“Plasminogen steal” and clot lysis

AbstractAlthough initially developed to reduce the risk of bleeding, second-generation (clot-selective) thrombolytic agents have been found to induce more prompt and frequent recanalizatton than do nonselective, first-generation agents. To determine whether they do so in part by preserving clot-associated plasminogen, human whole blood clots formed in Chandler tubes were studied. Addition of suprapharmacologic concentrations of recombinant tissue-type plasminogen activator (rt-PA) to the media bathing mature clots led to a paradoxic impairment of clot lysis and a concomitant concentration-dependent depletion of clot-associated plasminogen (Western blot analysis). In contrast, supplementation of the plasma with plasminogen (0.27 mg/ml) led to significant conservation of both plasma and clot-associated plasminogen (p ≤ 0.05, n = 4), and prevented the diminution of clot lysis (p ≤ 0.05; n = 4).Fibrinogen degradation products did not account for the attenuation of lysis with the highest concentrations of rt-PA. In concentrations equivalent to those that were induced by the highest concentrations of rt-PA evaluated, fibrinogen degradation products potentiated rather than inhibited lysis (p ≤ 0.05, n = 4), probably by stimulating rt-PA activity directly. When preformed clots were incubated with plasminogen-depleted plasma plus 1,000 ng/ml rt-PA, the plasminogen content in residual clot declined (9.36 ± 0.46 versus 12.39 ± 0.69 ng/mg clot found in nondepleted plasma; p ≤ 0.05; n = 6). Furthermore, clot lysis was attenuated completely.Thus, clot lysis induced by activation of plasminogen is dependent on clot-associated plasminogen, which in turn depends on the concentration of plasminogen in plasma. Depletion of both is likely to contribute to the lower frequency and rapidity of coronary recanalization induced with nonclot-selective compared with selective fibrinolytic agents because of the depletion of plasma plasminogen and the plasminogen steal they characteristically induce