TP-9201, A Glycoprotein IIb/IIIa Platelet Receptor Antagonist, Prevents Rethrombosis After Successful Arterial Thrombolysis in the Dog

Abstract

Background and Purpose We examined the ability of TP-9201, a platelet glycoprotein IIb/IIIa receptor antagonist, to prevent carotid artery rethrombosis in the anesthetized dog. Methods 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 μg/kg plus 3 μg · kg –1 · min –1 , 240 minutes; n=7), or high-dose TP-9201 (185 μg/kg plus 5 μg · kg –1 · min –1 , 240 minutes; n=7). Ex vivo platelet aggregation responses to ADP or arachidonic acid were determined. Results 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. Conclusions 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.