低剂量血小板纤维蛋白原受体拮抗剂与直接凝血酶抑制剂联合使用可显著改善溶栓效果。

Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis.

作者信息

Nicolini F A, Lee P, Rios G, Kottke-Marchant K, Topol E J

机构信息

Department of Cardiology, Cleveland Clinic Foundation, OH 44195.

出版信息

Circulation. 1994 Apr;89(4):1802-9. doi: 10.1161/01.cir.89.4.1802.

DOI:10.1161/01.cir.89.4.1802

PMID:8149546

Abstract

BACKGROUND

We evaluated the effects of a novel platelet fibrinogen receptor antagonist, Integrelin, and a direct thrombin inhibitor, recombinant hirudin, given together with recombinant tissue plasminogen activator (rTPA) in a canine experimental model of intracoronary thrombosis. We tested the hypothesis that combination of both agents at low doses would have an additive antithrombotic effect, resulting in a significant improvement in the efficacy of rTPA.

METHODS AND RESULTS

Thirty-two dogs with an electrically induced coronary thrombus were treated with rTPA (1 mg/kg over 20 minutes) together with one of the following adjunctive treatments in a random fashion. Eight dogs received saline for 90 minutes; Integrelin (5 micrograms.kg-1.min-1 for 90 minutes) was given to 8 dogs; 8 dogs received recombinant hirudin (20 micrograms.kg-1.min-1 for 90 minutes); and 8 dogs were treated with a low-dose combination of Integrelin (2.5 micrograms.kg-1.min-1) plus recombinant hirudin (10 micrograms.kg-1.min-1) for 90 minutes. Integrelin or recombinant hirudin, when given as single adjunct to rTPA, enhanced the lysis of the occlusive thrombus, causing full restoration of coronary blood flow (100% of its baseline value) for 29 +/- 16 and 26 +/- 5 minutes, respectively, whereas coronary blood flow was fully restored for only 5 +/- 1 minutes in dogs receiving rTPA plus saline (both P < .05). However, either Integrelin or recombinant hirudin failed to modify the reocclusion rate (57% and 63%, respectively) compared with saline (83%; all P = NS). Conversely, the low-dose combination therapy led to complete restoration of coronary blood flow for 92 +/- 19 minutes (P < .01 versus all treatments) and significantly reduced the reocclusion rate (25%; P < .05 versus saline).

CONCLUSIONS

These data show that inhibition of specific pathways of platelet and thrombin activity improves the extent and duration of rTPA-induced thrombolysis in the electrolytic canine model. Furthermore, our findings suggest that low doses of platelet IIb/IIIa and direct thrombin antagonists in combination may be used successfully during thrombolysis.

摘要

背景

我们在犬冠状动脉内血栓形成的实验模型中，评估了一种新型血小板纤维蛋白原受体拮抗剂Integrilin和一种直接凝血酶抑制剂重组水蛭素与重组组织型纤溶酶原激活剂（rTPA）联合使用的效果。我们检验了以下假设：低剂量的两种药物联合使用将具有相加的抗血栓作用，从而显著提高rTPA的疗效。

方法与结果

32只通过电诱导形成冠状动脉血栓的犬，随机接受rTPA（20分钟内1mg/kg）与以下辅助治疗之一联合使用。8只犬接受90分钟的生理盐水；8只犬给予Integrilin（5μg·kg-1·min-1，持续90分钟）；8只犬接受重组水蛭素（20μg·kg-1·min-1，持续90分钟）；8只犬接受低剂量的Integrilin（2.5μg·kg-1·min-1）加重组水蛭素（1μg·kg-1·min-1）联合治疗90分钟。Integrilin或重组水蛭素作为rTPA的单一辅助药物使用时，可增强闭塞性血栓的溶解，使冠状动脉血流分别在29±16分钟和26±5分钟完全恢复至基线值的100%，而接受rTPA加生理盐水的犬冠状动脉血流仅在5±1分钟完全恢复（P均<0.05）。然而，与生理盐水组（83%）相比，Integrilin或重组水蛭素均未能改变再闭塞率（分别为57%和63%；P均=无显著性差异）。相反，低剂量联合治疗使冠状动脉血流完全恢复92±19分钟（与所有治疗相比，P<0.01），并显著降低再闭塞率（25%；与生理盐水组相比，P<0.05）。