THROMBOSIS AND VASCULAR LESION FORMATION

在体内，机械剥脱动脉损伤启动血小板丰富的 血栓形成并随后引起内膜增生 血管病变形成（VLF），均在正常动脉中进行实验 临床上在动脉粥样硬化血管中进行介入治疗 有症状的疾病的程序。 我们假设， 导致机械损伤部位血管病变形成的过程 血管损伤包括：a）抗血栓形成和抗增殖的损失 内皮细胞（EC）功能; B）促有丝分裂凝血酶的产生 形成和愈合血栓的活性; c）血小板沉积， 衍生生长因子（PDGF）促有丝分裂活性从活化的 急性血栓形成期间血小板聚集;和d）局部 血管壁细胞合成生长因子，部分受 凝血酶和修饰凝血酶生成的蛋白质。 我们建议 使用特定的干预措施来测试这些假设， VLF的临床相关非人灵长类动物模型。 模拟 人类再狭窄病变的复杂性，这些VLF模型包括 测量对以下两种情况的反应：a）正常人的简单机械损伤 球囊导管血管成形术（BCA）产生的动脉，外科 动脉内膜切除术（EA）和植入的人工血管移植物（PVG）;以及 B）BCA损伤添加到先前由以下物质诱导的已经建立的VLF中： 既往BCA、EA和PVG。 初步研究将确定一个时间进程， 细胞增殖、血栓形成、凝血酶生成和生长 原位杂交和免疫组化检测因子基因表达 狒狒的动脉受到了一次或两次损伤。 后续 实验将具体测试假设a）尖锐 通过以下步骤建立损伤表面的汇合的内皮细胞衬里： 用自体内皮细胞接种; B）抑制凝血酶作用 在VLF期间使用无毒不可逆抗凝血酶 （D-Phe-Pro-Arg氯甲基酮）持续静脉输注; c）通过以下方式抑制血小板粘附至受损血管表面： 产生严重的血小板减少症， 抗血小板糖蛋白Ib，或降低血小板凝聚力， 持续静脉输注特定的血小板糖蛋白 IIb/IIIa合成环肽拮抗剂。

In vivo, mechanical denuding arterial injury initiates platelet-rich thrombus formation and subsequently gives rise to proliferative intimal vascular lesion formation (VLF), both experimentally in normal arteries and clinically in atherosclerotic vessels undergoing interventional procedures for symptomatic disease. We postulate that the complex processes leading to vascular lesion formation at sites of mechanical vascular damage include: a) loss of antithrombotic and antiproliferative endothelial cell (EC) functions; b) generation of thrombin mitogenic activity in forming and healing thrombus; c) deposition of platelet- derived growth factor (PDGF) mitogenic activity released from activated platelets accumulating during acute thrombus formation; and d) local synthesis by vascular wall cells of growth factors regulated in part by thrombin, and of proteins modifying thrombin generation. We propose to test these hypotheses using specific interventions in well-characterized clinically-relevant nonhuman primate models of VLF. To simulate the complexities of human restenotic lesions, these VLF models include measured responses to both: a) simple mechanical injury of normal arteries produced by balloon catheter angioplasty (BCA), surgical endarterectomy (EA), and implanted prosthetic vascular grafts (PVG); and b) BCA injury added to already established VLF previously induced by prior BCA, EA and PVG. Initial studies will establish a time-course for cell proliferation, thrombus formation, thrombin generation and growth factor gene expression by in situ hybridization and immunohistochemistry after single and double injuries of baboon arteries. Subsequent experiments will specifically test the hypotheses by a) acutely establishing confluent endothelial cell lining of the injured surface by sodding with autologous endothelial cells; b) inhibiting thrombin action during the period of VLF using a non-toxic irreversible antithrombin (D-Phe-Pro-Arg chlormethyl ketone) by continuous intravenous infusion; c) inhibiting platelet adhesion to the injured vessel surface by producing profound thrombocytopenia using a monoclonal antibody directed against platelet glycoprotein Ib, or reducing platelet cohesion by continuous intravenous infusions of a specific platelet glycoprotein IIb/IIIa synthetic cyclic peptide antagonist.