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(Stroke. 1997;28:1789-1796.)
© 1997 American Heart Association, Inc.
Articles |
TP-9201, A Glycoprotein IIb/IIIa Platelet Receptor Antagonist, Prevents Rethrombosis After Successful Arterial Thrombolysis in the Dog
From the Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Building III, Ann Arbor, Mich.
Correspondence to Benedict R. Lucchesi, PhD, MD, Professor, Department of Pharmacology, University of Michigan Medical School, 1301C MSRB III, Ann Arbor, MI 48109-0632. E-mail benluc{at}umich.edu
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.
Key Words: antiplatelet agents • platelets • thrombolysis • carotid arteries • dogs
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