RECOMBINANT LYS-PLASMINOGEN GIVEN BEFORE, BUT NOT AFTER, RECOMBINANT TISSUE-TYPE PLASMINOGEN-ACTIVATOR MARKEDLY IMPROVES CORONARY THROMBOLYSIS IN DOGS - RELATIONSHIP OF THROMBOLYTIC EFFICACY WITH PARAMETERS OFFIBRINOLYSIS

Recombinant tissue-type plasminogen activator (rt-PA) administration r apidly restores blood flow in thrombosed coronary arteries, but corona ry arteries often reocclude after initial thrombolysis. This occurs be cause of the short half-life of rt-PA and rapid increase in plasminoge n activator inhibitor (PAI-1) and alpha(2)-antiplasmin levels in plasm a. We hypothesized that administration of lys-plasminogen, which binds to fibrin with 10 times greater affinity and results in a loose fibri n structure (as compared with native glu-plasminogen), before rt-PA wo uld enhance the thrombolytic efficacy of rt-PA and modulate parameters of fibrinolysis. To examine this hypothesis, dogs with electrically i nduced stable thrombus in the left anterior descending coronary artery (LAD) were treated with saline (group A, n = 9) or lysplasminogen (gr oup B, 2 mg/kg, n = 5), followed 10 min later by rt-PA (1 mg/kg in 20 min). Four other dogs with occlusive LAD thrombus were first given rt- PA, followed by lys-plasminogen (2 mg/kg) 50 min later (group C). Lysp lasminogen given before rt-PA restored flow in all dogs in 14 +/- 4 mi n (vs. 22 +/- 9 min in group A, p < 0.05), continuing > 2 h (vs. 41 +/ - 15 min in group A, p < 0.02). Lys-plasminogen given after rt-PA did not potentiate the effect of rt-PA. Plasma t-PA antigen concentrations were highest in group B dogs at 2 h after rt-PA infusion. PAI-1 and a lpha(2)-antiplasmin plasma levels were suppressed in all dogs receivin g lys-plasminogen whether it was given before or after rt-PA. Therefor e, lys-plasminogen given before rt-PA markedly potentiates the effect of rt-PA and alters the parameters of fibrinolysis. In contrast, lys-p lasminogen given after rt-PA does not influence the thrombolytic effec t of rt-PA, whereas it suppresses PAI-1 and alpha(2)-antiplasmin level s in plasma. This study also suggests that binding of plasminogen to t he clot is more important than the plasma levels of PAI-1 and alpha(2) -antiplasmin.