Paradoxical attenuation of fibrinolysis attributable to “plasminogen steal” and its implications for coronary thrombolysis

Clot-selective, relatively fibrin-specific plasminogen activators were initially developed because of the likelihood that they would preserve hemostatic integrity. Somewhat surprisingly, however, after intravenous administration they were found to induce coronary recanalization more rapidly and more frequently than first-generation agents. We hypothesized that their increased efficacy is related to sparing of free plasminogen and consequent preservation of the clot-associated plasminogen in equilibrium. To test this hypothesis, clots were formed from whole human blood in Chandler tubes and incubated with 100 to 8000 ng/mL of tissue-type plasminogen activator. At low concentrations, lysis was dose dependent. At concentrations exceeding 1500 ng/mL, paradoxical attenuation of lysis occurred by as much as 45%, associated with marked diminution of free plasminogen (greater than 80% depletion in 2 hours with 8000 ng/mL of tissue-type plasminogen activator). The decrease of free plasminogen was accompanied by depletion of clot-associated plasminogen measured in extracts. Prevention of both by repeated supplementation with plasminogen throughout incubations prevented attenuation of clot lysis, even with the highest concentrations of tissue-type plasminogen activator employed. The results indicate that depletion of free plasminogen, typical of that seen with all therapeutically effective doses of first-generation fibrinolytic agents in vivo, is likely to result in “plasminogen steal” and paradoxical attenuation of clot lysis