THE EFFECT OF HEPARIN AND FIBRIN ON THE ENZYMATIC EFFICIENCIES OF THROMBOLYTICS IN_ VITRO

Selective fibrinolysis may be achieved physiologically by the binding of both endogenous plasminogen activator (t-PA) and plasminogen to fibrin. It has been suggested that t-PA may also exhibit fibrin-selectivity when used at therapeutic doses for acute myocardial infarction whereas the other principal thrombo-lytics, urokinase (UK) and streptokinase (SK).plasminogen, are not bound. However, in the present kinetic studies it was found that plasminogen activation by SK.lys-plasminogen was enhanced by soluble fibrin (the effect mainly on K_m), the affinity of binding to fibrin was similar to t-PA (dissociation constant approx. 100 nM) and the reaction mechanism appeared similar (Rapid Equilibrium Ordered Bireactant). When evaluating the in vivo significance of fibrin-enhancement, variation in the form of the substrate (i.e., glu₁- or lys₇₇-forms) and the contribution of heparin must also be considered. Both t-PA and UK activities were potentiated by heparin (the effect mainly on K_m) but in the presence of fibrin the effect of heparin on t-PA was attenuated; SK.plasminogen enzymatic activity was unaffected by heparin. Thus, in the presence of heparin, in vivo, there may be an exacerbation of the systemic action of t-PA. As differences in fibrin binding and enhancement between t-PA and intact SK.plasminogen - the activator that is produced from APSAC (Eminase) - are relative rather than absolute, therapeutic activity will be influenced more by the dosage regimen and the clearance rate.