Thrombolytic activity of YM866, a novel modified tissue-type plasminogen activator,in a rabbit model of jugular vein thrombosis

The thrombolytic activity of a novel modified t-PA analog, YM866, was compared with that of recombinant t-PA (t-PA) in rabbits with experimental jugular vein thrombosis. Thrombus was induced in an isolated segment of the jugular vein from a mixture of whole autologous blood and thrombin. Thirty minutes after the induction of thrombus, YM866 was administered by iv bolus injection, while t-PA was given by the same method or by a 60-min iv infusion. Thrombi were removed 70 min after iv bolus injection or 10 min after the termination of iv infusion, and thrombus size was measured by total protein content in the isolated thrombus. Both YM866 and t-PA exhibited dose-dependent thrombolysis; the thrombolytic activity of YM866, however, was 4 times greater than that of t-PA. The improved thrombolytic activity of YM866 correlated with its relatively higher antigen levels in plasma, which result from its prolonged biological half-life. Depletion of plasma fibrinogen to less than 20% of baseline levels was observed in all groups. Template bleeding time was not significantly altered in any group. These results suggest that YM866 offers the potential for clinical use in thrombolytic therapy by iv bolus injection for patients with venous thromboembolic diseases. © 1994 Wiley-Liss, Inc.