Enhancing the fibrinolytic activity of rt-PA appears to be a difficult task. Both heparin and pure thrombin inhibitors, such as hirudin, have failed to enhance the fibrinolytic activity of rt-PA. Third-generation plasminogen activators, hybrids and mutants of t-PA and single-chain urokinase plasminogen activator (scu-PA), showed only minor, if any, advantages over rt-PA in terms of fibrinolytic activity.
Inhibiting the accretion of new fibrin on the thrombi to permit a positive balance toward thrombolysis after rt-PA bolus is an attractive approach. This objective could be achieved with 2 different strategies. The first consists of adopting an effective antithrombotic treatment in conjunction with the bolus thrombolytic treatment. The second is based on the use of a bolus of plasminogen activators with prolonged half-life, since they are potentially able to lyse newly formed fibrin.
We have performed studies in experimental animals to assess the value of both strategies.
Study of Heparin as Adjunctive Antithrombotic Therapy with rt-PA
Data on heparin as an adjunct to rt-PA therapy are quite controversial, probably due to the different doses of heparin used in the various studies. To test this hypothesis, we performed a dose-ranging study with heparin given along with bolus rt-PA in rabbits.
Fibrinolysis and thrombus growth inhibition were assessed as previously described in this article. Thrombolysis was assessed by thrombus wet weight. Rabbits treated with saline served as controls.