COMPARISON OF THE RECOMBINANT ESCHERICHIA COLI-PRODUCED PROTEASE DOMAIN OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR WITH ALTEPLASE, RETEPLASE AND STREPTOKINASE IN A CANINE MODEL OF CORONARY-ARTERY THROMBOLYSIS

Recent in vitro studies have shown that although recombinant Escherich ia coli-produced protease domain of tissue-type plasminogen activator (t-PA) has no appreciable fibrin binding and less plasmin-forming acti vity compared to the wild-type, it is nevertheless an effective fibrin olytic agent in a dynamic in vitro plasma clot lysis system. The purpo se of the present study was to evaluate the pharmacological profile of the protease in a canine model of coronary artery thrombosis. The eff ects of a single i.v. bolus injection of 1 mg/kg protease were compare d with those of alteplase, reteplase and streptokinase at clinically r elevant doses and dosing regimens in eight dogs per group. The proteas e rapidly restored coronary blood flow at 12+/-1 min in all treated do gs with a significantly higher maximal coronary blood flow than in the reference groups, but was associated with short cycles of reocclusion in 4/8 animals. Overall, the coronary blood flow quality of the prote ase was not significantly different from that of the reference thrombo lytics. Although fibrinogen was nearly completely degraded during prot ease treatment, the bleeding time was not significantly more prolonged than in reference groups. In conclusion, the protease domain is a rap idly acting, effective, bolus-injectable thrombolytic agent associated with a systemic lytic state and does not appear to cause significantl y more bleeding than the reference thrombolytic agents.