REVIEW Review High on Treatment Platelet Reactivity Omar Ait-Mokhtar a,∗ , Laurent Bonello a , Saida Benamara b and Franck Paganelli a a Department of Cardiology, Centre Hospitalier Universitaire Nord, Marseille 13015, France b Department of Cardiology, Centre Hospitalier Universitaire de Beni Messous, Algiers, Algeria The addition of clopidogrel to aspirin for patients undergoing percutaneous coronary intervention (PCI) had signifi- cantly reduced cardiovascular events. However, despite dual antiplatelet therapy ischaemic events still occur, especially stent thrombosis, which is associated with a high mortality rate. Inter-individual response to clopidogrel is highly vari- able. It was shown that 4–46% could be considered as high on treatment platelet reactivity (HTPR). Recent studies had demonstrated a relationship between HTPR and ischaemic events in the setting of PCI. Actually the assessment of platelet reactivity in routine practice and its interpretation to make a decision is a debatable issue. (Heart, Lung and Circulation (2012);21:12–21) © 2011 Published by Elsevier Inc on behalf of Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Keywords. Platelet testing; Platelet function; Platelet reactivity T he addition of clopidogrel to aspirin for patients undergoing percutaneous coronary intervention (PCI) had significantly reduced cardiovascular events. However, despite dual anti-platelet therapy ischaemic events still occur [1,2], especially stent thrombosis, which is associated with a high mortality rate. Inter- individual response to clopidogrel is highly variable. It was shown that 4–46% could be considered as having high on treatment platelet reactivity (HTPR). Recent stud- ies had demonstrated a relationship between HTPR and ischaemic events in the setting of PCI [3]. The aim of the present review is to define HTPR, summarise the mech- anisms leading to HTPR and its potential therapeutic management. P2Y12 Receptor Inhibitors Metabolism Clopidogrel selectively and irreversibly inhibits the P2Y12-ADP receptor [4]. It is an inactive pro-drug that requires two oxidations by the hepatic cytochromes P450 (CYP) to generate an active metabolite. However, ∼85% of the pro-drug is hydrolysed by esterases in the blood to an inactive metabolite, and only ∼15% of the pro- drug is metabolised by the CYP system in the liver to Received 9 February 2011; received in revised form 19 April 2011; accepted 22 August 2011; available online 13 October 2011 Abbreviations: PCI, percutaneous coronary intervention; HTPR, high on treatment platelet reactivity; LTA, light transmission aggregometry; VASP, VAsoactive stumulated phosphoprotein; PR, platelet reactivity; PRI, platelet reactivity inhibition; ACS, acute coronary syndrome; AMI, acute myocardial infarction; LD, loading dose; T2DM, Type 2 diabetes mellitus; PPI, proton pump inhibitors. ∗ Corresponding author. Tel.: +33 491968858; fax: +33 491968979. E-mail address: aitmokhtar1@yahoo.fr (O. Ait-Mokhtar). generate an active metabolite which forms a disulfide bridge between one or more cysteine residues of the P2Y12 receptor, resulting in its irreversible blockade for the life span of the platelet. Thus, P2Y12 receptor blockade acts early in the cascade of events leading to the formation of the platelet thrombus and effectively inhibits platelet aggregation. In fact, platelet P2Y12 blockade prevents platelet degranulation and the release reaction, which elaborates prothrombotic and inflammatory mediators from the platelet, and also inhibits the transformation of the GP IIb/IIIa receptor to the form that binds fibrino- gen and links platelets. The mechanism and the site of action of prasugrel are the same as clopidogrel, the major difference is the metabolism, prasugrel is also a prodrug but requires only one oxidation in the liver to generate an active metabolite; interestingly, the oxidation of prasugrel is less dependent of the CYP 450 2C19 polymorphism than clopidogrel. Finally ticagrelor is a non-thienopyridine, reversible P2Y12 receptor antagonist and is an active drug and overcome the resistance linked to the metabolism pro- cess. Methods to Assess Platelet Responsiveness to ADP and P2Y12 Receptor Reactivity Several techniques may be used to assess platelet function (Table 1) [5,6]. The main techniques are described herein. Light transmittance aggregometry (LTA) is the current gold standard for assessing platelet function. It measures platelet aggregation in response to a given agonist (e.g. ADP, arachidonic acid, and thrombin receptor-activating peptide) ex vivo. However, variations in the dose of agonist and nature of anticoagulant may result in poor reproducibility and thus variability in the prevalence of resistance. Alternatively, flow cytometry technique may © 2011 Published by Elsevier Inc on behalf of Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. 1443-9506/04/$36.00 doi:10.1016/j.hlc.2011.08.069