CONTROL OF BLOOD ACTIVATION BY SYNTHETIC SURFACES

通过合成表面控制血液活化

• 批准号: 2223479
• 负责人: L HENRY EDMUNDS
• 金额: $ 34.8万
• 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 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2223479
• 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; drug interactions; 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.

肝素化血与心肺的合成表面接触 机器启动复杂的化学和细胞反应 血液会导致血栓形成和出血问题，并在“整个”中 身体炎症反应。”该提案旨在识别和 有选择地抑制激活的初始反应和激动剂 血液凝血，纤维蛋白溶解和免疫化学防御机制 在心肺旁路（CPB）期间。 该提案将利用几个 新开发的免疫化学测定法，以破译机制 血小板$中性粒细胞和补体以及纤维蛋白水解和接触系统 在CPB期间，患者的蛋白质被激活 模拟体外循环（SECC）的体外模型和新的 体内狒狒模型。 新开发的针对因子的鼠抗体 xii，prekallikrein和高分子量吉诺原和特定 诸如硼酸氨酸Kallikrein抑制剂之类的肽首先将是 在我们的体外模型中，然后在狒狒中进行测试。 该项目也是如此 寻求肝素的替代品，例如Hirudin和硼酸氨酸肽， 以及精蛋白，例如血小板因子4，因为肝素和精神蛋白 是已知的血动激动剂。 纤溶酶和纤维蛋白溶解的作用 CPB期间和之后的中性粒细胞弹性酶将使用新的 纤维蛋白和纤维蛋白原片段的特定测定法。 纤维蛋白水解 抑制剂 - tranexemic Acid，Epsilon氨基酸和蛋白蛋白蛋白酶 - 将在患者和狒狒中评估。 该项目试图使用 特定的肽和组合策略可逆地阻止 中性粒细胞和血小板激活。 患者研究将进行， 发现并定量激活接触系统和纤维蛋白水解 系统蛋白质，血小板和中性粒细胞。 未批准的药物， 将在体外研究特定的肽和单克隆抗生素， 首先使用人血，然后在狒狒中，因为大多数人 免疫化学测定与狒狒血交叉反应。 最近的进步 血液学和免疫化学提供选择性的现实前景 可以抑制表面激活的血液成分，并 CPB在非常年轻且非常老的CPB的发病率和死亡率 可以减少。