Proteolysis, Fibrinolysis, and Coagulation

The fibrinolytic mechanism, one of the blood protease systems, constitutes a fourth phase of clotting, which contributes to maintenance of coagulation in delicate balance. "Shwartzman"-induced in vivo coagulation, combined with fibrinolysin, produces profound clotting defects with severe hemostatic failure, in contrast to the relative innocuousness of either alone. The same defects are obtainable in vitro. The thrombin-fibrinogen interaction is blocked, simulating the in vivo "afiibrinogenemia." These observations are pertinent to thrombolytic therapy invoked for conditions where intravascular clotting may be occurring. Fibrinogen clottability is also blocked by trypsin. Apparently, fibrinolysin, thrombin, and trypsin are competitive for fibrinogen. Trypsin, as, well as other proteases, markedly activates factors II, VII, and X, resembling the action of thromboplastin. In contrast, fibrinolysin and thrombin are inert on these clotting factors, whereas on factor V they first activate and then destroy it. This explains why factor V depression is observed in thrombolytic therapy. The activating effect of trypsin on factors II, VII, and X precludes its use in thrombolytic therapy, and also draws attention to the tryptase-antitryptase equilibrium in normal and certain thrombotic states. The experimental observations help elucidate some clinical and clinicolaboratory findings in acquired "afibrinogenemia" and therapeutically induced "fibrinolytic" states. The retarded thrombin clotting time of the plasma, and reduction in prothrombic activity attributable to fibrinolytic depression of factor V, may be valuable guides to thrombolytic therapy.