Potentiative effect of heparin in thrombolytic therapy of evolving myocardial infarction with natural pro-urokinase

Abstract

In order to find out if concomitant heparin therapy is really necessary when using pro-urokinase as a thrombolytic agent, we have treated 18 patients with evolving myocardial infarction with a combined therapy consisting of 250 000 iu urokinase as a i.v. bolus and 4.5 or 6.5 Mio latent Urokinase U of pro-urokinase infused i.v. within 40 min. Nine patients were treated without simultaneous heparinisation (group 1), while in 9 additional patients (group II) thrombolytic therapy was started with a 5000 heparin bolus followed by continuous i.v. heparin infusion of 1250 iu/h. In only 1 of the patients not heparinised (group 1) primary patency of the infarct-related vessel could be demonstrated angiographically within 90 min into thrombolysis, while in 7 out of 9 patients heparinised prior to thrombolysis (group II) an open infarct-related coronary artery was documented with the first coronary angiogram performed (p < 0.02). After a 5000 iu i.v. heparin bolus in 7 of the 8 group I patients with primarily non-patent coronary artery, reopening of the infarct-related vessel could be achieved with a second i.v. pro-urokinase infusion of 4.5 Mio latent Urokinase U within another 40 min (p < 0.01). With both regimens used, fibrinogen levels decreased only slightly (3.0 ± 1.5 g/l to 2.8 ± 1.4 g/l and 3.9 ± 1.6 g/l to 3.8 ± 1.2 g/1; differences not significant). The combination of heparin, 250 000 iu of Urokinase plus 4.5 Mio latent Urokinase U of pro-urokinase infused intravenously has an excellent thrombolytic potency and is highly fibrin specific. This thrombolytic regimen thus seems to meet the characteristics of an ideal thrombolytic therapy. Thrombin-antithrombin III complex levels measured in 13 of the 18 patients with values averaging 11.6 ± 14.9 μg/l at study entry indicate strongly elevated circulating thrombin activities already before onset of therapy. Fifteen min into thrombolysis, they decrease slightly but insignificantly to 8.5 ± 5.4 gmgl (n.s.) but steadily and even stronger increase again thereafter averaging 21.8 ± 21.6 μg/l 2 h into thrombolysis (p < 0.05). Possible mechanisms, to which the potentiative effect on the thrombolytic potency of pro-urokinase may be related are discussed. It has been demonstrated in vitro that pro-urokinase can be inactivated by the action of thrombin. Thus, it is tempting to speculate that thrombin-induced pro-urokinase inactivation in vivo also accounts for the strong heparin-related potentiation of the substance.