Summary

Clopidogrel is considered to be an important therapeutic advancein anti-platelet therapy.We investigated whether inhibitionby clopidogrel results in a reduced capacity of platelets to adhereand stimulate pro-atherothrombotic and inflammatoryfunctions in polymorphonuclear leukocytes (PMN) and inmonocytes (MN). An eventual effect on these processes couldfurther substantiate anti-atherothrombotic properties of thisdrug.The effects of clopidogrel or of its active metabolite wereinvestigated on ADP or thrombin receptor-induced platelet activationand on platelet-leukocyte interactions ex vivo in themouse or in vitro in isolated human cells or whole blood, respectively.Clopidogrel inhibited platelet aggregation, expressionof P-selectin, platelet-PMN adhesion and platelet-dependent ROS production in mouse PMN. Similarly pretreatment ofhuman platelets with the active metabolite of clopidogrel in vitroresulted in a profound inhibition of platelet P-selectin expression,platelet-PMN adhesion and production of ROS byPMN. Pretreatment with the active metabolite of clopidogrelsignificantly impaired the ability of platelets to up-regulate theexpression of TF procoagulant activity in MN, in a washed cellsystem. Moreover, the active metabolite of clopidogrel inhibitedrapidTF exposure on platelet as well as on leukocyte surfaces inwhole blood. By reducing platelet-dependent up-regulation ofinflammatory and pro-atherothrombotic functions in leukocytes,clopidogrel may reduce inflammation that underlies thechronic process of atherosclerosis and its acute complications.