Clopidogrel inhibits platelet-leukocyte adhesion and plateletdependent leukocyte activation

Virgilio Evangelista; Stefano Manarini; Giuseppe Dell’Elba; Nicola Martelli; Emanuela Napoleone; Angelomaria Di Santo; Pierre Savi; Roberto Lorenzet

doi:10.1160/TH05-01-0020

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(03): 568-577
DOI: 10.1160/TH05-01-0020

Platelets and Blood Cells

Schattauer GmbH

Clopidogrel inhibits platelet-leukocyte adhesion and plateletdependent leukocyte activation

Virgilio Evangelista

¹Laboratory of Vascular Biology and Pharmacology.

,

Stefano Manarini

¹Laboratory of Vascular Biology and Pharmacology.

,

Giuseppe Dell’Elba

¹Laboratory of Vascular Biology and Pharmacology.

,

Nicola Martelli

¹Laboratory of Vascular Biology and Pharmacology.

,

Emanuela Napoleone

²“Antonio Taticchi” Unit of Cellular and Molecular Biology of Blood Coagulation. Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), Italy

,

Angelomaria Di Santo

²“Antonio Taticchi” Unit of Cellular and Molecular Biology of Blood Coagulation. Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), Italy

,

Pierre Savi

³Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, Toulouse, France

,

Roberto Lorenzet

²“Antonio Taticchi” Unit of Cellular and Molecular Biology of Blood Coagulation. Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), Italy

⁴Present address: Research Laboratories, Center of High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

› Author Affiliations

Abstract

Summary

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.

Keywords

Clopidogrel - P-selectin - platelet-leukocyte interaction - ROS - tissue factor

Full Text

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