Comparative Study of a Mutant Tissue-type Plasminogen Activator, YM866, with a Tissue-type Plasminogen Activator in a Canine Model of Femoral Arterial Thrombosis

Abstract

Abstract Because tissue-type plasminogen activator (tPA), used to treat myocardial infarction, has several disadvantages thought to be connected with its low half-life, mutants of tPA have been prepared with longer half-lives. We have compared the thrombolytic effect of such a mutant, YM866, with that of tPA in copper-coil-induced femoral arterial thrombosis in dogs. One hour after thrombus formation, YM866 was administered by intravenous bolus injection, while tPA was given by the same method or by 60-min infusion under adequate heparinization. Both agents exhibited dose-dependent thrombolysis without systemic fibrinogenolysis. The recanalization rate and recanalization time of YM866 by bolus at 0.2 mg kg−1 were, however, equivalent to those of tPA by infusion at 0.4 mg kg−1 (total dose), whereas the recanalization rate of tPA by bolus was low (0.4 mg kg−1). No significant difference in reocclusion rate, reocclusion time, or patency status after successful thrombolysis was seen. These results suggest that YM866 administered at a lower dose by intravenous bolus injection exerted a thrombolytic effect equivalent to that of tPA by infusion, and that heparin could not prevent reocclusion after successful thrombolysis even under adequate anticoagulation.