BLOOD ELEMENTS DURING EXTRACORPOREAL BYPASS

体外循环期间的血元素

基本信息

批准号：
3335745
负责人：
L HENRY EDMUNDS
金额：
$ 30.32万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-04-01 至 1993-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3335745
关键词：
anticoagulants antithrombogenic surface arginine biomaterial interface interaction blood coagulation disorders blood drug blood oxygenator blood proteins cell adhesion cell cell interaction coagulation factor V coagulation factor XI coagulation factor XII complement pathway dogs enzyme complex enzyme linked immunosorbent assay extracorporeal circulation fibrinogen fluorescence spectrometry glycoproteins heart /lung bypass heart surgery human tissue immunochemistry immunodiffusion immunoelectrophoresis kallikreins lactoferrin leukocyte activation /transformation leukocytes membrane activity membrane structure miniature swine peptidases platelet aggregation platelet aggregation inhibitors platelets prosthetic heart valve protease inhibitor radioimmunoassay radiotracer scanning electron microscopy superoxides surfactant synthetic peptide tissue /cell culture trypsin inhibitors

项目摘要

This investigation represents an alternative approach to the development of synthetic, non-thrombogenic surfaces. The active and complex metabolic processes of the endothelial cell, the only known non-thrombogenic surface, mitigate against discovery of truly non-thrombogenic, synthetic materials. Alternatively, we seek to determine which elements of the hemostatic system are directly activated by contact with synthetic surfaces, and then to discover inhibitors that prevent activation of these elements. Previous work has shown that synthetic surfaces directly activate Factor XII of the contact pathway, platelets and possibly white cells. In this proposal, we will study three new inhibitors of the contact pathway: corn trypsin inhibitor, a specific inhibitor of Factor XIIa; Ala 357 Arg358 alpha-1-antitrypsin, a double mutant of alpha-1-antitrypsin and a selective inhibitor of kallikrein and Factor XIIa; and arginine-15-aprotinin, a selective inhibitor of kallikrein and Factor XIa. We will determine the ability of these inhibitors to inhibit the contact pathway during in vitro and in vivo (dog) extracorporeal circulation. We will also determine whether neurtrophils are directly activated by surface contact or via the classical or alternative complement pathways and will develop strategies to inhibit neutrophil activation during extracorporeal circulation. We will determine the changes that occur in platelet membrane ADP, adrenergic and thromboxane receptors during clinical cardiopulmonary bypass and study three new strategies to inhibit platelet adhesion to and activation by synthetic surfaces. We will study three new platelet inhibitors to the platelet fibrinogen binding receptor GPIIb/IIIa: trigramin, a natural snake peptide; and two synthetic peptides, RGDS and "Ruggieri" peptide. We will also study in vitro and in vivo the role of von Willebrand factor in platelet adhesion to synthetic surfaces and the use of degraded fibrinogen to precoat synthetic materials to prevent platelet adhesion. Lastly, by combining inhibitors to the contract pathway, platelets and if necessary neutrophils, we hope to achieve extracorporeal circulation in vitro and in vivo without heparin and thus provide a new method to control the thrombotic and bleeding complications of synthetic materials in contact with blood.

这项调查代表了一种替代方法开发合成的、非血栓形成的表面。活跃的内皮细胞和复杂的代谢过程是唯一的已知的非血栓形成表面，减轻发现真正的非血栓合成材料。或者，我们试图确定止血系统的哪些要素通过与合成表面接触直接激活，然后发现阻止这些元素激活的抑制剂。先前的工作表明，合成表面直接激活接触途径的因子 XII、血小板和可能的白色细胞。在本提案中，我们将研究三种新的抑制剂接触途径：玉米胰蛋白酶抑制剂，一种特异性抑制剂因子XIIa； Ala 357 Arg358 α-1-抗胰蛋白酶，双突变体 α-1-抗胰蛋白酶和激肽释放酶的选择性抑制剂以及因子XIIa；和精氨酸-15-抑肽酶，一种选择性抑制剂激肽释放酶和因子 XIa。我们将确定这些人的能力抑制剂在体外和体内抑制接触途径体内（狗）体外循环。我们还将确定中性粒细胞是否通过表面接触直接激活或通过经典或替代补体途径并且将制定抑制中性粒细胞活化的策略体外循环。我们将确定血小板膜发生的变化临床期间的 ADP、肾上腺素能和血栓素受体体外循环并研究三种新的抑制策略血小板粘附到合成表面并被合成表面激活。我们将研究三种新型血小板纤维蛋白原抑制剂结合受体 GPIIb/IIIa：trigramin，一种天然蛇肽；以及两种合成肽，RGDS 和“Ruggieri”肽。我们还将在体外和体内研究冯维勒布兰德的作用血小板粘附到合成表面的因素以及使用降解纤维蛋白原预涂合成材料以防止血小板粘附。最后，通过结合收缩途径的抑制剂，血小板如果需要中性粒细胞，我们希望能够实现体外无需肝素即可进行体外和体内循环，从而提供控制血栓和出血并发症的新方法与血液接触的合成材料。