A comparison of the rates of clot lysis in a plasma milieu induced by tissue plasminogen activator (t-PA) and rec-pro-urokinase: Evidence that t-PA has a more restricted mode of action

Abstract

Tissue plasminogen activator (t-PA) and pro-urokinase (pro-UK) were previously found to have distinct and complementary mechanisms of action in a plasma milieu. The t-PA activated primarily plasminogen bound to intact fibrin (internal lysine-bound), whereas pro-UK activated plasminogen bound to partially degraded fibrin (C-terminal lysine-bound). These observations therefore suggested that each of these activators was restricted in its fibrin-dependent lytic effect. At least this is true at activator concentrations where activation of plasminogen is strictly fibrin dependent; at some high concentration all plasminogen is activated including free plasminogen in the ambient plasma. However, since some pro-UK is converted to UK at the plasmin rich fibrin surface during the course of lysis and since UK is a non-selective plasminogen activator, the pro-UK/UK system should not be similarly restricted. The present study was therefore designed to examine whether this is the case by determining the highest rates of lysis achievable at the threshold of specificity for t-PA and for pro-UK/UK respectively. Maximal rates of clot lysis by t-PA (0.1–5 μg/ml) and by rec-pro-UK (0.5–5 μg/ml) were determined and correlated with the degree of preservation of fibrinogen. The highest rate of clot lysis induced by a fibrin-specific (<10% fibrinogen degradation) dose of rec-pro-UK was 80%/h. A similar rate could not be induced by t-PA without causing >80% fibrinogen degradation. The highest fibrin-specific rate of lysis achievable with t-PA was only 42%/h. When a small amount of t-PA was added at intervals during clot lysis induced by rec-pro-UK, the t-PA significantly foreshortened the lag phase, but it did not enhance the maximal rate of clot lysis. By contrast, when rec-pro-UK was added during the course of clot lysis induced by a large, but fibrin-specific amount of t-PA, rec-pro-UK accelerated the rate of lysis thereby demonstrating the presence of some fibrin-bound plasminogen not activated by t-PA. The study indicates that in a plasma milieu t-PA is more restricted in its action and activates only about half the fibrin-bound plasminogen which is activated by rec-pro-UK/UK.