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Increased platelet activity is a risk factor of thrombotic events in cardiovascular patients. We studied the relationship between platelet function, platelet size, and the content of reticulated platelets (RP) in patients with coronary heart disease (CHD, n = 55) and acute coronary syndrome (ACS, n = 95) receiving acetylsalicylic acid + clopidogrel or ticagrelor, respectively. The control group consisted of patients with risk factors for CHD, but with no CHD/ACS and free of antiplatelet drugs (n = 66). Platelet function was evaluated by the exposure of activated glycoprotein (GP) IIb-IIIa and P-selectin. In the control group, platelets were activated by TRAP (Thrombin Receptor Activating Peptide) 10 µM, and ADP 20, 5, 2.5 µM, and in the CHD/ACS groups, by TRAP 10 µM, and ADP 20 5 µM (±epinephrine 20 µM). Platelet size was assessed by the mean volume, % large forms, and forward scattering. RP were stained by thiazole orange. In the control group, activated GP IIb-IIIa and P-selectin correlated with platelet size and RP content after platelet activation by all agonists. Despite the decrease in platelet activity by antiplatelet drugs, most correlations (primarily for activated GP IIb-IIIa) were preserved in the CHD/ACS patients. In conclusion, increased platelet size and RP content are associated with increased platelet activity and the reduced efficacy of antiplatelet therapy.

Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Echeverría et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Platelet functional activity was assessed in healthy volunteers (HV, n=92), patients with stable angina pectoris (SA, n=42) and acute coronary syndrome (ACS, n=73), treated with acetylsalicylic acid (ASA) + clopidogrel and ASA + ticagrelor, respectively. In all HV and patients we have compared parameters of platelet aggregation (maximum light transmission and velocity, Tmax and Vmax) and parameters, characterizing exposure of platelet activation markers, evaluated by flow cytometry. HV platelets were activated by 10 μM, 1 μM TRAP, and 20 μM, 5 μM, 2.5 μM ADP; patient platelets were activated by 10 μM TRAP and by 20 μM and 5 μM ADP. Strong and significant correlations between the aggregation and flow cytometry parameters (the r correlation coefficient from 0.4 up to >0.6) most frequently were registered in HV platelet during activation by 1 μM TRAP and in SA patients during platelet activation by 20 μM and 5 μM ADP. However, in many other cases these correlations were rather weak (r < 0.3) and sometimes statistically insignificant. In HV the differences in PAC-1 binding parameters between platelets activated by 10 μM TRAP (the strongest agonist) and all ADP concentrations were negligible (≤ 10%), while CD62P binding (at all ADP concentrations) and LTA parameters for (5 μM and 2.5 μM ADP) were significantly lower (by 40-60%). Antiplatelet therapy in patients decreased all parameters as compared to HV, but to varying extents. For 10 μM TRAP the MFI index for PAC-1 binding (40-50% decrease) and for both ADP concentrations the Tmax values (60-85% decrease) appeared to be the most sensitive in comparison with the other parameters that decreased to a lesser extent. The data obtained indicate a possibility of inconsistency between different LTA and flow cytometry parameters in assessing platelet activity and efficacy of antiplatelet drugs.

Background: The Platelet function analyzer-200 (PFA-200) can determine the effect of clopidogrel in cats, but analysis traditionally must be performed at point-of-care (POC). The ability to ship samples of blood to a laboratory would allow widespread access., Objectives: We aimed to validate the shipping of blood samples for PFA-200 analysis in cats to determine the effect of clopidogrel., Methods: Twenty healthy cats and 10 cats receiving clopidogrel were recruited. Blood was collected from cats and aliquoted into two samples, one was analyzed at POC within 2 hours using the PFA-200, and the other was packaged and transported to a location 4 km away, stored, and transported back to the lab for analysis the following day., Results: Median closure times (CTs) with the collagen/adenosine diphosphate (COL/ADP) cartridge in healthy cats were 51.5 seconds (POC) and 78.8 seconds (shipped), which were significantly different (P < 0.001), and for cats on clopidogrel, median CTs were 147.5 seconds (POC) and 190 seconds (shipped), which were not significantly different (P = 0.131). Median CTs with the P2Y cartridge in healthy cats were 50.5 seconds (POC) and 64.9 seconds (shipped), which were significantly different (P = 0.03), and in cats receiving clopidogrel, median CTs were 300 seconds (POC) and 300 seconds (shipped) which were not significantly different (P = 1.000). Reference intervals for CTs differed for COL/ADP at POC (19.8-89.7 seconds) and shipped (50.9-161.6 seconds) and for P2Y at POC (35.5-118.8 seconds) and shipped (35.1-108.9 seconds). Receiver operating characteristics showed similar areas under the curve (AUCROCs) regarding the effect of clopidogrel for COL/ADP at POC (0.994 seconds) and shipped (0.932) and for P2Y at POC (0.904 seconds) and shipped (0.975 seconds). When classifying for the presence of clopidogrel effects, Cohen's Kappa was 0.62 for COL/ADP and 1.00 for P2Y., Conclusions: Shipping blood samples for PFA analysis are feasible with similar performance to POC analyses for determining the effect of clopidogrel in cats., (© 2023 The Authors. Veterinary Clinical Pathology published by Wiley Periodicals LLC on behalf of the American Society for Veterinary Clinical Pathology.)

The Platelet Function Analyzer 200 (PFA-200; Siemens) is an in vitro substitute for in vivo bleeding time that is designed to investigate platelet function in a more physiologic manner than traditional aggregometry. The analyzer reports a closure time (CT) as a marker of platelet function, and may also report the calculated platelet function measurement primary hemostasis components, PHC1 and PHC2. These incorporate the measured total volume (TV) of blood aspirated and the initial flow rate (IF). We determined, for the COL/ADP and P2Y cartridges, the median total volume (TV median ), and RIs for CT, IF, TV, PHC1, and PHC2, and investigated the sensitivity and specificity of those parameters at the determined interpretation thresholds in determination of the clopidogrel effect. Healthy client-owned cats were recruited prospectively to determine RIs for CT, IF, TV, PHC1, and PHC2. Healthy blood-donor cats and cats on clopidogrel therapy were included retrospectively to determine test performance. In 20 healthy cats, RIs for COL/ADP were CT (19.5-87.2 s), IF (199-278 µL/min), TV (199-332 µL), PHC1 (94-106%), and PHC2 (52-148%); and for P2Y, CT (4.2-94.3 s), IF (112-208 µL/min), TV (151-294 µL), PHC1 (35-178%), and PHC2 (90-109%). CVs were calculated for all of these values. Specificity for detection of the clopidogrel effect was calculated from a group of healthy blood donors, and sensitivity for detection of the clopidogrel effect from a group of cats with known clopidogrel effect. Sensitivity and specificity were, for COL/ADP: CT (83.3%, 66.6%), IF (41.4%, 83.3%), TV (83.3%, 100%), PHC1 (100%, 100%) and PHC2 (100%, 83.3%); and for P2Y: CT (100%, 94.4%), IF (30%, 44.4%), TV (100%, 94.4%), PHC1 (100%, 100%), and PHC2 (100%, 97.7%). These PFA-200 values may be beneficial in the determination of platelet function in cats., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To precisely prevent stroke, we evaluated three platelet function tests and their associations with clinical outcomes in ischemic stroke patients., Methods: On-treatment platelet reactivity of acute minor stroke patients taking aspirin plus clopidogrel was tested by light transmittance aggregometry (LTA), thromboelastography (TEG) and platelet function analyzer (PFA). Mann-Whitney U tests and receiver operating characteristic (ROC) curve analysis were used to assess their associations with recurrent events and clinical outcome prediction., Results: 127 acute minor stroke patients were stringently selected and followed for 13 months. Eight patients (6.3%) self-reported the recurrence and 13 (10.2%) patients self-reported bleeding. Recurrent patients displayed significantly higher on-treatment platelet reactivity when measured with LTA ( p = 0.030) and PFA ( p < 0.001). Further ROC analysis demonstrated that LTA and PFA had modest-to-fair ability to predict stroke recurrence (LTA: area under the curve [AUC], 0.765; 95% CI, 0.584-0.945, PFA: AUC, 0.832; 95% CI, 0.658-1.000). However, TEG (measured by the platelet inhibition rate) could not detect the difference between recurrent patients and non-recurrent patients ( p = 0.515) and predict recurrent events (AUC, 0.569; 95% CI, 0.368-0.770). None of the tests were associated with bleeding except for PFA ( p < 0.001), with AUC of PFA reaching 0.772 (0.726-0.818)., Conclusions: Of the three tests assessed, the predictive accuracies of PFA and LTA were satisfying for aspirin secondary prevention, while TEG's performance was poor. Only PFA could provide accurate prognostic information for bleeding.

Background and Purpose: Overweight or obese patients exhibit poorer platelet responses to clopidogrel. However, the mechanisms behind this phenotype remain to be elucidated. Here, we sought to discover whether and why obesity could affect the metabolic activation of and/or platelet response to clopidogrel in obese patients and high-fat diet-induced obese mice., Experimental Approach: A post hoc stratified analysis of an observational clinical study was performed to investigate changes in residual platelet reactivity with increasing body weight in patients taking clopidogrel. Furthermore, high-fat diet-induced obese mice were used to reveal alterations in systemic exposure of clopidogrel thiol active metabolite H4, ADP-induced platelet activation and aggregation, the expression of genes involved in the metabolic activation of clopidogrel, count of circulating reticulated and mature platelets, and proliferation profiles of megakaryocytes in bone marrow. The relevant genes and potential signalling pathways were predicted and enriched according to the GEO datasets available from obese patients., Key Results: Obese patients exhibited significantly attenuated antiplatelet effects of clopidogrel. In diet-induced obese mice, systemic exposure of clopidogrel active metabolite H4 was reduced but that of its hydrolytic metabolite was increased due to down-regulation of certain P450s but up-regulation of carboxylesterase-1 in the liver. Moreover, enhanced proliferation of megakaryocytes and elevated platelet count also contributed., Conclusion and Implications: Obesity attenuated metabolic activation of clopidogrel and increased counts of circulating reticulated and mature platelets, leading to impaired platelet responsiveness to the drug in mice, suggesting that clopidogrel dosage may need to be adjusted adequately in overweight or obese patients., (© 2021 The British Pharmacological Society.)

Aim: Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in a background of chronic liver disease and prolonged inflammation. A major contributor in the complex molecular pathogenesis of HCC is the highly intertwined cross-talk between the tumor and the surrounding stromal cells, such as hepatic stellate cells, endothelial cells, macrophages and other immune cells. These tumor-stroma interactions actively fuel tumor growth and modulate the hepatic microenvironment to benefit tumor invasion and disease progression. Platelets have been reported to interact with different cell types in the tumor microenvironment, including tumor cells, stellate cells and macrophages., Materials and Methods: Mice were treated with hepatocarcinogenic compound diethylnitrosamine for 25 weeks to induce HCC in the background of fibrosis and inflammation. From week 10, anti-platelet drug Clopidogrel was added to the drinking water and mice were given ad libitum access., Key Findings: In this study, we show that activated platelets promote tumor cell proliferation and contribute to the adverse tumor-stroma cross-talk that fuels tumor progression. We also show that inhibiting platelet activation with the P2Y12-inhibitor Clopidogrel decreases the number of tumors in a chemically induced mouse model for HCC., Significance: These results suggest an important role for platelets in the pathogenesis of HCC and that the use of anti-platelet drugs may be therapeutically relevant for patients with liver cancer., (Copyright © 2021. Published by Elsevier Inc.)

Dual antiplatelet therapy (DAPT) is standard in acute coronary syndrome but confers a bleeding risk. To compare effects of clopidogrel single antiplatelet therapy (SAPT) with clopidogrel-based DAPT on hemostatic system activation we conducted a randomized clinical trial in 44 volunteers (clopidogrel (d1: 600 mg, d2-6: 150 mg) ± aspirin (100 mg)). Multiple electrode aggregometry-adenosine diphosphate (MEA-ADP) and MEA-arachidonic acid (MEA-AA) triggered aggregometry, vasodilator-stimulated phosphoprotein (VASP), beta thromboglobulin, p-selectin, thromboxane B 2 , d-Dimer, prothrombin fragment 1.2 (f1.2), and a phospholipid-dependent clotting time were measured in venous blood. Changes are described by mean differences (Δmean (95% confidence interval (CI)) or geometric mean ratios (95% CI)). DAPT and SAPT comparably and significantly decreased MEA-ADP at 2 hours (-60% vs. -63%; P = 0.35, Δmean -4.9, 95% CI -15.4 to 5.5). At 24 hours (-59% vs. -47%, P = 0.04, Δmean -11.1, 95% CI -21.7 to -0.4]) and 8 days (-61% vs. -53%, P = 0.04, Δmean -11.3, 95% CI -22.0 to -0.6). Both treatments significantly reduced VASP and MEA-AA after 2 hours and 8 days. DAPT inhibited MEA-AA significantly stronger at 2 hours (-77% vs. -30%; P < 0.0001, Δmean -39.6, 95% CI -54.2 to -25.0), at 24 hours (-80% vs. -27%, P < 0.0001, Δmean -47.8, 95% CI -62.3 to -33.3), and 8 days (-79% vs. -27%, P < 0.0001, Δmean -48.9, 95% CI -62.5 to -35.4). Neither treatment significantly influenced beta thromboglobulin or p-selectin. DAPT abolished and SAPT reduced thromboxane B 2 after 24 hours and 8 days. The d-Dimer was reduced by DAPT (0.94, 95% CI 0.89-1.00, P = 0.04) at 2 hours but not after 24 hours and 8 days. SAPT did not decrease d-Dimer. Neither treatment affected f1.2. DAPT and SAPT comparably affect platelet and coagulation activation in venous blood., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Trimethylamine-N-oxide (TMAO) can activate platelets and increase thrombosis risk in clinical and experimental models. Meanwhile, the patients with coronary artery disease have higher serum TMAO level. However, it remains unknown whether Clopidogrel Resistance (CR) could be attributed to TMAO. The present study aimed investigate the effects of TMAO on clopidogrel in ischemia and reperfusion (IR) model in rats. Clopidogrel could (1) promote the production of platelets, induce an increase in the platelet-larger cell ratio; (2) prolong the tail bleeding time; (3) reduce platelet aggregation function, induced by ADP, and alleviate myocardial thrombus burden. TMAO could partially offset the effects of clopidogrel and induce CR. Thus, the present study demonstrated that circulating TMAO could reduce the inhibitory effects of clopidogrel on platelet aggregation. TMAO may be a potential mediator of clopidogrel resistance.

