Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation.
Clopidogrel is considered to be an important therapeutic advance in anti-platelet therapy. We investigated whether inhibition by clopidogrel results in a reduced capacity of platelets to adhere and stimulate pro-atherothrombotic and inflammatory functions in polymorphonuclear leukocytes (PMN) and in monocytes (MN). An eventual effect on these processes could further substantiate anti-atherothrombotic properties of this drug. The effects of clopidogrel or of its active metabolite were investigated on ADP or thrombin receptor-induced platelet activation and on platelet-leukocyte interactions ex vivo in the mouse or in vitro in isolated human cells or whole blood, respectively. Clopidogrel inhibited platelet aggregation, expression of P-selectin, platelet-PMN adhesion and platelet-dependent ROS production in mouse PMN. Similarly pretreatment of human platelets with the active metabolite of clopidogrel in vitro resulted in a profound inhibition of platelet P-selectin expression, platelet-PMN adhesion and production of ROS by PMN. Pretreatment with the active metabolite of clopidogrel significantly impaired the ability of platelets to up-regulate the expression of TF procoagulant activity in MN, in a washed cell system. Moreover, the active metabolite of clopidogrel inhibited rapidTF exposure on platelet as well as on leukocyte surfaces in whole blood. By reducing platelet-dependent up-regulation of inflammatory and pro-atherothrombotic functions in leukocytes, clopidogrel may reduce inflammation that underlies the chronic process of atherosclerosis and its acute complications.
Evangelista
Virgilio
V
Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud,Via Nazionale, 8/A 66030, Santa Maria Imbaro, Italy. evangelista@negrisud.it
Manarini
Stefano
S
Dell'Elba
Giuseppe
G
Martelli
Nicola
N
Napoleone
Emanuela
E
Di Santo
Angelomaria
A
Lorenzet
Pierre Savi Roberto
PS
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013237:Stereoisomerism; D013925:Thromboplastin / Q000378:metabolism; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; D013925:Thromboplastin; D000077144:Clopidogrel; D013988:Ticlopidine