Clopidogrel acts on the P2Y12 adenosine diphosphate (ADP) purinergic receptors on human platelets. The aim of this study was to establish if a loading dose of clopidogrel inhibits platelet activation in patients with peripheral arterial disease (PAD). Two indices of platelet activation were considered: platelet shape change (PSC) and aggregation. Citrated blood was collected from ten PAD patients who were not on aspirin, at baseline (0 hours) and 2 and 4 hours after these patients ingested a loading dose (300 mg) of clopidogrel. ADP (5,mol/L)-induced platelet aggregation in whole blood was inhibited after 2 hours (free platelet count, 47% ± 19% vs. 68% ± 15%; p < 0.001) and 4 hours (47% ± 19% vs. 66% ± 16%; p 5 0.001). There was also a significant inhibition of 5-hydroxytrypta-mine (5HT, 5.0 Amol/L)-induced platelet aggregation at 2 hours. This trend was also observed for 10-,umol/L ADP-induced aggregation. ADP (0.3-0.4 /imol/L)-induced PSC was significantly inhibited at 4 hours (increase in median platelet volume, 6.3%, 1.8-10.7 vs. 1.2%, 0-5.3; p = 0.01). 5HT (0.5 /Lmol/L)-induced PSC at 4 hours was also significantly inhibited (8.1, 5.3-10.6 vs. 3.0, 0-8.2; p = 0.03). A loading dose of clopidogrel (300 mg) inhibits platelet activation in PAD patients, as early as 2 hours. To the authors' knowledge, no other study considered the effect of a loading dose of clopidogrel in PAD.
1. CAPRIE steering committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet1996;348:1329-1329.
2.
2. Bertrand ME, Rupprecht HJ, Urban P, et al. 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). Circulation2000;102:624-624.
3.
3. Berger PB, Bell MR, Rihal CS, et al. Clopidogrel versus ticlopidine after intracoronary stent placement. JAm Coll Cardiol1999;34:1891-1891.
4.
4. Calver AL, Blows LJ, Harmer S, et al. Clopidogrel for prevention of major cardiac events after coronary stent implantation: 30-day and 6-month results in patients with smaller stents. Am Heart J2000;140:483-483.
5.
5. Moussa I, Oetgen M, Roubin G, et al. Effectivness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation1999;99:2364-2364.
6.
6. Yusuf S, Zhao F, Metha SR, et al. 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 Med2001;345:494-494.
7.
7. Muller C, Buttner HJ, Petersen J, et al. A randomised comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation2000;101:590-590.
8.
8. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost2000;84:891-891.
9.
9. Mikhailidis DP, Jagroop IA. Is clopidogrel markedly superior to aspirin in patients with peripheral vascular disease?Platelets1998;9:273-273.
10.
10. Wilde JI, Retzer M, Siess S, et al. ADP-induced platelet shape change: An investigation of the signaling pathways involved and their dependence on the methods of platelet preparation. Platelets2000;11:286-286.
11.
11. Geiger J, Birch J, Honig-Liedl P.Specific impairment of human platelet P2YAC ADP receptor-mediated signiling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol1999;19:2007-2007.
12.
12. Daniel JL, Dangelmaier C, Jin J, et al. Molecular basis for ADP-induced platelet activation. I. Evidence for three distinct ADP receptors on human platelets. J Biol Chem1998;273:2024-2024.
13.
13. Gachet C.Identification, characterization, and inhibition of platelet ADP receptors. Int J Haematol2001;74:375-375.
14.
14. Kunapuli SP.Functional characterisation of platelet ADP receptors. Platelets1998;9:343-343.
16. Matsagas MI, Geroulakos G, Mikhailidis DP.The role of platelets in peripheral arterial disease: therapeutic implications. Ann Vasc Surg2002;16:246-246.
17.
17. Hiatt WR. Preventing atherothrombotic events in peripheral arterial disease: the use of antiplatelet therapy. JIntern Med2002;251:193-193.
18.
18. Robless P, Mikhailidis DP, Stansby. Systemic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg2001;88:787-787.
19.
19. Montalescott G.Value of antiplatelet therapy in preventing thrombotic events in generalised vascular disease. Clin Cardiol2000;23:18-18.
20.
20. Reininger CB, Boeger CA, Steckmeier B, et al. Mechanisms underlying increased platelet reactivity in patients with peripheral arterial disease. Preliminary results. Int Angiol1999;18:163-163.
21.
21. Barradas MA, Stansby G, Hamilton G, et al. Diminished platelet yield and enhanced platelet aggregability in platelet-rich plasma of peripheral vascular disease patients. IntAngiol1994;13:202-202.
22.
22. Saniabadi AR, Lowe GD, Baebenel JC, et al. The effect of dipyridamole on spontaneous platelet aggregation in whole blood decreases with the time after venepuncture: Evidence for the role of ADP. Thromb Haemost1987;58:744-744.
23.
23. Frojmovic MM, Milton JC, Duchastel A.Microscopic measurements of platelet aggregation reveal a low ADP-dependent process distinct from turbidometrically measured aggregation. J Lab Clin Med1983;101:964-964.
