Attenuation of the inhibitory effect of prostacyclin on platelet function after tissue plasminogen activator or streptokinase infusion in the rabbit

Abstract

The inhibitory effect of prostacylcin (PGI 2) on ex vivo platelet function was assessed after i.v. administration of tissue plasminogen activator (t-PA) or streptokinase (SK) to anaesthetised rabbits. Infusion of effective fibrinolytic doses of t-PA or SK caused marked enhancement of ex vivo platelet aggregation in response to collagen or arachidonic acid. This effect was most pronounced when subthreshold aggregating responses in the control period were convered to full, threshold, irreversible aggregating responses after fibrinolytic administration. Furthermore, the anti-aggregatory effect of PGI 2 on ex vivo platelet function was attenuated after infusion of t-PA or SK. Haemostatic and pharmacokinetic parameters were analysed in rabbits receiving t-PA infusion. Circulating plasma levels of plasminogen, fibrinogen and α2-antiplasmin were all decreased significantly and fibrinogen degradation products (FDP) were elevated significantly. To elucidate the mechanism(s) responsible for marked platelet hyperresponsiveness and loss of the inhibitory effect of PGI 2 after t-PA infusion, thromboxane B 2 (TxB 2) levels were measured in plasma from the same rabbits in which ex vivo platelet function was assessed. Fifteen min after t-PA infusion, TxB 2 levels were elevated significantly over control values. The findings of the present study revealed that fibrinolytic therapy induced a state of platelet hyperaggregability, with concomitant attenuation of PGI 2 activity on ex vivo platelet aggregation, as well as an elevation in circulating levels of thromboxane. As such, fibrinolytic-induced platelet activation may contribute to acute vascular reocclusion of recanalised coronary arteries after coronary thrombolysis and may thus limit the full therapeutic response to fibrinolytic agents.