A BLEEDING MODEL IN RABBITS DEMONSTRATE FRESH CLOT SELECTIVITY FOR A GENETICALLY ENGINEERED VARIANT OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR AND FOR STREPTOKINASE

The way in which three thrombolytic agents, tissue-type plasminogen ac tivator (t-PA), streptokinase (SK) and a genetically engineered varian t of t-PA composed of the second kringle and the protease domain (K2P) , cause the dissolution of haemostatic plugs of differing ages was inv estigated in a novel rabbit model. Standardized incisions were made on the rabbit ear and the wounds were left to hcal for 0.5 h or 24 h, be fore the thrombolytic agents were infused. In the absence of heparin, t-PA showed little discrimination between clots of different ages (36% and 28% lysis of the 0.5 h and 24 h wounds, respectively). In contras t, K2P and SK showed a pronounced fresh clot selectivity since they we re significantly more effective in lysing fresh clots than old ones (6 8% and 4% lysis for K2P and 72% and 36% for SK, respectively). In the presence of heparin the potency of t-PA on fresh clots was considerabl y increased whilst the effect on old clots was not affected, a fresh c lot selectivity for t-PA (64% lysis of fresh clots, 24% lysis of old c lots) was thus effected. Heparin did not significantly affect the fres h clot selectivity of K2P or SK, although lysis of old clots was incre ased (from 4% to 36%) when it was given together with K2P. Furthermore , heparin did not affect the time to onset of bleeding nor was the ble eding time prolonged by its addition. The bleeding time observed for t -PA (20-25 min) was markedly shorter than that found for K2P or SK (40 -50 min). No significant differences in fibrinogen degradation were ob served 60 min after administration of the three agents with and withou t heparin.