Variability in P-glycoprotein (P-gp) efflux transporting activity was supposed to be involved in altered intestinal absorption and bioavailability of clopidogrel in patients; however, reliable evidence is still lacking. In this study, we sought to determine whether P-gp could play an important role in the metabolic activation of and platelet response to clopidogrel in mice. Abcb1a/1b knock-out (KO) and wild-type (WT) mice were used to evaluate differences in the intracellular accumulation of clopidogrel in the intestine, liver, and brain tissues and in systemic exposure of clopidogrel and its main metabolites as well as the mechanisms involved. Results indicated that, compared with WT mice, KO mice exhibited an 84% increase in systemic exposure of clopidogrel active thiol metabolite H4 and a 14.5% rise of suppression of ADP-induced platelet integrin αIIbβ3 activation, paralleled by a 41% decrease in systemic exposure of clopidogrel due to enhanced systemic clearance. Furthermore, KO mice displayed a 45% increase in Cyp3a11 but a 23% decrease in Ces1 at their protein levels compared with WT mice. Concurrently, intracellular clopidogrel concentrations in the tissues examined did not differ significantly between KO and WT mice. We conclude that although P-gp does not transport clopidogrel and its major metabolites in mice, P-gp-deficient mice exhibit elevated formation of the active metabolite H4 and enhanced antiplatelet effect of clopidogrel through up-regulation of Cyp3a11 and down-regulation of Ces1, suggesting that P-gp activity may correlate inversely with the formation of H4 and antiplatelet efficacy of clopidogrel in clinical settings due to P-gp and CYP3A4 interplay., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The present study compared performances of the three major methods used for assessing platelet reactivity (PR)-VerifyNow, light transmission aggregometry (LTA) and thromboelastography (TEG)-to predict ischaemic events in patients receiving clopidogrel. PubMed, EMBASE and the Cochrane Library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices include sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA and TEG, respectively. A total of 26 prospective studies involving 22 185 patients were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67-0.75) for VerifyNow, 0.60 (95% CI: 0.55-0.64) for LTA and 0.81 (95% CI: 0.77-0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08-1.30) and lower than that of TEG (0.88, 95% CI: 0.82-0.94). TEG outperformed the other two methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR and NLR. Despite a lack of studies that directly compared the three methods, our findings suggest that TEG should be recommended., (© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Glucocorticoids cause hypercoagulability, but it is unknown if they counteract clopidogrel's antiplatelet effects., Hypothesis/objectives: Determine the effects of clopidogrel and prednisone on platelet function., Animals: Twenty-four healthy dogs., Methods: Double-blinded, placebo-controlled randomized trial. Platelet function was evaluated using a platelet function analyzer and impedance aggregometry (days 0, 14, and 28) for dogs treated with placebo, clopidogrel (2-3 mg/kg/d), prednisone (2 mg/kg/d), or prednisone with clopidogrel PO for 28 days. Results were categorized as nonresponder versus responder (platelet function analyzer), and inadequate, ideal, or excessive response (aggregometry). Results were compared using mixed model, split-plot repeated measures analysis of variance and generalized estimating equation proportional odds models. P < .05 was considered significant., Results: Closure times differed by treatment (F [3, 20] = 10.5; P < .001), time (F [2, 40] = 14.3; P < .001), and treatment-by-time (F [6, 40] = 3.4; P = .01). Area under the curve (AUC) differed by treatment (F [3, 20] = 19.6; P < .001), time (F [2, 40] = 35.4; P < .001), and treatment-by-time (F [6, 40] = 13.5; P < .001). Based on closure times, 5/6 dogs each in the clopidogrel and prednisone/clopidogrel groups were responders. All dogs in the prednisone/clopidogrel group were overcontrolled based on AUC (days 14 and 28), whereas 5/6 (day 14) and 2/6 (day 28) dogs treated with clopidogrel were overcontrolled. Compared to clopidogrel, dogs receiving prednisone/clopidogrel were 11 times (P = .03) more likely to have an excessive response., Conclusions and Clinical Importance: Administration of clopidogrel/prednisone increases platelet dysfunction in healthy dogs., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Although thrombelastography (TEG) has been widely implemented in the clinical setting of endovascular intervention, consensus on the optimal parameter for defining high ischemic risk patients is lacking due to the limited data about the relationship between various TEG parameters and clinical outcomes. In this article, we report a post hoc analysis of a prospective, single-center cohort study, including 447 patients with acute coronary syndrome (ACS). Arachidonic acid (AA)- or adenosine diphosphate (ADP)-induced platelet-fibrin clot strength (MA AA or MA ADP ) was indicative of the net residual platelet reactivity after the treatment with aspirin or clopidogrel, respectively. AA% or ADP% was indices of the relative platelet inhibition rate on AA or ADP pathway. We found that each parameter alone was predictive of the risk of 6-month ischemic event, even after adjusting for confounding factors. However, the association between AA% and clinical outcome disappeared when further adjusted for MA AA . Likewise, inclusion of MA ADP changed the significant relation between ADP% and clinical outcome. MA ADP  > 47.0 mm and MA AA  > 15.1 mm were identified as the optimal cutoffs by receiver operating characteristic analysis. High MA AA (HR = 3.963; 95% CI: 1.152-13.632; P = 0.029) and high MA ADP (HR = 5.185; 95% CI: 2.228-12.062; P < 0.001) were independent predictors when both were included in multivariable Cox regression hazards model. Interestingly, an even higher risk was found for the coexisting high MA AA and high MA ADP (HR = 7.870; 95% CI: 3.462-17.899; P < 0.001). We conclude that when performing TEG to predict clinical efficacy, residual platelet reactivity has superiority over platelet inhibition rate as a measure of thrombotic risk in patients treated with aspirin and clopidogrel after ACS.

