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DOI: 10.1055/s-0037-1613242
Inhibition of ADP-induced P-selectin Expression and Platelet-Leukocyte Conjugate Formation by Clopidogrel and the P2Y12 Receptor Antagonist AR-C69931MX but not Aspirin
Publication History
Received
11 February 2002
Accepted after resubmission
20 May 2002
Publication Date:
08 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200203/lookinside/thumbnails/10-1055-s-0037-1613242-1.jpg)
Summary
Platelet-leukocyte interactions are recognised to have pro-inflammatory effects, which may be important in the pathophysiology of ischaemic heart disease. Clopidogrel and the novel intravenous antithrombotic agent AR-C69931MX act at the level of the platelet P2Y12 receptor, which is known to amplify platelet activation, aggregation and other responses induced by numerous platelet agonists. We studied the effects of clopidogrel and aspirin on ADP-induced platelet-leukocyte conjugate formation and P-selectin expression in healthy volunteers. The effects of clopidogrel and AR-C69931MX administered to patients with ischaemic heart disease were also assessed. AR-C69931MX and aspirin were also studied in vitro. Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect. These effects of clopidogrel and AR-C69931MX may confer therapeutic benefits in the management of acute coronary syndromes.
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References
- 1 Kunapuli SP. Functional characterization of platelet ADP receptors. Platelets 1998; 09: 343-51.
- 2 Hollopeter G, Jantzen H-M, Vincent D, Li G, England L, Ramakrishnan V, Yang R-B, Nurden P, Nurden A, Julius D, Conley PB. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-7.
- 3 Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001; 86: 222-32.
- 4 Trumel C, Payrastre B, Plantavid M, Hechler B, Vial C, Presek P, Martinson EA, Cazenave J-P, Chap H, Gachet C. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR-1 activating peptide through the late activation of phosphoinositide 3-kinase. Blood 1999; 94: 4156-65.
- 5 Paul BZ, Jin J, Kunapuli SP. Molecular mechanism of thromboxane A2-induced platelet aggregation. Essential role for P2TAC and α2A receptors. J Biol Chem 1999; 274: 29108-14.
- 6 Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S. The central role of the P 2T receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000; 110: 925-34.
- 7 Ravanat C, Leon C, Cazenave JP, Gachet C. Involvement of the P2cyc but not the P2Y1 ADP receptor in the phosphatidylserine exposure of activated platelets. Haematologica 2000; 85 (the Platelet ADP Receptors Suppl.): 94.
- 8 Storey RF. The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets 2001; 12: 197-209.
- 9 Savi P, Labouret C, Delesque N, Guette F, Lupker J, Herbert JM. P2Y12 a new platelet ADP receptor, target of clopidogrel. Biochem Biophys Res Comm 2001; 283: 379-83.
- 10 Ingall AH, Dixon J, Bailey A, Coombs ME, Cox D, McInally JI, Hunt SF, Kindon ND, Teobald BJ, Willis PA, Humphries RG, Leff P, Clegg JA, Smith JA, Tomlinson W. Antagonists of the platelet P 2T receptor: a novel approach to antithrombotic therapy. J Med Chem 1999; 42: 213-20.
- 11 Larsen E, Celi A, Gilbert GE, Furie BC, Erban JK, Bonfanti R, Wagner DA, Furie B. PADGEM protein: A receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 1989; 59: 305-12.
- 12 Hamburger SA, McEver RP. GMP-140 mediates adhesion of stimulated platelets to neutrophils. Blood 1990; 75: 550-4.
- 13 Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-51.
- 14 Furie B, Furie BC, Flaumenhaft R. A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost 2001; 86: 214-21.
- 15 Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost 2001; 85: 401-7.
- 16 Bertrand ME, Rupprecht H-J, Urban P, Gershlick AH. for the CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624-9.
- 17 Schror K. The basic pharmacology of ticlopidine and clopidogrel. Platelets 1993; 04: 252-61.
- 18 Savcic M, Hauert J, Bachmann F, Wyld PJ, Geudelin B, Cariou R. Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects. Sem Thromb Haemost 1999; 25 (Suppl. 02) 15-9.
- 19 Rinder H, Bonan JL, Rinder C, Ault KA, Smith BR. Activated and unactivated platelet adhesion to monocytes and neutrophils. Blood 1991; 78: 1760-9.
- 20 Rinder CS, Student LA, Bonan JL, Rinder HM, Smith BR. Aspirin does not inhibit adenosine diphosphate-induced platelet alpha-granule release. Blood 1993; 82: 505-12.
- 21 Yeo EL, Sheppard J, Feuerstein IA. Role of P-selectin and leukocyte activation in polymorphonuclear cell adhesion to surface adherent activated platelets under physiologic shear conditions (an injury vessel wall model). Blood 1994; 83: 2498-507.
- 22 Kuijper PHM, Torres HG, Houben LAMJ, Lammers J-WJ, Zwaginga JJ, Koenderman L. P-selectin and MAC-1 mediate monocyte rolling and adhesion to ECM-bound platelets under flow conditions. J Leuk Biol 1998; 64: 467-73.
- 23 Weyrich AS, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA. Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumour necrosis factor-α secretion. J Clin Invest 1995; 95: 2297-303.
- 24 Weyrich AS, Elstad MR, McEver RP, McIntyre TM, Moore KL, Morrissey JH, Prescott SM, Zimmerman GA. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 1996; 97: 1525-34.
- 25 Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induced the expression of tissue factor on monocytes. Proc Nat Acad Sci USA 1994; 91: 8767-71.
- 26 Moon DG, van Der Zee H, Weston LK, Gudewicz PW, Fenton JW, Kaplan JE. Platelet modulation of neutrophil superoxide anion production. Thromb Haemost 1990; 63: 91-6.
- 27 Del Maschio A, Gorvazier E, Maillet F, Kazatchkine MD, Maclouf J. Platelet-dependent induction and amplification of polymorphonulcear leucocyte lysosomal enzyme release. Br J Haematol 1989; 72: 329-35.
- 28 Cooper D, Butcher CM, Berndt MC, Vadas MA. P-selectin interacts with a β2-integrin to enhance phagocytosis. J Immunol 1994; 153: 3199-209.
- 29 Azar RR, Waters DD. The inflammatory etiology of unstable angina. Am Heart J 1996; 132: 1101-6.
- 30 Lefer AM, Campbell B, Scalia R, Lefer DJ. Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reperfusion: role of selectins. Circulation 1998; 98: 1322-8.
- 31 The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
- 32 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.