THROMBOSIS AND VASCULAR LESION FORMATION

在体，机械性剥离动脉损伤启动富含血小板 血栓形成，继而引起增生性内膜 血管病变形成(VLF)，两者均发生在正常动脉 以及临床上接受介入治疗的动脉粥样硬化血管 针对症状性疾病的程序。我们假设这个综合体 导致机械性损伤部位血管损伤形成的过程 血管损伤包括：a)丧失抗血栓和抗增殖剂 内皮细胞(EC)功能；b)凝血酶有丝分裂生成 血栓形成和愈合的活性；c)血小板沉积- 从激活后释放的衍生生长因子(PDGF)有丝分裂活性 急性血栓形成过程中的血小板积聚；以及d)局部 血管壁细胞合成生长因子部分受 凝血酶，以及修改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 临床相关的VLF非人类灵长类动物模型。要模拟 人类再狭窄病变的复杂性，这些甚低频模型包括 对两者的测量反应：a)正常的简单机械损伤 球囊导管血管成形术(BCA)所产生的动脉，外科 动脉内膜剥脱术(EA)和植入人造血管移植物(PVG)；以及 B)在先前已建立的甚低频的基础上增加BCA损伤 之前的BCA、EA和PVG。初步研究将确定一个时间表，以 细胞增殖、血栓形成、凝血酶生成和生长 用原位杂交和免疫组织化学方法检测因子基因表达 在单个和双个狒狒动脉损伤后。后续 实验将通过a)敏锐地具体检验假说 创面融合内皮细胞衬里的建立 与自体内皮细胞结合；b)抑制凝血酶作用 VLF治疗期间使用无毒、不可逆抗凝血酶 (D-Phe-Pro-Arg氯甲基酮)连续静脉滴注； C)通过以下方式抑制血小板与受损血管表面的黏附 用单抗导向产生严重的血小板减少症 抗血小板糖蛋白Ib，或通过以下方式降低血小板凝聚力 持续静脉输注一种特定的血小板膜糖蛋白 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.