Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator

To determine whether tissue-type plasminogen activator (t-PA) may prevent coronary thrombosis or accelerate the lysis of clot formed under conditions in which increased concentration of the activator is present before thrombosis, clot lysis studies were undertaken in vitro and in vivo. In vitro, exogenous t-PA (6 to 100,000 ng/ml) accelerated the lysis of clot in a dose-dependent fashion when the clot was formed either from whole plasma or from euglobulin fractions (n = 316 determinations). Adding t-PA before clot formation shortened the time to lysis by at least threefold with euglobulin fractions and by at least 10-fold with whole plasma clots, which is consistent with the presence of inhibitors of fibrinolysis in whole plasma and with the binding of t-PA to nascent fibrin. In an intact dog preparation of coronary thrombosis (n = 25), occlusive thrombus formation was prevented when t-PA was present in subthrombolytic concentrations (430 to 1200 ng/ml, n = 5). Occlusive thrombus formation occurred after only discontinuation of the t-PA infusion and clearance of t-PA. Lower concentrations of t-PA (147 to 427 ng/ml, n = 6) significantly delayed occlusion (26 +/- 6.5 vs 7.8 +/- 2.8 min for controls). In animals with t-PA concentrations of less than 140 ng/ml (n = 4), the time to occlusion was unaltered (7.7 +/- 4.5 min). The present study demonstrates that t-PA present before clot formation inhibits thrombosis or accelerates thrombolysis depending on concentration, and that subthrombolytic doses of t-PA can prevent thrombus formation in vivo.