On the mechanism of thrombolysis by plasmin.

• On theoretical grounds, the high level of circulating antiplasmin in man was considered an objection to the clinical use of plasmin. Norman postulated that normal human plasma contains at least 30 times the amount of antiplasmin necessary to neutralize the plasmin which could be formed by activating all circulating plasminogen. Nevertheless, in controlled clinical studies" plasmin proved to be an effective clot-dissolving agent in a variety of thrombo-embolic conditions. Since the therapeutic dose of plasmin in these studies was insufficient to neutralize all circulating inhibitors, its mode of action remained an intriguing question. Several investigators have reported the high affinity of plasmin to fibrin" and suggested that the enzyme, once in high concentration on the clot, is not susceptible to inhibition by circulating antiplasmin. Others suggested that plasmin is not responsible for thrombolysis per se, but attributed therapeutic effects to its ability to activate plasminogen trapped into the clot. It was found' in our laboratory, that after an infusion of labeled plasmin into dogs, fibrinolytic activity of the blood rapidly decreases, while radioactivity persists in the circulation for a long time. The question arose whether in these experiments, circulating radioactivity does not represent a plasmin-