THROMBOLYSIS AND REOCCLUSION IN EXPERIMENTAL JUGULAR-VEIN AND CORONARY-ARTERY THROMBOSIS - EFFECTS OF A PLASMINOGEN-ACTIVATOR INHIBITOR TYPE 1-NEUTRALIZING MONOCLONAL-ANTIBODY

Background Thrombolytic therapy for acute myocardial infarction is oft en complicated by reocclusion of the initially reperfused artery. Plat elets have been shown to play an important role in this process. We de termined the contribution of plasminogen activator inhibitor type 1 (P AI-1), stored in the alpha-granules of platelets, to thrombolysis resi stance and to reocclusion. Methods and Results In a rabbit jugular vei n thrombosis model, the effect of a PAI-1-neutralizing monoclonal anti body (CLB-2C8) on thrombolysis and thrombus growth was assessed. The e ffect on reperfusion, reocclusion, and duration of vessel patency was studied in a canine model of coronary artery thrombosis superimposed o n a high-grade stenosis and endothelial damage. In the rabbit jugular vein model, the intravenous administration of 1 mg/kg anti-PAI-1 antib ody significantly enhanced the endogenous thrombolysis from 5.5+/-1.3% in the animals treated with a nonspecific monoclonal antibody (contro l) to 13.7+/-2.6% in the animals treated with the anti-PAI-1 antibody. Thrombus growth was reduced significantly, from 41.3+/-2.6% in the co ntrol animals to 22.8+/-2.8% in the animals treated with the anti-PAI- 1 antibody. In combination with a single bolus injection of recombinan t tissue-type plasminogen activator (rTPA; 0.25 mg/kg), the anti-PAI-1 antibody reduced thrombus growth significantly, from 21.5+/-2.7% in t he animals treated with rTPA alone to 12.2+/-2.6% in the animals treat ed with rTPA and the antibody. No additional effect of the anti-PAI-1 antibody was observed on rTPA-induced thrombolysis. In the canine coro nary artery thrombosis model, the administration of a suboptimal dose of rTPA (0.45 mg/kg) induced reperfusion in 7 of the 8 dogs after 19.5 +/-8.2 minutes. Reperfusion was followed by reocclusion in all animals after 3.3+/-2.6 minutes. Administration of the anti-PAI-1 antibody in combination with rTPA significantly reduced time to reperfusion (8.1/-5.2 minutes) and delayed the occurrence of reocclusion to 11.6+/-12. 5 minutes. Conclusions Administration of the anti-PAI-1 antibody (CLB- 2C8) results in increased endogenous thrombolysis and inhibition of th rombus growth in a venous thrombosis model in rabbits and facilitated reperfusion and reduction of reocclusion in a canine model of coronary artery thrombosis.