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 "plasminogen steal," was originally believed to be due to depletion of extrinsic plasminogen and consequent leaching of clot-bound plasminogen. We report that administration of increasing concentrations of recombinant human tissue plasminogen activator (tPA) to fibrin gels resulted in lysis rates that displayed a maximum, with significantly slower rates 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 added to fibrin suspensions preincubated with increasing tPA. Thus, intrinsic plasminogen leakage and alpha 2-antiplasmin were not required for the decreased lysis at high tPA. No maximum was observed for increasing concentrations of urokinase. Using fibrin suspensions or gels preincubated with tPA before addition of plasmin, we report that tPA, but not urokinase, caused a dose-dependent inhibition of the fibronolytic action of plasmin. With respect to optimal dosage schemes and the design of novel lytic agents, these findings indicate that (a) there exists a biochemical mechanism against minimizing reperfusion time with increasing tPA dosages and (b) the fibrin affinity of tPA may cause reduced fibrinolysis by plasmin.
Wu
J H
JH
Department of Chemical Engineering, State University of New York at Buffalo 14260, USA.
Diamond
S L
SL
D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis; D005782:Gels; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D046911:Macromolecular Substances; D010958:Plasminogen / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000737:chemistry; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
D005782:Gels; D046911:Macromolecular Substances; D005337:Fibrin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator