Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy.

Background-The adenosine diphosphate (ADP) receptor P2Y 12 plays a pivotal role in platelet aggregation, as demonstrated by the benefit conferred by its blockade in patients with cardiovascular disease. Some studies have shown interindividual differences in ADP-induced platelet aggregation responses ex vivo, but the mechanisms underlying this variability are unknown. Methods and Results-We examined ADP-induced platelet aggregation responses in 98 healthy volunteers, and we identified 2 phenotypic groups of subjects with high and low responsiveness to 2 mol/L ADP. This prompted us to screen the recently identified G i -coupled ADP receptor gene P2Y 12 for sequence variations. Among the 5 frequent polymorphisms thus identified, 4 were in total linkage disequilibrium, determining haplotypes H1 and H2, with respective allelic frequencies of 0.86 and 0.14. The number of H2 alleles was associated with the maximal aggregation response to ADP in the overall study population (Pϭ0.007). Downregulation of the platelet cAMP concentration by ADP was more marked in 10 selected H2 carriers than in 10 noncarriers. Conclusions-In

The endothelial cell protein C (PC) receptor (EPCR) facilitates PC activation by the thrombin-thrombomodulin complex. A soluble form of this receptor (sEPCR) found in plasma inhibits both activated PC (aPC) activity and PC activation by competing for PC with membrane-associated EPCR. Elevated sEPCR levels are found in approximately 20% of healthy subjects, but the mechanisms underlying this interindividual variability are unknown. We measured sEPCR levels in 100 healthy male volunteers, and observed 2 phenotypic groups of subjects. The temporal stability of sEPCR levels suggested genetic control. Extensive analysis of the EPCR gene in these subjects revealed 13 polymorphisms in complete linkage disequilibrium; these defined 3 haplotypes, 1 of which (A3) was strongly associated with high sEPCR levels. The high constitutive sEPCR levels observed in A3 haplotype carriers might reduce the efficiency of the PC system and predispose these subjects to venous thrombosis. By studying 338 patients with venous thrombosis and 338 age- and sex-matched healthy subjects, we found that the A3 haplotype was overrepresented in the patients. In multivariate analysis, subjects carrying the A3 haplotype had an increased risk of thrombosis (odds ratio [OR] = 1.8; P = .004). Thus, the A3 haplotype, which is associated with elevated plasma sEPCR levels, is a candidate risk factor for venous thrombosis.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is however relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare.This manuscript highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration of MIPD in healthcare.Considerations are brought up herein that will need addressing to see MIPD become 'widespread clinical practice': amongst those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.This article is protected by copyright. All rights reserved. 4 PRELUDEThis article appears in the so called 'State of the Art' section of the journal. 'State of the Art' is often considered to be cutting edge and the highest level of development in a given area. However, coining something as 'State of the Art' is a subliminal admission to the fact that the subject area has not yet become 'popular'. This article is a culmination of discussions and debates between many key opinion leaders, beyond the authorship, on the issue of model-informed precision dosing (MIPD), and why it has remained and is treated as 'State of the Art' rather than being used as 'widespread' clinical practice. It is hoped that the report provides a roadmap to advance the position of MIPD to a common clinical practice under the umbrella of precision medicine.

To cite this article: Reny J-L, de Moerloose P, Dauzat M, Fontana P. Use of the PFA-100 TM closure time to predict cardiovascular events in aspirintreated cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 444-50.Summary. Background: PFA-100 TM is a point-of-care assay that evaluates platelet reactivity in high-shear-stress conditions by measuring the closure time (CT) of a membrane aperture. When determined with a collagen/epinephrine cartridge (CEPI), the CT is usually prolonged by aspirin. Studies of the predictive value of a short PFA-100 TM CT CEPI for ischemic events in aspirin-treated patients have given variable results. Objectives: To conduct a systematic review and metaanalysis of studies on the clinical predictive value of a short PFA-100 TM CT CEPI in aspirin-treated cardiovascular patients. Patients and methods: Relevant studies were identified by scanning electronic databases. Studies were selected if they included aspirin-treated patients with symptomatic atherosclerosis, measured the PFA-100 TM CT CEPI , used a CT cut-off value to define aspirin ÔrespondersÕ and Ônon-respondersÕ, and reported ischemic events. Results: We selected seven nonprospective studies (1466 patients) and eight prospective studies (1227 patients). In non-prospective studies, the PFA-100 TM CT CEPI was performed after the ischemic clinical endpoint, and a publication bias was identified. In prospective studies, the global odds ratio (OR) for the recurrence of an ischemic event in Ôaspirin non-respondersÕ relative to Ôaspirin respondersÕ was 2.1 [95% confidence interval (CI) 1.4-3.4, P < 0.001]. Pooled analysis with a random effect model revealed no heterogeneity (Q Cochran P = 0.36 and I 2 = 9.4%). Conclusions: A short PFA-100 TM CT CEPI is associated with increased recurrence of ischemic events in aspirintreated cardiovascular patients. This finding needs to be confirmed in stable ischemic patients, and the PFA-100 TM CT CEPI cut-off needs to be refined in these patients.

SwitzerlandTo cite this article: Combescure C, Fontana P, Mallouk N, Berdague P, Labruyere C, Barazer I, Gris JC, Laporte S, Fabbro-Peray P, Reny JL for the CLOVIS study group. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 923-33.

Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular cells, plays a key role in platelet activation. We examined the range of PAR-1 expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects and found a 2-fold interindividual variation in receptor numbers (95% CI 858-1700). Because PAR-1 density was stable with time (r 2 76%, P < .001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the 2 1 genotype according to receptor density and platelet mRNA expression data. We found that the number of PAR-1 receptors on the platelet surface is associated with the intervening sequence IVSn14 A/T intronic variation. The number of receptors was also found to govern the platelet response to the SFLLRN agonist, in terms of aggregation and P-selectin expression. The T allele (allelic frequency, 0.14) can be considered as an allele with decreased expression , because it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn14 A/T intronic variation may therefore be clinically relevant. (Blood.

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