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 stoke relies o n timely reperfusion. The current study examines the efficacy of antip latelet agents as adjuvants for thrombolytic therapy. METHODS: Using a n established rabbit model of clot embolization and a randomized blind ed design, rabbits (n = 8 in each group) were orally pretreated daily for 5 days with adjuvant aspirin (1 mg/kg body weight or 20 mg/kg), ti clopidine (100 mg/kg), or vehicle (sodium carbonate). On the 6th day, tissue plasminogen activator (6.3 mg/kg administered intravenously ove r 2 h), was initiated 1 hour after embolization. RESULTS: In all group s, cerebral blood flow (CBF) was reduced to <10 ml/100 g/min immediate ly after clot embolization. After the initiation of tissue plasminogen activator (t-PA), there was significant restoration of CBF in the con trol (t-PA only) and ticlopidine groups (P < 0.05) only. Restoration o f 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, resp ectively (ticlopidine versus aspirin, P < 0.05). Clot lysis was identi cal in the control and ticlopidine groups, with 6 of 8 animals demonst rating complete clot lysis. Aspirin antagonized clot lysis in a dose-r elated manner, with low- and high-dose aspirin groups noting clot lysi s in four of eight and two of eight animals, respectively. CONCLUSIONS : Pretreatment with ticlopidine significantly reduced brain infarct si ze when compared with aspirin treatment (P < 0.05). Moreover, whereas ticlopidine treatment did not affect clot lysis or CBF relative to t-P A alone, aspirin therapy resulted in antagonism of clot lysis and was associated with a more modest restoration of blood flow. This study pr ovides a background for a more comprehensive understanding of the bala nce of thrombogenicity and thrombolysis and may assist in the developm ent of novel therapies to expedite cerebrovascular patency and reduce ischemic and reperfusion-mediated neuronal injury.