CONTROL OF BLOOD ACTIVATION BY SYNTHETIC SURFACES

通过合成表面控制血液活化

• 批准号: 3366421
• 负责人: L HENRY EDMUNDS
• 金额: $ 33.74万
• 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 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3366421
• 关键词: affinity chromatography; anticoagulants; aprotinin; baboons; biomaterial interface interaction; blood /lymphatic pharmacology; blood cell count; blood coagulation; butyrates; coagulation factor XII; complement pathway; cyclohexane /cyclohexene carboxylate; disease /disorder model; elastases; extracorporeal circulation; fibrinogen; fibrinolysis; heart /lung bypass; heparin; hirudins; human subject; immunocytochemistry; kallikreins; macroglobulins; monoclonal antibody; neutralizing antibody; neutrophil; plasmin; plasminogen activator; platelet activation; protamines; radioimmunoassay; thrombin

Contact of heparinized blood with synthetic surfaces of the heart-lung machine initiates complex chemical and cellular reactions within the blood that result in thrombotic and bleeding problems and in a "whole body inflammatory response." This proposal seeks to identify and to selectively inhibit the initial reactions and agonists that activate blood coagulation, fibrinolysis and immunochemical defense mechanisms during cardiopulmonary bypass (CPB). The proposal will utilize several newly developed immunochemical assays to decipher the mechanisms whereby platelets$ neutrophils and complement and fibrinolytic and contact system proteins are activated during CPB in patients, in our well-established in vitro model of simulated extracorporeal circulation (SECC) and in a new in vivo baboon model. Newly developed murine antibodies against Factor XII, prekallikrein and high molecular weight kininogen, and specific peptides such as a boroarginine kallikrein inhibitor, will first be tested in our in vitro model and then in the baboon. The project also seeks alternatives to heparin, such as hirudin and boroarginine peptides, and to protamine, such as platelet factor 4, since heparin and protamine are known blood agonists. The role of fibrinolysis by both plasmin and neutrophil elastase during and after CPB will be studied using new specific assays for fibrin and fibrinogen fragments. Fibrinolytic inhibitors - tranexemic acid, epsilon amino caproic acid and aprotonin - will be evaluated in patients and baboons. The project seeks to use specific peptides and combination strategies to reversibly block neutrophil and platelet activation. Patient studies will be done to, discover and quantitate activation of contact system and fibrinolytic system proteins, and platelets and neutrophils. Unapproved drugs, specific peptides and monoclonal antibiotics will be studied in vitro, first using human blood and then in baboons, since most human immunochemical assays cross-react with baboon blood. Recent advances in hematology and immunochemistry offer realistic prospects that selective inhibition of surface-activated blood constituents can be achieved and that the morbidity and mortality of CPB in the very young and very old can be reduced.

肝素化血液与心肺合成表面接触 机器在体内引发复杂的化学和细胞反应 导致血栓和出血问题的血液以及“整体” 身体炎症反应。”该提案旨在识别并 选择性抑制初始反应和激活的激动剂 凝血、纤溶和免疫化学防御机制 体外循环 (CPB) 期间。 该提案将利用多个 新开发的免疫化学测定法可破译其机制 血小板$中性粒细胞和补体以及纤溶和接触系统 在我们成熟的研究中，蛋白质在患者体外循环期间被激活 模拟体外循环（SECC）的体外模型和新的 狒狒体内模型。 新开发的针对因子的鼠抗体 十二、前激肽释放酶和高分子量激肽原，以及特异性 肽，例如硼精氨酸激肽释放酶抑制剂，将首先被 在我们的体外模型中进行了测试，然后在狒狒中进行了测试。 该项目还 寻找肝素的替代品，例如水蛭素和硼精氨酸肽， 以及鱼精蛋白，例如血小板因子 4，因为肝素和鱼精蛋白 是已知的血液激动剂。 纤溶酶和纤溶酶的纤溶作用 将使用新方法研究 CPB 期间和之后的中性粒细胞弹性蛋白酶 纤维蛋白和纤维蛋白原片段的特异性测定。 纤溶 抑制剂 - 氨甲环酸、ε氨基己酸和抑质子 - 将在患者和狒狒身上进行评估。 该项目旨在利用 可逆阻断的特定肽和组合策略 中性粒细胞和血小板活化。 将进行患者研究， 发现并定量接触系统和纤溶的激活 系统蛋白、血小板和中性粒细胞。 未经批准的药物， 将在体外研究特定肽和单克隆抗生素， 首先使用人类的血液，然后使用狒狒的血液，因为大多数人类 免疫化学测定与狒狒血液发生交叉反应。 最近的进展 血液学和免疫化学提供了选择性的现实前景 可以实现对表面活性血液成分的抑制，并且 幼儿和老年人的 CPB 发病率和死亡率 可以减少。