Figure 6. Illustration of ProuPA vs M5 at therapeutic concentrations in plasma and of the lysis of hemostatic vs occlusive fibrin by tPA and M5.

A. At therapeutic concentrations of prouPA or M5, their intrinsic activities can activate plasminogen in plasma and the plasmin generated will then activate these proenzymes to their respective enzymes uPA and tcM5. The latter is irreversibly inactivated by C1I, which prevents the positive feedback, thereby preventing non-specific plasmin generation responsible for hemorrhagic side effects. B. Hemostatic fibrin, being protected from degradation physiologically, contains only the plasminogen binding site on the fibrin fragment-D domain of intact fibrin. At therapeutic concentrations, tPA, being free of its inhibitor PAI-1, will bind to an adjacent site to plasminogen resulting in its activation and bleeding from the degraded hemostatic site. Occlusive thrombus triggers the release of tPA from the vessel wall which initiates its degradation physiologically. This exposes new plasminogen binding site, particularly the high affinity site on fibrin fragment E domain with its three C-terminal lysine. Plasminogen binding to this site undergoes a conformational shape change which permits its activation by M5 causing lysis. TPA will also lyse the occlusive clot since other plasminogen binding sites remain. The two plasminogen activators are complementary and synergistic in their fibrinolytic mechanisms.