Fibrinolytic activity in blood is regulated by a dynamic process that includes control of production, secretion, inhibition, and clearance of fibrinolytic proteins. The concentration of active tissue plasminogen activator (tPA) in the region of the thrombus controls the rate of fibrinolytic activation. We have developed a first-generation kinetic model that can be used to simulate the effects of secretion, inhibition, and clearance reactions on the concentrations of active tPA, active plasminogen activator inhibitor type 1 (PAI-1), and tPA/PAI-1 complex in the circulation. This model was used to estimate the rate and pattern of secretion of tPA and PAI-1 in individual subjects. We also undertook a laboratory evaluation of fibrinolysis in patients with a history of myocardial infarction. Elevated PAI-1 activity in the absence of elevations in other acute-phase proteins suggested an intrinsic increase in PAI-1 secretion in patients post-myocardial infarction. Cardiopulmonary bypass (CPB) results in a major increase in fibrinolytic activity that has been associated with an increased risk for hemorrhage. Fibrinolytic proteins were sampled from patients both during surgery and for 2 days postoperatively. Total tPA antigen rose throughout CPB and returned to baseline in the post-operative period. PAI-1 activity fell during the initial bypass and by the end of bypass had returned to baseline. On the first to second postoperative day there was a large increase in PAI-1 activity and a significant decrease in tPA activity. These data suggest that during this period there is a window of risk for a thromboembolic event. There was, however, a large individual variability in patient response to CPB.