The Mechanism of Clot Dissolution by Plasmin*

Normal human and animal sera contain a glob-ulin, plasminogen, which in the presence of acti-vators is rapidly converted to plasmin, a pro-teolytic enzyme active at neutral hydrogen ion concentrations. Plasmin is an enzyme of wide specificity and will attack such varied substrates as gelatin, casein, certain synthetic esters, accelera-tor globulin, complement, fibrinogen and most im-portantly fibrin. Plasminogen activation occurs spontaneously (1), or as a result of contact with activators of tissue (2), body fluid (3, 4), or bacterial origin (5). The conversion of plas-minogen to plasmin involves the loss of a peptide moiety and there is evidence to suggest that the plasmin obtained by different modes of activation may vary in composition (6). Biochemically, considerable species differences exist not only between the plasminogen system of man and animals, but more particularly between the systems of various animals; this variability is most extreme with regard to the differential effec-tiveness of streptokinase. Rigid kinetic studies (6) reveal that the activation of human plasmino-gen under the influence of streptokinase (an ex-tracellular product of hemolytic streptococcal me-tabolism), trypsin and urokinase (prepared from human urine) results from a first order enzymatic reaction. Since physiological fibrinolytic phenomena re-sult from activity of the plasminogen system, at-tempts to use plasmin or plasminogen activators to effect therapeutic thrombolysis have been nu-merous. Animal experiment, despite the difficul-ties and confusion of species variability, has yielded striking findings (7, 8, 9). Though the demon-stration of experimental thrombolytic action has been of an unequivocal nature, the precise mecha-nism of its production has hitherto been obscure. The present communication describes in vitro * This work was supported by grants from the Na-