Gallo R, Padurean A, Toschi V, Bichler J, Fallon J T, Chesebro J H, Fuster V, Badimon J J
Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, New York, NY, USA.
Circulation. 1998 Feb 17;97(6):581-8. doi: 10.1161/01.cir.97.6.581.
Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA.
Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolus + 0.7 mg/kg per day for 2 days), and long-term (bolus + 0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58+/-3% versus 35+/-3%; P<.001). No differences were observed among the bolus and short-term hirudin groups and the control group.
Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA. Therefore an adequate and prolonged administration of thrombin inhibitors is needed to "passivate" the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach.
经皮腔内冠状动脉成形术（PTCA）后动脉损伤会引发急性血栓形成和凝血酶生成。水蛭素是一种强效直接凝血酶抑制剂，可预防动脉损伤后血栓形成。两项大型临床试验表明，在短期使用凝血酶抑制剂期间，急性临床事件显著减少，但在减少再狭窄方面并无长期益处。我们的假设是，通过抑制所有凝血酶依赖性机制来充分维持凝血酶抑制作用，将减少PTCA后的新生内膜形成。
36只猪接受了三种不同方案的水蛭素治疗：推注（1毫克/千克）、短期（推注+每天0.7毫克/千克，共2天）和长期（推注+每天0.7毫克/千克，共14天）。将冠状动脉成形术后4周时新生内膜形成的结果与对照组（100国际单位肝素/千克推注）进行比较。通过输液泵持续给予水蛭素2周。血管成形术后长达2周，体内凝血酶生成持续增加。凝血酶活性抑制14天可使管腔狭窄减少40%（58±3%对35±3%；P<0.001）。推注组和短期水蛭素组与对照组之间未观察到差异。
我们的结果表明，PTCA后存在持续且显著的凝血酶生成，至少持续2周。给予重组水蛭素2周可显著减少PTCA后的新生内膜形成。这一观察结果如果外推至人类，可能解释了在抗凝血酶药物的临床试验中尽管对减少PTCA后的急性血栓并发症有明显益处，但对再狭窄却无效果的原因。因此，需要充分且延长凝血酶抑制剂的给药时间，以“钝化”血栓形成底物（受损动脉壁）并充分发挥这种治疗方法的益处。
