PHYSIOLOGY OF BLOOD DURING EXTRACORPOREAL BYPASS

体外搭桥期间的血液生理学

• 批准号: 2215216
• 负责人: L HENRY EDMUNDS
• 金额: $ 35.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2215216
• 关键词: anticoagulants; antileukocyte isoantibody; blood coagulation; cell adhesion; complement pathway; coronary bypass; disease /disorder model; extracorporeal circulation; fibrinolysis; heparin; hirudins; human subject; iloprost; kallikreins; kininogens; leukocyte activation /transformation; monocyte; neutrophil; nonhuman therapy evaluation; platelet activation; platelet aggregation inhibitors; protease inhibitor; sheep; thrombin; thromboplastin; vascular endothelium

DESCRIPTION: (Adapted from investigator's abstract) This investigation seeks to identify and selectively inhibit the reactions that occur in blood during cardiopulmonary bypass (CPB) and long-term extracorporeal life support (ECLS). Extracorporeal perfusion activates four plasma protein systems: coagulation, contact, complement and fibrinolysis, and four blood cells: neutrophils, monocytes, platelets and endothelial cells. Inhibition of these reactions should prevent the bleeding, thrombotic and inflammatory complications associated with CPB and ECLS and is the strategy of this project. The investigators have recently found that monocytes express tissue factor (TF) during prolonged extracorporeal perfusion.They intend to pursue this discovery by examining the assembly of coagulation factors on the surface of monocytes and also platelets during extracorporeal perfusion. Because monocyte expression of TF is delayed, they will study the timing of monocyte mRNA transcription for TF and other coagulant proteins. They will test the hypothesis that cell-bound thrombin, which is shielded from heparin during CPB and ECLS, is the agonist for activation of procoagulant mechanisms. They will study specific inhibitors of monocyte coagulant protein expression using leukospecific antibodies, factor Xa inhibitors and peptides of high molecular weight kininogen. They will study platelet coagulation protein assembly using iloprost, a disintegrin, and specific antibody fragments. Lastly, they will study direct thrombin inhibitors (r-hirudin, small peptide derivatives of hirudin, a boroarginine peptide and a chloromethyl-ketone for their ability to inhibit cell-bound thrombin. Studies of blood activation during ECLS and the possible role of surface- bound heparin are severely compromised by the lack of an appropriate animal model. The investigators propose to "complete the sheep model" by developing additional assays of plasma proteases and blood cell activation. They plan to study the mechanism of platelet adhesion during CPB and ECLS and the mechanisms by which single dose disintegrins and surface-bound heparin reduce adhesion and apparently preserve platelet function. In the final year, the investigators plan to devise an inhibitory "cocktail" to block blood activation during CPB and ECLS by first inhibiting cell-bound thrombin and platelet activation and then adding a protease inhibitor to block contact, complement and neutrophil activation.

描述：（根据调查员的摘要进行了改编）此调查 试图识别并有选择地抑制发生的反应 心肺旁路（CPB）和长期体外期间的血液 生命支持（ECLS）。体外灌注激活四个血浆 蛋白质系统：凝血，接触，补体和纤维蛋白溶解，以及 四个血细胞：中性粒细胞，单核细胞，血小板和内皮 细胞。 抑制这些反应应防止出血， 与CPB和ECL相关的血小板和炎症并发症 这是该项目的策略。 研究人员最近发现单核细胞表达组织 长期体外灌注期间因素（TF）。 通过检查凝血因素的组装来追求这一发现 在体外期间单核细胞和血小板的表面 灌注。因为TF的单核细胞表达延迟，他们将研究 TF和其他凝结剂的单核细胞mRNA转录的时间 蛋白质。 他们将检验以下假设，即结合细胞的凝血酶 在CPB和ECLS期间被屏蔽的肝素，是 促凝机制的激活。 他们将研究特定 使用白细胞特异性的单核细胞凝结蛋白表达的抑制剂 高分子量的抗体，Xa抑制剂和肽 动力学。他们将使用 伊洛列前列素，崩解蛋白和特定的抗体片段。最后，他们 将研究直接凝血酶抑制剂（R-Hirudin，小肽 Hirudin，硼酸氨酸肽和氯甲基酮的衍生物 因为它们能够抑制细胞结合的凝血酶。 ECL中血液激活的研究以及表面的可能作用 由于缺乏适当的 动物模型。调查人员建议通过 开发血浆蛋白酶和血细胞的其他测定 激活。他们计划研究血小板粘附的机理 CPB和ECLS以及单剂量解体和 表面结合的肝素减少粘附，显然保留血小板 功能。 在最后一年，调查人员计划设计一种抑制作用 “鸡尾酒”首先阻止CPB和ECL期间的血液激活 抑制细胞结合的凝血酶和血小板激活，然后添加 蛋白酶抑制剂可阻止接触，补体和中性粒细胞 激活。