To cite this article: Frelinger AL III, Gachet C, Mumford AD, Noris P, Mezzano D, Harrison P, Gresele P, for the Subcommittee on Platelet Physiology. Laboratory monitoring of P2Y12 inhibitors: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16: 2341-6.Dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 platelet adenosine diphosphate (ADP) receptor antagonist reduces ischemic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) but also increases bleeding [1][2][3]. Residual high on-treatment platelet reactivity (HPR) and low on-treatment platelet reactivity (LPR) in response to P2Y 12 receptor stimulation, as measured by different platelet function testing (PFT) methodologies, are associated with increased risk of ischemic and bleeding outcomes, respectively (see [4,5] and the references contained therein for descriptions of PFT assays and definitions of HPR and LPR), suggesting that altering antiplatelet therapy based on PFT would reduce adverse events. Small randomized and non-randomized studies demonstrated a reduction in ischemic events when P2Y 12 inhibitor therapy was modified if PFT indicated HPR (guided therapy) [6,7]. However, larger randomized controlled trials, using different PFT methods and different therapeutic strategies, demonstrated no improved outcome with vs. without guided therapy [8][9][10][11]. PFT has also been proposed as a means to determine when platelet function has recovered sufficiently to enable surgery with minimum risk of bleeding following P2Y 12 inhibitor withdrawal [12] and more recently to guide de-escalation therapy in ACS patients treated with PCI [13]. Goals of this position statement are to provide expert opinion on the utility of laboratory monitoring of P2Y 12 inhibitors to reduce ischemic and bleeding events in patients on DAPT and to guide timing of surgery if needed in P2Y 12 inhibitor-treated patients.Clopidogrel is a second-generation (after ticlopidine) thienopyridine oral antiplatelet drug that inhibits ADPinduced platelet aggregation and decreases major adverse cardiovascular events (MACE) when combined with aspirin, compared to aspirin alone [1]. Clopidogrel requires conversion by cytochrome P450 (CYP) enzymes to an active metabolite (CAM), which irreversibly inhibits platelet P2Y 12 [14].CYP gene variants influence production of CAM and the pharmacodynamic response to the drug [15]. Loss of function alleles leading to reduced generation of CAM (e.g. CYP2C19*2) have been associated with poor clinical outcomes [16,17], leading the Food and Drug Administration to issue a boxed warning advising that clopidogrel's effectiveness may be diminished in CYP2C19*2 carriers. Although CYP2C19 variants account for more than 10% of the variability in response to clopidogrel, other factors may contribute to most of the variation, including non-adherence, under-dosing, poor absorption, co-medications (atorvastatin, proton pump inhibitors and calcium antagonists), accelerated platelet turnover, inflammation and...