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The thrombolytic therapy is usually associated with bleeding risks due to a systemic fibrinogenolysis. We investigated whether it is possible to block fibrinogenolysis without impairing the lytic activity of fibrin-bound plasmin molecules. The present data show that at increased a2-antiplasmin levels as high as 6-fold the normal concentration fibrinolysis was not impaired, while the haemostatic parameters as aPTT, TT and the fibrinogen concentration remained normal. Essentially similar results were observed with all plasminogen activators (streptokinase, urokinase and a t-PA mutant) assayed. The use of a2-macroglobulin leads to identical observations. With aprotinin, however, a complete inhibition of the lysis was observed. The data presented here show that it is possible with the combined use of a plasminogen activator and a2-antiplasmin to reach at least in vitro a normal fibrinolysis without impairment of the haemostatic parameters.

The pharmacological and pharmacokinetic behaviour of a recombinant tissue-type plasminogen activator (t-PA) mutant with Asn 117 and Asn 184 substituted by Gln (G4) was compared to t-PA wild type expressed in the same cell line. Although the t 1 2 α and β were almost similar for both molecules, the plasma clearance of the partially deglycosylated molecules was 2.3 times slower than that of the native molecule. The relative size of the area under the curve in the β-phase was markedly increased from 27–54.4%. Infusion of less than half of the dose of t-PA wild type (mg/kg) resulted in similar thrombolytic effects. The data presented show that the mutant analysed is more potent than t-PA wild type in vivo. Although the mutant has an increased specific activity and a lowered clearance rate, the thrombolytic data do not demonstrate that these properties are cumulative.