24.
24. Jagroop IA, Barradas MA, Mikhailidis DP. A low molecular weight heparin, nadroparin (Fraxiparine), inhibits thrombin induced platelet shape change and does not enhance spontaneous platelet aggregation. Br J Clin Pharmacol1996;41:163-163.
25.
25. Barradas MA, Jagroop A, O'Donoghue S, et al. Effect of milrinone in human platelet shape change, aggregation and thromboxane A2 synthesis: An in vitro study. Thromb Res1993;71:227-227.
26.
26. Barradas MA, Stansby G, Hamilton G, et al. Effect of naftidrofuryl and aspirin on platelet aggregation in peripheral vascular disease. In Vivo1993;7:543-543.
27.
27. Whitworth NH, Barradas MA, Mikhailidis DP, et al. An investigation into the effects of bacterial lipopolysaccharide on human platelets. Eur J Haematol1989;43:112-112.
28.
28. Mikhailidis DP, Barradas MA, Epemolu O, et al. Ethanol ingestion inhibits human whole blood platelet impedance aggregation. Am J Clin Pathol1987;88:342-342.
29.
29. Jagroop IA, Geroulakos G, Matsagas M, et al. The effect of clopidogrel (Plavix) function in patients with peripheral vascular disease-comparison with aspirin. 1st International symposium on cardiovascular science from bench to bedside, Hong Kong. J Cardiac Surg2002; in press.
30.
30. Jagroop IA, Burnstock G, Mikhailidis DP.Both the ADP receptors, P2Y1 and P2Y,2, play a role in controlling shape change in humans platelets. Platelets2002; in press.
31.
31. Jagroop IA, Mikhailidis DP. Doxazosin, an alphal-adrenoceptor antagonist, inhibits serotonin-induced shape change in human platelets. J Human Hypertens2001;15:203-203.
32.
32. Jagroop IA, Mikhailidis DP. Angiotensin II can induce and potentiate shape change in human platelets: Effect of losartan. J Human Hypertens2000;14:581-581.
33.
33. Jagroop IA, Clatworthy I, Lewin J, et al. Shape change in human platelets: Measurement with a channelyzer and visualisation by electron microscopy. Platelets2000;11:28-28.
34.
34. Jagroop IA, Mikhailidis DP. An investigation of the serotonergic effects of fenfluramine, dexfenfluramine and dexnorfenfluramine using platelets as neuronal models. Platelets2000;11:156-156.
35.
35. Jagroop IA, Mikhailidis DP. Effect of endothelin-1 on human platelet shape change: Reversal of activation by naftidrofuryl. Platelets2000;11:272-272.
36.
36. Barradas MA, O'Donoghue S, Mikhailidis DP.Measurement of platelet volume using a channelyzer: Assessment of the effect of agonists and antagonists. In vivo1992;6:629-629.
37.
37. Jagroop IA, Tsiara S, Mikhailidis DP. Mean platelet volume as an indicator of platelet activation: Methodological issues. Platelets2002; in press.
38.
38. Barradas MA, Gill DS, Fonseca VA, et al. Intraplatelet serotonin in patients with diabetes mellitus and peripheral vascular disease. Eur J Clin Invest1988;4:399-399.
39.
39. Savcic M, Hauert J, Bachmann F, et al. Clopidogrel loading dose regimes: Kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost1999;25:15-15.
40.
40. Qawi I, Robson SC. New developments in antiplatelet therapies: Potential use of CD39/vascular ATP diphosphohydrolase in thrombotic disorders. Curr Drug Targets2000;1:285-285.
41.
41. Umemura K, Ishihara H, Nakashima M.Anti-platelet effects of clopidogrel in rat middle cerebral artery thrombosis model. Thromb Res1995;80:209-209.
42.
42. Yao SK, McNatt J, Cui K, et al. Combined ADP and thromboxane A2 antagonism prevents cyclic flow variations in stenosed and endothelium-injured arteries in non-human primates. Circulation1993;88:2888-2888.
43.
43. Hirata Y, Umemura K, Uematsu T, et al. An experimental myocardial infarction model in the rat and its properties. Jap J Pharmacol1995;67:51-51.
44.
44. Dale J, Myhre E, Rootwelt K.Effects of dipyridamole and acetylsalicylic acid on platelet functions in patients with aortic ball-valve prostheses. Am Heart J1975;89:613-613.
45.
45. Fuster V, Chesebro JH, Frye RL, et al. Platelet survival and the development of coronary artery disease in the young adult: Effects of cigarette smoking, strong family history and medical therapy. Circulation1981;63:546-546.
46.
46. Maurer-Spurej E, Devine DV.Platelet aggregation is not initiated by platelet shape change. Lab Invest2001;81:1517-1517.
47.
47. Cheshire HJ, Wolfe JH, Barradas MA, et al. Smoking and plasma fibrinogen, lipoprotein (a) and serotonin markers for postoperative infrainguinal graft stenosis. Eur J Endovasc Surg1996;4:479-479.
