Effects of GP IIb/IIIa Receptor Inhibitor Tirofiban (Aggrastat) in Ex Vivo Canine Arteriovenous Shunt Model of Stent Thrombosis

Abstract

The authors investigated the effects of the platelet glycoprotein IIb/IIIa platelet inhibitor, tirofiban, on stent thrombosis in an ex vivo canine arteriovenous shunt model of high-shear blood flow. Control nitinol stents (n = 64) were expanded to 2 mm in diameter in a tubular perfusion chamber interposed in the shunt and exposed to flowing arterial blood at a shear rate of 2100/s for 20 min (n = 385 perfusion runs). Seven animals were treated with intravenous tirofiban (0.3, 3.0, and 30.0 microg x kg-1x min-1) with or without heparin (50 U/kg). Effects on thrombus weight, platelet aggregation, platelet P-selectin expression, bleeding time, D-dimer levels, and activated clotting time were quantified. Dethrombotic and antithrombotic effects were examined in stents with and without preformed thrombus, respectively. Tirofiban alone produced a dose-dependent reduction in preformed stent thrombus weight with 21% +/- 20% and 36% +/- 15% inhibition at 3- and 30-microg x kg-1x min-1 doses, respectively (P < 0.01). De novo stent thrombus formation was inhibited by 80% at 0.3 and >95% at 3- and 30-microg x kg-1x min-1 doses, respectively (all P < 0.001). Treatment with heparin and tirofiban produced no incremental inhibitory effect on stent thrombosis compared with tirofiban alone, except for the antithrombotic effect observed with the 0.3 microg x kg-1x min-1 dose. The inhibitory effects of tirofiban were associated with >95% suppression of platelet aggregation at 0.3 microg x kg-1x min-1 and complete inhibition at higher doses. Bleeding time was prolonged from 3.5 +/- 1.0 to 13 +/- 6 min at the 0.3 microg x kg-1x min-1 dose and >30 min at higher doses, but activated clotting time and circulating platelet P-selectin expression remained unchanged with tirofiban. A modest but significant platelet deaggregation effect and an increase in plasma D-dimer levels were observed with tirofiban at the 30-microg x kg-1x min-1 dose. Thus, tirofiban produced a dose-dependent dethrombotic effect on stent thrombosis and inhibited acute de novo stent thrombosis under high-shear flow conditions.