Depletion of plasminogen in vitro or during thrombolytic therapy limits fibrinolytic potential

Abstract

Thrombolytic therapy frequently induces a "lytic state" associated with a decrease in plasma plasminogen concentration that could limit therapeutic efficacy. We therefore investigated the influence of soluble plasminogen concentration on in vitro lysis of retracted whole-blood clots in plasma from normal subjects and from patients undergoing thrombolytic therapy. With recombinant tissue plasminogen activator (1000 ng/ml) or two-chain urokinase plasminogen activator (250 U/ml), minimal clot lysis occurred in normal plasma depleted of plasminogen by lysine Sepharose chromatography. Clot lysis induced by two-chain urokinase plasminogen activator increased progressively in normal plasma at initial plasminogen concentrations between 0.06 to 6 U/ml, whereas maximum lysis with recombinant tissue plasminogen activator occurred between 0.5 U/ml and 1 U/ml and was less at lower and higher concentrations of plasminogen. Incubation of whole-blood clots in normal plasma with recombinant tissue plasminogen activator resulted in little change in plasminogen concentration during 6 hours, with a constant rate of clot lysis. Incubation with two-chain urokinase plasminogen activator, however, caused a rapid decrease in plasminogen concentration and a corresponding decrease in lysis rate; lysis rate was restored after repletion with purified plasminogen. The effect of in vivo activator-induced plasminogen depletion on in vitro clot lysis rates was tested with plasma obtained from patients 90 to 120 minutes after they had received 30 mg of acylated plasminogen-streptokinase activator complex that showed depletion of plasminogen to 14% +/- 2%. These plasma samples produced only 4% +/- 1% in vitro clot lysis during 4 hours but lysis increased progressively after repletion with 1, 2, and 4 U/ml plasminogen.(ABSTRACT TRUNCATED AT 250 WORDS)