THROMBOLYTIC ACTION OF TICLOPIDINE - POSSIBLE MECHANISMS

Ticlopidine (Ticlide), an anti-platelet drug with a broad scope of cli nical applications, is claimed to be an antagonist of adenosine diphos phate on platelet receptors. In vitro this antagonism cannot be demons trated. Ex vivo it is detectable many hours after oral administration of the drug, perhaps subsequently to its biotransformation to an unkno wn metabolite. Here, we report for the first time that in patients wit h peripheral arterial disease and in cats with extracorporal circulati on ticlopidine evokes instantaneous thrombolytic or fibrinolytic effec ts which are not associated with inhibition of platelet aggregation. S hortening of euglobulin clot lysis time and increase in plasma levels of tissue plasminogen activator were observed 1-2 h after oral ingesti on of ticlopidine at a single dose of 500 mg. In cats ticlopidine prod uced instantaneous anti-thrombotic and thrombolytic effects at doses o f 0.3-1 mg/kg and 10-15 mg/kg i.v., respectively. Thrombolysis by ticl opidine (10 mg/kg i.v.) was comparable to that by prostacyclin at a do se of 0.3 mu g/kg i.v. Ticlopidine at a concentration of 100 mu M incr eased endothelial thromboresistance in vitro. The drug did not inhibit the activity of cyclooxygenase-1 or 12-lipoxygenase while it inhibite d lipid autooxidation (IC50 = 18 mu M) in rat liver microsomes. Our da ta point to a possibility that the therapeutic efficacy of ticlopidine might be associated not only with its delayed anti-platelet effects b ut also with its immediate thrombolytic action which is likely to be m ediated by endothelial prostacyclin and tissue plasminogen activator r ather than by platelet mechanisms.