TISSUE-PLASMINOGEN ACTIVATOR (TPA) INHIBITS PLASMIN DEGRADATION OF FIBRIN - A MECHANISM THAT SLOWS TPA-MEDIATED FIBRINOLYSIS BUT DOES NOT REQUIRE ALPHA(2)-ANTIPLASMIN OR LEAKAGE OF INTRINSIC PLASMINOGEN

Thrombolysis is dramatically slower when high concentrations of lytic agent are used, This paradoxical observation, first described as ''pla sminogen steal,'' was originally believed to be due to depletion of ex trinsic plasminogen and consequent leaching of clot-bound plasminogen, We report that administration of increasing concentrations of recombi nant human tissue plasminogen activator (tPA) to fibrin gels resulted in lysis rates that displayed a maximum, with significantly slower rat es found at higher tPA, regardless of whether plasminogen was supplied extrinsically or intrinsically. A similar maximum in lysis rates was observed in a system lacking an extrinsic phase when plasminogen was a dded to fibrin suspensions preincubated with increasing tPA, Thus, int rinsic plasminogen leakage and alpha(2)-antiplasmin were not required for the decreased lysis at high tPA, No maximum was observed for incre asing concentrations of urokinase, Using fibrin suspensions or gels pr eincubated with tPA before addition of plasmin, we report that tPA, bu t not urokinase, caused a dose-dependent inhibition of the fibrinolyti c action of plasmin, With respect to optimal dosage schemes and the de sign of novel lytic agents, these findings indicate that (a) there exi sts a biochemical mechanism against minimizing reperfusion time with i ncreasing tPA dosages and (b) the fibrin affinity of tPA may cause red uced fibrinolysis by plasmin.