Effects of orally active glycoprotein IIb/IIIa antagonists on platelet CD40 ligand (CD154) expression and platelet-heteroaggregate formation

Within the targeted dosing range of roxifiban and orbofiban used in clinical trials, we did not observe any significant effects of these oral GP IIb/IIIa antagonists on platelet CD40L surface expression or sCD40L levels. We also found there was no increase in the number of platelet-heteroaggregates with orbofiban treatment and that roxifiban-induced increases only occur with concentrations higher than those occurring during normal dosing of the drug. We have also investigated the effect of a IV GP IIb/IIIa inhibitor, eptifibatide [Integrilin®], finding very similar results to the two oral inhibitors, in that eptifibatide does not cause any changes in CD40L expression or platelet-leukocyte aggregation over a wide range of concentrations (0, 50, 100, 200, 300, 500, 1000, and 3000 nM) (unpublished data). However, it is possible that other glycoprotein IIb/IIIa inhibitors, such as Abciximab [ReoPro®] or tirofiban [Aggrastat®], do lead to greater CD40L expression, thereby increasing vascular inflammation. Additionally, different effects could occur within patients with these inhibitors where treatment times are longer than in this in vitro study. However, we feel that while both CD40L surface expression and increase in platelet-leukocyte aggregates may play a role in the overall effects of some GP IIb/IIIa inhibitors under some conditions, we feel neither explanation can be broadly applied to explain the increased mortality caused by this class of drugs.