Comparative studies of thrombolysis with single-chain and two-chain recombinant tissue-type plasminogen activators in...

Tissue-type plasminogen activator (t-PA) can occur in two different forms, single- and two-chain t-PA. Such a difference in structure of the t-PA molecule may induce different biological functions. We compared the thrombolytic efficacy of single-chain t-PA with that of two-chain t-PA and urokinase in a canine thrombosis model. The thrombolytic properties of single- and two-chain recombinant t-PA and urokinase with equivalent activity in vitro after intravenous infusion were examined in 24 anesthetized, open-chest dogs with intracoronary thrombi. Repeated coronary angiography showed that the time to reperfusion was 29.0 +/- 4.8, 32.5 +/- 6.3, and 39.2 +/- 6.8 min, respectively. One dog in the single-chain t-PA group and all dogs in the vehicle group showed no recanalization. Plasma t-PA antigen reached similar plateau levels within 15. min in both the single- and two-chain t-PA groups. The infusion of single- and two-chain t-PA was not associated with systemic fibrinolytic activation, except for a decrease in alpha 2-plasmin inhibitor in single-chain t-PA. However, the infusion of urokinase was associated with significant depletion of fibrinogen. These findings suggest that single-chain t-PA has potent thrombolytic effect without systemic fibrinolytic activity similar to that of two-chain t-PA in a canine coronary artery thrombosis model.