Scott N A, Nunes G L, King S B, Harker L A, Hanson S R
Division of Cardiology, Emory University Hospital, Atlanta, GA 30322.
Circulation. 1994 Oct;90(4):1951-5. doi: 10.1161/01.cir.90.4.1951.
Platelet-dependent thrombosis can be effectively inhibited by intravenous administration of direct thrombin antagonists. However, an increased propensity for abnormal bleeding has been associated with systemic administration of these agents. The goal of this study was to determine whether local delivery of a potent thrombin inhibitor, D-Phe-L-Pro-L-Arg chloromethyl ketone (PPACK), could inhibit platelet-dependent thrombosis without altering systemic hemostatic function.
Thrombus formation was measured by quantitative imaging of 111In-labeled platelet deposition on segments of thrombogenic vascular graft interposed in arteriovenous shunts in a porcine model. Intravenous administration of PPACK inhibited platelet deposition at a dose of 12.5 micrograms/kg per minute, which was associated with significant prolongations of both template bleeding times and activated partial thromboplastin times. By contrast, local infusion of PPACK at a dose of 0.02 micrograms/kg per minute (ie, a 600-fold smaller dose) into the fluid boundary layer at the interface between flowing blood and the thrombogenic segment produced equivalent inhibition of platelet deposition without prolonging either the bleeding time or the activated partial thromboplastin time. In addition, static exposure of a mural thrombus to solutions of PPACK at concentrations > or = 2.5 mg/mL for 15 minutes produced sustained inhibition of platelet-dependent thrombosis with no change in hemostatic measurements.
These results indicate that local delivery of the direct antithrombin PPACK, by either boundary layer infusion or static application techniques, effectively inhibits platelet-dependent thrombosis at doses that are several orders of magnitude less than the systemic dose required for an equivalent antithrombotic effect. In contrast to the systemic administration of PPACK, local delivery produced maximal inhibition of thrombosis without alterations in hemostasis.
静脉注射直接凝血酶拮抗剂可有效抑制血小板依赖性血栓形成。然而，全身应用这些药物会增加异常出血的倾向。本研究的目的是确定局部递送强效凝血酶抑制剂D-苯丙氨酸-L-脯氨酸-L-精氨酸氯甲基酮（PPACK）是否能在不改变全身止血功能的情况下抑制血小板依赖性血栓形成。
在猪模型中，通过对插入动静脉分流的致血栓性血管移植物节段上111铟标记的血小板沉积进行定量成像来测量血栓形成。静脉注射PPACK，剂量为每分钟12.5微克/千克时可抑制血小板沉积，这与模板出血时间和活化部分凝血活酶时间的显著延长相关。相比之下，以每分钟0.02微克/千克的剂量（即小600倍的剂量）将PPACK局部注入流动血液与致血栓节段之间界面处的流体边界层，可产生同等程度的血小板沉积抑制，且不延长出血时间或活化部分凝血活酶时间。此外，将壁血栓在浓度≥2.5毫克/毫升的PPACK溶液中静态暴露15分钟，可产生持续的血小板依赖性血栓形成抑制，而止血测量无变化。
这些结果表明，通过边界层输注或静态应用技术局部递送直接抗凝血酶PPACK，在剂量比产生同等抗血栓作用所需的全身剂量小几个数量级的情况下，能有效抑制血小板依赖性血栓形成。与全身应用PPACK不同，局部递送在不改变止血功能的情况下产生最大程度血栓形成抑制。
