The nature of synergy between tissue-type and single chain urokinase-type plasminogen activators

Enhancement of thrombolysis with combinations of tissue-type and single chain urokinase plasminogen activators (t-PA and scu-PA) has been demonstrated in vivo but has not been seen consistently in vitro. This study was designed to characterize interactions between t-PA and scu-PA with respect to rate of and extent of thrombolysis in vitro and to delineate mechanisms responsible. Combinations of t-PA and scu-PA at selected concentrations synergistically enhanced thrombolysis in vitro compared with thrombolysis induced by either activator alone. Enhanced thrombolysis did not occur at the expense of fibrin specificity since the extent of fibrinogenolysis and consumption of alpha 2-antiplasmin were significantly less with synergistic combinations of t-PA and scu-PA compared with equi-effective concentrations of either activator alone. Attenuation of complex formation of t-PA and two chain u-PA (tcu-PA), formed from scu-PA, with plasma proteins did not appear to contribute to enhancement of thrombolysis as assessed by fibrin autography. Binding of 125I-t-PA to thrombi was increased by 27% at 1 hr and by 21% at 2 hr in the presence of scu-PA (p less than 0.001 for both). Conversion of scu-PA to tcu-PA was enhanced when thrombi were exposed to scu-PA in the presence of t-PA. Results of this study indicate that t-PA and scu-PA at selected concentrations enhance thrombolysis in vitro synergistically without compromising fibrin specificity. Enhanced binding of t-PA to thrombi in the presence of scu-PA and enhanced conversion of scu-PA to tcu-PA appear to contribute to synergy between t-PA and scu-PA for thrombolysis.