SIGNAL-TRANSDUCTION IN THE PLATELET ACTIVATION-INDUCED BY IGG ANTISTREPTOKINASE AND ANISOYLATED PLASMINOGEN-STREPTOKINASE ACTIVATOR COMPLEX

Streptokinase (SK) is one of the plasminogen activators currently used in therapeutics. SK antibodies may appear in the blood after thrombol ytic therapy with SK or after beta-hemolytic streptococci infection. S uch antibodies may both activate platelets and neutralize the ability of SK to convert plasminogen into plasmin. We previously demonstrated that platelet activation induced by the combination of IgG anti-SE and anisoylated plasminogen-SE activator complex (APSAC) is mediated by E c gamma RIIa1 receptor, However, the mechanism by which IgG anti-SE an d APSAC (or SE) transduce an activating signal across the platelet pla sma membrane remains unknown. We have demonstrated in the present stud y that the platelet aggregation induced by the combination of IgG anti -SE and APSAC is accompanied by an increase in inositol phosphate, Ca2 + mobilization and thromboxane (Tx) A2 generation. Neomycin, erbstatin and GF 109203X, which inhibit phospholipase C (PLC), protein tyrosine kinase (PTK) and protein kinase C (PKC) activities, respectively, abo lished platelet aggregation induced by IgG anti-SE plus APSAC, indicat ing the pivotal roles of the PLC, PTK and PKC pathways in this immunol ogical activation. In addition, TxA2 generation is also important sinc e aspirin, a cyclooxygenase inhibitor and SQ 29548, a TxA2 receptor an tagonist, showed significant inhibition of the platelet response. The contribution of released ADP was confirmed using apyrase, which signif icantly inhibited IgG anti-SE plus APSAC-induced platelet aggregation. Finally, WEB 2086, a platelet-activating factor (PAF) receptor antago nist, was not effective, indicating that PAF is not involved in this p rocess. APSAC- or SK-induced platelet activation may limit the therape utic effectiveness of the drug and may contribute to the pathogenesis of early reocclusion. The study of the mechanism leading to APSAC-indu ced platelet activation could be relevant for a better understanding o f the physiopathology of immune complex disorder diseases and thrombol ytic treatment failure.