ENDARTERECTOMY PREVENTION OF THROMBOSIS & RESTENOSIS

机械性血管损伤时暴露的组织因子(TF) 假设启动凝血酶的产生，血管血栓形成和 新生内膜病变形成。我们已经在以下方面测试了这一假设 通过测量灭活因子对狒狒的影响 重组人活化的介入性血管手术 被D-Phe-Phe-Arg不可逆转地失活的凝血因子VII 氯甲基酮(FFR-rFVIIa)。FFR-rFVIIa剂量反应抑制 Tf在新鲜动脉内膜切除的同种异体动脉节段上的表达 在体外测定主动脉，并在此基础上进行慢性动脉插管。 外置式股动静脉分流术。后来， 期间给予抗血栓剂量的FFR-rFVIIa(1 mg/kg) 三种临床相关的血管手术1)外科颈动脉 动脉内膜切除术，2)股动脉球囊导管血管成形术，3) 动静脉血管植入术。FFR-rFVIIa的测量 血液水平、止血、外科出血、111In-血小板沉积炎 比较治疗后和30天内血管病变的形成。 对照组。FFR-rFVIIa抑制血管形成 动脉内膜切除术后的主动脉节段血栓形成呈剂量依赖关系 方式(使用0.05 mg/kg的中效，并完全 阻断剂量1.0 mg/kg)。用FFR-rFVIIa从血液中清除 -约110分钟的阶段T50和约7小时的a阶段T50。 在介入治疗过程中，FFR-rFVIIa水平为6 fg/ml 最初6小时，和&gt；1 fg/ml，24小时。FFR-rFVIIa治疗 减少动脉内膜剥脱术部位的111In-血小板沉积 术后至少24小时植入血管移植物 (P&lt；0.05)。FFR-rFVIIa治疗并未显著延长出血时间 次数(p&gt；0.2)，或增加手术出血(p&gt；0.2)。注射用药 血管损伤时rFFR-rFVIIa(1 mg/kg)显著 30天新生内膜血管病变的简化形态计量测量 股动脉球囊导管血管成形术(P=0.003)。瞬变 FFR-rFVIIa(1 mg/kg)对组织因子活性的灭活作用 机械性血管损伤显著减少血管血栓形成和 减少狒狒继发的内膜增生性病变的形成 而不会增加手术出血。为NIH/HL41619免费提供资金 分机12/01/97-11/30/02出版物Harker，L.A.，Marzec，U.M. 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容 预防血管血栓形成和新血管内膜损伤 组织因子拮抗剂在静脉推注中的作用 D-Phe-Phe-Arg灭活重组人因子VIIa 介入治疗中狒狒体内氯甲基酮(FFR-rFVIIa) 血管手术。发行量(在印中)。PR51RR00165-38 1/1/98- 12/31/98耶克斯地区灵长类研究中心

Tissue factor (TF) exposed during mechanical vascular injury is postulated to initiate thrombin production, vascular thrombosis and neointimal lesion formation. We have tested this hypothesis in baboons by measuring the effects of inactivating TF during interventional vascular procedures using recombinant human activated Factor VII that has been irreversibly inactivated by D-Phe-Phe-Arg chloromethyl ketone (FFR-rFVIIa). FFR-rFVIIa dose-response inhibition of TF expressed on segments of freshly endarterectomized homologous aorta was determined in vitro, and after interposition in chronic exteriorized femoral arteriovenous shunts. Subsequently, antithrombotic dosing of FFR-rFVIIa (1 mg/kg) was administered during three clinically relevant vascular procedures 1) surgical carotid endarterectomy, 2) femoral balloon catheter angioplasty, and 3) arteriovenous vascular graft implantation. Measurements of FFR-rFVIIa blood levels, hemostasis, surgical bleeding, 111In-platelet depositi on, and 30-day vascular lesion formation were compared for treated vs control groups. FFR-rFVIIa inhibited the formation of vascular thrombosis on endarterectomized aortic segments in a dose-dependent manner (intermediate effects using 0.05 mg/kg, and complete interruption by 1.0 mg/kg). FFR-rFVIIa was cleared from blood with an -phase T50 of approximately 110 min and a a-phase T50 of about 7 hrs. During the interventional procedures FFR-rFVIIa levels were >6 fg/mL for the initial 6 hrs, and >1 fg/mL for 24 hrs. FFR-rFVIIa therapy decreased 111In-platelet deposition at sites of endarterectomy and implanted vascular grafts for at least 24 hrs postoperatively (p<0.05). FFR-rFVIIa therapy did not significantly prolong bleeding times (p>0.2), or increase surgical blood loss (p>0.2). Injections of rFFR-rFVIIa (1 mg/kg) at the time of vascular injury significantly reduced morphometric measurements of 30-d neointimal vascular lesions induced by femoral balloon catheter angioplasty (p=0.003). Transient inactivation of tissue factor activity by FFR-rFVIIa (1 mg/kg) during mechanical vascular injury markedly reduces vascular thrombosis and decreases subsequent intimal proliferative lesion formation in baboons without increasing surgical bleeding. FUNDING NIH / HL41619 No cost extension 12/01/97 - 11/30/02 PUBLICATIONS Harker, L.A., Marzec, U.M., Kelly, A.B., Lumsden, A.B., Yokoyama, T., Hedner, U., Ezban, M. and Hanson, S.R. Prevention of vascular thrombosis and neointimal lesion formation by tissue factor antagonist effects of intravenous bolus recombinant human factor VIIa inactivated by D-phe-phe-arg chloromethyl ketone (FFR-rFVIIa) in baboons undergoing interventional vascular procedures. Circulation (In press). PR51RR00165-38 1/1/98 - 12/31/98 Yerkes Regional Primate Research Center