GENETICALLY ENHANCED ANGIOACCESS VASCULAR GRAFTS

活化蛋白C(APC)是一种生理性抗凝剂 凝血酶与内皮血栓调节蛋白结合后的血浆蛋白C (商标)。APC通过失活来下调凝血酶的产生 凝血因子V和的临界辅因子功能 研究评估重组人的抗血栓疗效和安全性 人可溶(RHS)TM在狒狒体内。RHsTM剂量反应为 确定血栓形成、凝血酶失活、生成 APC、止血功能和药代动力学。血栓形成 测量为自体111In-血小板的沉积和 ~(125)I-纤维蛋白在富血小板动脉型和高血压型中的蓄积 双组分血栓形成中的富含纤维蛋白的静脉型血栓形成 置入慢性股动静脉分流术的装置。例如 Vivo，rHsTM灭活可溶性凝血酶，但不结合凝血酶，以及 通过可溶性凝血酶和结合凝血酶催化APC的生成。 用T50从血浆中清除静脉注射rHsTM 6小时；2)产生剂量依赖的血栓形成抑制 (剂量为1 mg/kg的rHsTM可消除111In-血小板的沉积 和~(125)I-纤维蛋白在静脉型富纤维蛋白血栓形成中的作用， 5 mg/kg rHsTM可消除111In-血小板和125I-纤维蛋白 动脉型富血小板形成过程中的堆积 血栓)；3)以剂量依赖的方式抑制凝血；4) 抑制设备介导的全身性APC水平的增加 (归因于rHsTM依赖的可溶性凝血酶失活 由此减少了内皮-TM产生的APC)；以及5) 轻微损害的血小板止血功能，由 模板出血时间。当体内APC的产生被以下物质阻止时 在注射HPC4单抗(Moab)前注射5 mg/kg 注射rHsTM后，血栓形成显著增加， 这表明APC的产生对 RHsTM注射液的抗血栓作用。RHsTM生产 安全、剂量依赖、抗血栓作用，可归因于 直接灭活可溶性凝血酶，结合局部 结合凝血酶和可溶性凝血酶共同介导的APC的产生。 资助NIH/HL53222$287,244 8/01/98-7/31/99出版物Harker， L.A.，Marzec，U.M.，Mohri，M.，Fernandez，J.A.，Kelly，A.B.，Hanson， S.R.，Esmon，C.T.和Griffin，J.H.抗血栓疗效和安全性 重组人可溶性血栓调节蛋白在非人灵长类动物体内的表达 凝血酶失活与激活蛋白生成增强 C.循环(印中)。PR51RR00165-38 1998年1月1日-1998年12月31日耶克斯 区域灵长类研究中心

Activated Protein C (APC) is a physiologic anticoagulant generated from plasma protein C by thrombin bound to endothelial thrombomodulin (TM). APC downregulates the production of thrombin by inactivating critical cofactor functions of coagulation factors V and VIII. This study evaluates the antithrombotic efficacy and safety of recombinant human soluble (rHs)TM in baboons. rHsTM dose responses were determined for thrombus formation, thrombin inactivation, generation of APC, hemostatic function, and pharmacokinetics. Thrombus formation was measured as the deposition of autologous 111In-platelets and accumulation of 125I-fibrin for both platelet-rich arterial-type and fibrin-rich venous-type thrombosis in a two-component thrombogenic device interposed in chronic femoral arteriovenous (AV) shunts. Ex vivo, rHsTM inactivated soluble thrombin, but not bound thrombin, and catalyzed the generation of APC by both soluble and bound thrombin. Bolus intravenous rHsTM in babo ons 1) cleared from plasma with a T50 of 6 hrs; 2) produced dose-dependent inhibition of thrombus formation (dosing rHsTM at 1 mg/kg abolished the deposition of 111In-platelets and 125I-fibrin in the formation of venous-type fibrin-rich thrombus, and 5 mg/kg rHsTM eliminated 111In-platelet and 125I-fibrin accumulation in the formation of arterial-type platelet-rich thrombus); 3) inhibited coagulation in a dose-dependent manner; 4) suppressed device-mediated increases in systemic APC levels (attributed to rHsTM-dependent inactivation of soluble thrombin with consequent reduction in APC generation by endothelial-TM); and 5) minimally impaired platelet hemostatic function, as measured by the template bleeding time. When in vivo APC generation was prevented by injecting 5 mg/kg HPC4 monoclonal antibody (MoAb) prior to administering rHsTM, thrombus formation was substantially augmented, indicating that APC generation contributed significantly to the antithrombotic effects produced by rHsTM infusi ons. rHsTM produces safe, dose-dependent, antithrombotic effects that are attributable to direct inactivation of soluble thrombin, coupled with the local generation of APC mediated by both bound and soluble thrombin. FUNDING NIH / HL53222 $287,244 8/01/98 - 7/31/99 PUBLICATIONS Harker, L.A., Marzec, U.M., Mohri, M., Fernandez, J.A., Kelly, A.B., Hanson, S.R., Esmon, C.T. and Griffin, J.H. Antithrombotic efficacy and safety of recombinant human soluble thrombomodulin in non-human primates Inactivation of thrombin and enhanced generation of activated protein C. Circulation (In press). PR51RR00165-38 1/1/98 - 12/31/98 Yerkes Regional Primate Research Center