Prevention of Reocclusion by MCI-9038, a Thrombin Inhibitor, Following t-PA-lnduced Thrombolysis in a Canine Model of Femoral Arterial Thrombosis

Abstract

SummaryWe compared a selective thrombin inhibitor (MCI-9038; Argatroban), a thromboxane A2 (TXA2) receptor antagonist (L-670,596) and a serotonin-2 receptor antagonist (ketanserin) for their ability to hasten clot lysis and delay reocclusion in a canine model of femoral arterial thrombosis. Occlusive thrombosis was induced by insertion of a thrombogenic copper coil. Femoral arterial blood flow velocity (FABFV) was monitored directly and continuously by Doppler flowmetry. Thrombolysis was induced with tissue plasminogen activator (t-PA; 0.8 mg/kg, i.v.), starting 60 min after thrombotic occlusion and continued for 90 min. Ten minutes after occlusion, dogs received an intravenous infusion of either vehicle, MCI-9038 (10 Μ;g kg−1 min−1), ketanserin (0.1 mg/ kg bolus plus 5 pg kg−1 min−1), D670,596 (1 mg/kg bolus plus 17 pg kg−1 min−1) or a combination of D670,596 and ketanserin. All infusions were discontinued 1 h after stopping the t-PA, and were followed by a 30 min observation period. The times to thrombolysis were similar for all treatments (mean ± SEM = 47 ± 3; all groups). MCI-9038 prevented reocclusion, defined as permanent cessation of FABFV during the hour after stopping the t-PA. All dogs receiving MCI-9038 reoccluded within 30 min after stopping its infusion (71 ± 3 min). Reocclusion occurred in all other dogs, except one vehicle-treated dog and a second dog that received L-670,596 plus ketanserin. Vehicle-treated dogs reoccluded within 23 ± 8 min. Reocclusion was not delayed significantly by ketanserin, L-670,596 or the combination of the two. Thus, in this model, MCI-9038 prevented reocclusion, suggesting that thrombin may be an important mediator of arterial rethrombosis after t-PA-induced thrombolysis.