OHS期间的血反应通常是相互依存的，因此我们计划研究抑制剂的组合，我们认为这些抑制剂会协同作用。