Rebello S S, Driscoll E M, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
Stroke. 1997 Sep;28(9):1789-96. doi: 10.1161/01.str.28.9.1789.
We examined the ability of TP-9201, a platelet glycoprotein IIb/IIIa receptor antagonist, to prevent carotid artery rethrombosis in the anesthetized dog.
Occlusive thrombosis was induced by electrolytic injury of the left carotid artery. Thirty minutes later, 0.05 U/kg of anisoylated plasminogen streptokinase activator complex (APSAC) was infused locally to achieve clot lysis. Carotid artery recanalization was followed immediately by the infusion of either saline (10 mL/h, 240 minutes; n = 9), low-dose TP-9201 (120 micrograms/kg plus 3 micrograms.kg-1.min-1, 240 minutes; n = 7), or high-dose TP-9201 (185 micrograms/kg plus 5 micrograms.kg-1.min-1, 240 minutes; n = 7). Ex vivo platelet aggregation responses to ADP or arachidonic acid were determined.
TP-9201 produced complete inhibition of platelet aggregation in citrated platelet-rich plasma but a partial and dose-dependent inhibition in heparinized platelet-rich plasma. A twofold and eightfold increase in the template bleeding time was associated with the infusion of low-dose and high-dose TP-9201, respectively. There were frequent cyclic flow reductions in both the saline and low-dose TP-9201-treated groups after thrombolysis. However, the high-dose TP-9201-treated group exhibited a sustained flow with minimal evidence of cyclic flow reductions. At the conclusion of the protocol, patent vessels were found more frequently in the high-dose TP-9201 (5/7; P = .0048) than in the low-dose TP-9201 treatment group (2/7; P = .17) when compared with the saline group (0/9). Infusion of high-dose TP-9201 was associated with a significant reduction in the thrombus mass as compared with the control vessels.
Administration of TP-9201 in conjunction with successful thrombolysis inhibited ex vivo platelet aggregation and prevented rethrombosis of the canine carotid artery. This study demonstrates that TP-9201, an inhibitor of the platelet GPIIb/IIIa receptor, can inhibit platelet-vessel wall interaction and thus prevent rethrombosis.
我们研究了血小板糖蛋白IIb/IIIa受体拮抗剂TP - 9201预防麻醉犬颈动脉再血栓形成的能力。
通过电解损伤左颈动脉诱导闭塞性血栓形成。30分钟后，局部输注0.05 U/kg的茴香酰化纤溶酶原链激酶激活剂复合物（APSAC）以实现血栓溶解。颈动脉再通后立即输注生理盐水（10 mL/h，240分钟；n = 9）、低剂量TP - 9201（120微克/千克加3微克·千克⁻¹·分钟⁻¹，240分钟；n = 7）或高剂量TP - 9201（185微克/千克加5微克·千克⁻¹·分钟⁻¹，240分钟；n = 7）。测定体外血小板对ADP或花生四烯酸的聚集反应。
TP - 9201在枸橼酸化富血小板血浆中可完全抑制血小板聚集，但在肝素化富血小板血浆中呈部分且剂量依赖性抑制。低剂量和高剂量TP - 9201输注分别使模板出血时间增加两倍和八倍。溶栓后，生理盐水组和低剂量TP - 9201治疗组均频繁出现周期性血流减少。然而，高剂量TP - 9201治疗组血流持续，周期性血流减少的证据最少。在实验结束时，与生理盐水组（0/9）相比，高剂量TP - 9201组（5/7；P = 0.0048）比低剂量TP - 9201治疗组（2/7；P = 0.17）更频繁地发现血管通畅。与对照血管相比，高剂量TP - 9201输注使血栓质量显著降低。
TP - 9201与成功溶栓联合应用可抑制体外血小板聚集并预防犬颈动脉再血栓形成。本研究表明，血小板糖蛋白IIb/IIIa受体抑制剂TP - 9201可抑制血小板与血管壁的相互作用，从而预防再血栓形成。
