Platelet inhibition clopidogrel

Clopidogrel is indicated for prevention of vascular ischaemic events in patients with symptomatic atherosclerosis. It is also used, along with aspirin, for the prevention of thromboembolism after placement of an intracoronary stent. Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose is usually administered. Although rare, severe neutropenia and also thrombotic thrombocytopenic purpura may occur. 

Clopidogrel has fewer adverse effects than ticlopidine and is rarely associated with neutropenia. Thrombotic thrombocytopenic purpura associated with clopidogrel has been reported. Because of its superior side effect profile and dosing requirements, clopidogrel is preferred over ticlopidine. The antithrombotic effects of clopidogrel are dose-dependent within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. The maintenance dose of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. The duration of the antiplatelet effect is 7-10 days. 

Activation of platelets is considered an essential process for arterial thrombosis. Thus, treatment with platelet-inhibiting drugs such as aspirin and ticlopidine or clopidogrel is indicated in patients with transient ischemic attacks and strokes or unstable angina and acute myocardial infarction. In angina and infarction, these drugs are often used in conjunction with -blockers, calcium channel blockers, and fibrinolytic drugs. 

Clopidogrel inhibits platelet aggregation in a dose-dependent fashion, Several studies have shown that a loading dose of clopidogrel results in a much more rapid onset of platelet inhibition than that achieved by regular low doses (II), and recommended loading doses in acute coronary syndromes (ACS) management are 300 mg followed by 75 mg once daily. 

A single dose of 400 mg induces 40% inhibition of platelet aggregation two hours later (12), and the level of platelet inhibition can be maintained with a daily dose of 75 mg. However, larger loading doses (450-600 mg) have been used in recent studies (13). Two recent trials have clearly addressed this matter. In the ALBION study, Montalescot and coworkers have demonstrated that a loading dose of 600 mg of clopidogrel achieves a better level of platelet inhibition than... 

Flow cytometric determinations of P-selectin and activated GPIIb/llla receptor expression following ADP stimulation have been used to assess platelet inhibition by clopidogrel. Flow cytometry is also a cumbersome method and requires sophisticated instrumentation and well-trained technicians. The phosphorylation state of vasodilator-stimulated phos-phoprotein (VASP) is a specific intracellular marker of clopidogrel-induced P2Y 2 receptor inhibition and can also be measured by flow cytometry. Permeation of the membrane and the use of monoclonal antibodies specific for phosphory-lated VASP are required in this method (15,88). 

The TEG using the platelet mapping assay with ADP as the agonist, and the recently developed VerifyNow P2YI2 assay have been proposed as reproducible point-of-care methods to assess platelet inhibition by clopidogrel (21,89,90). These methods are undergoing investigation in clinical studies. 

The mechanisms responsible for clopidogrel response variability are incompletely defined. Pharmacokinetic and pharmacodynamic differences in clopidogrel metabolism have been proposed to explain variable platelet inhibition. 

Sankyo Co. Ltd. Tokyo, Japan) is a new thienopyridine derivative that produces more potent platelet inhibition, and a rapid onset of action. The latter properties may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of nonresponsiveness (I I I). 

Jaremo R Lindahl TL, Fransson SG, Richter A. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002 252 233-238. 

ADP, thromboxane A2, fibrin, and serotonin. Prostacyclin (PGI2) from endothelial cells and cAMP are naturally occurring compounds that inhibit platelet aggregation. Clopidogrel and ticlopi-dine are antagonists of ADP that are used both in acute coronary syndromes and as alternatives to ASA for prophylaxis post-MI and for transient ischemic attacks (TLAs). 

Serebruany VL, Mahnin AI, Calldian KP, Gurbel PA Steinhubl SR Statins do not affect platelet inhibition with clopidogrel during coronary stenting. A roscUrosis (2001) 159, 239-41. 

Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Calcium-chaimel blockers decrease clopidogrel-mediated platelet inhibition. Heart 2010 96 186-9. 

Riondino S, Petrini N, Donato L, Torremeo C, Tanzilli G, Pulcinelli FM, Barilla F. Effects of rosuvastatin on platelet inhibition by clopidogrel in cardiovascular patients. J Thromb Thrombolysis 2009 28 151-5. 

Malmstrom RE, Ostergren J, Jorgensen L, Hjemdahl P. Influence of statin treatment on platelet inhibition by clopidogrel—a randomized comparison of rosuvastatin, ator-vastatin and simvastatin co-treatment. J Intern Med 2009 266 457-66. 

Bliden KP, Dichiara J, Lawal L, Singla A, Antonino MJ, Baker BA, Bailey WL, Tantry US, Gurbel PA. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008 52(7) 531-3. 

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