The effect of oral antiplatelet agents on tissue plasminogen activator-mediated thrombolysis in a rabbit model of thromboembolic stroke

OBJECTIVE The success of thrombolytic therapy in acute stroke relies on timely reperfusion. The current study examines the efficacy of antiplatelet agents as adjuvants for thrombolytic therapy. METHODS Using an established rabbit model of clot embolization and a randomized blinded design, rabbits (n = 8 in each group) were orally pretreated daily for 5 days with adjuvant aspirin (1 mg/kg of body weight or 20 mg/kg), ticlopidine (100 mg/kg), or vehicle (sodium carbonate). On the 6th day, tissue plasminogen activator (6.3 mg/kg administered intravenously over 2 h), was initiated 1 hour after embolization. RESULTS In all groups, cerebral blood flow (CBF) was reduced to < 10 ml/100 g/min immediately after clot embolization. After the initiation of tissue plasminogen activator (t-PA), there was significant restoration of CBF in the control (t-PA only) and ticlopidine groups (P < 0.05) only. Restoration of CBF generally correlated with brain infarct size (percent hemisphere, mean +/- standard error of the mean), which was 18.0 +/- 7.0 in the t-PA only group versus 11.0 +/- 3.3, 26.5 +/- 5.8, and 21.5 +/- 3.4 in the ticlopidine, low-dose aspirin, and high-dose aspirin groups, respectively (ticlopidine versus aspirin, P < 0.05). Clot lysis was identical in the control and ticlopidine groups, with 6 of 8 animals demonstrating complete clot lysis. Aspirin antagonized clot lysis in a dose-related manner, with low-and high-dose aspirin groups noting clot lysis in four of eight and two of eight animals, respectively. CONCLUSIONS Pretreatment with ticlopidine significantly reduced brain infarct size when compared with aspirin treatment (P < 0.05). Moreover, whereas ticlopidine treatment did not affect clot lysis or CBF relative to t-PA alone, aspirin therapy resulted in antagonism of clot lysis and was associated with a more modest restoration of blood flow. This study provides a background for a more comprehensive understanding of the balance of thrombogenicity and thrombolysis and may assist in the development of novel therapies to expedite cerebrovascular patency and reduce ischemic and reperfusion-mediated neuronal injury.