Comparative thrombolytic and immunogenic properties of staphylokinase and streptokinase

Abstract

The comparative thrombolytic properties of natural (STAN) and recombinant (STAR) staphylokinase (STA) and of streptokinase were studied in hamsters with a pulmonary embolus consisting of a platelet-poor, platelet-rich (300000 platelets/μI), platelet-enriched (1500 000 platelets/ μl) or mechanically compressed human plasma clot. Intravenous infusion over 1 h in doses ranging between 0 and 0.50 mg/kg induced dose-dependent progressive clot lysis without systemic fibrinogen breakdown. The relative thrombolytic potencies, on a weight base, of the STA preparations versus streptokinase were comparable in the platelet-poor clot model (50% lysis requiring 13 μg/kg STA and 12 μg/kg streptokinase) and in the platelet-rich clot model (50% lysis with 28 μg/kg STA and with 32 μg/kg streptokinase), but 5-fold higher in the platelet-enriched clot model (50% lysis with 46 μg/kg STA and with 210 μ/kg streptokinase) and 2-fold higher in the mechanically compressed clot model (50% lysis with 36 μg/kg STA and with 71 μg/kg streptokinase). Dog plasma at baseline contained streptokinase-neutralising activity (neutralising 0.24±0.14 μg streptokinase per ml plasma in a human plasma-based clot lysis assay, mean ±SD) but apparently no STA-neutralising activity. Repeated administration of 40 μg/kg over 1 h of streptokinase at weekly intervals in 5 dogs, increased the streptokinase-neutralising titre to 1.1±0.98 μg/ml plasma after 2 weeks and to 2.9±2.5 μg/ml after 3 weeks (p=0.13 and 0.05 versus baseline, respectively), whereas the thrombolytic potency towards a 125I-fibrin-labelled plasma clot inserted into an extracorporeal arteriovenous loop was reduced from 58±4% at baseline to 10±3% after 2 weeks and 4±1% after 3 weeks (p<0.001 vs baseline). Repeated weekly administration of an equipotent dose of STA (4 μg/kg) did not induce measurable STA-neutralising activity after 2 weeks and was associated with persistent, although somewhat reduced clot lysis (58 ± 4% lysis at baseline and 33±7% at 2 weeks, p=0.02). After 3 weeks however, STA-neutralising activity became detectable in plasma (0.34±0.30 μg/ml, p=0.07 vs baseline) and resistance to clot lysis became obvious (6±2% versus a baseline value of 58±4%, p<0.01). Thus, in the hamster model, STA has a thrombolytic potency towards platelet-poor and platelet-rich clots comparable to that of streptokinase, but it is relatively more efficient than streptokinase for the dissolution of platelet-enriched or retracted clots. Furthermore, STA might be less immunogenic than streptokinase as evidenced by less rapid induction of antibody formation and resistance to clot lysis upon repeated administration. Thrombolytic therapy of patients with acute myocardial infarction with STA thus might constitute a potential alternative to treatment with streptokinase, with a better efficacy towards platelet-rich arterial clots and possibly with reduced allergic side effects.