Purpose: Drugs inhibiting the platelet P2Y 12 receptor, such as clopidogrel and prasugrel, are potent antithrombotic agents and are widely used in cardiovascular disease. However, the adverse effects of these drugs have limited their clinical use. For example, clopidogrel resistance occurs in approximately one third of patients, while prasugrel increases the risk of major bleeding. Therefore, new generations of such drugs are of clinical interest., Methods: In this study, the pharmacodynamics of a new P2Y 12 antagonist, CN-218, was compared with that of clopidogrel and prasugrel in rats and mice. The differences between CN-218 and clopidogrel include deuteration of the 7-position methyl carboxylate and the introduction of cinnamate in the 2-position of thiophene., Results: CN-218 had an antiaggregatory efficacy that was at least five times more potent than that of clopidogrel but not as potent as that of prasugrel. It had a significant impact on activated partial thromboplastin time (APTT), whereby the APTT of CN-218-treated rats was approximately 9 s longer than that of the vehicle- or clopidogrel-treated group, while it had no impact on prothrombin time (PT) in rats. CN-218 had a similar potent antithrombotic effect to that of prasugrel and clopidogrel and also reduced the risk of bleeding compared to prasugrel., Conclusion: CN-218 may be a promising antithrombotic agent, with potent antiplatelet and significant anticoagulant activity, as well as a lower risk of bleeding compared to clopidogrel and prasugrel.

Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its influence on platelet ADP-P2Y12 receptor inhibitors lack consistency. Thus, we conducted a systematic review and meta-analysis of already existing data/studies to further explore this issue. PubMed, Web of science, EMBASE, Clinical Trials, and the Cochrane Library were searched from inception to March 2018. Studies investigating the residual platelet reactivity categorized by smoking status and patients treated with platelet ADP-P2Y12 receptor inhibitors qualified the inclusion criteria. The primary outcome was P2Y12 reaction unit (PRU) value measured by VerifyNow P2Y12 assay, compared with different smoking status in ADP-P2Y12 receptor inhibitors treatment groups. Secondary outcome was post-treatment with 5 μmol/L ADP-inhibition of platelet aggregation (ADP-IPA) measured by light transmittance aggregometry (LTA). Of the 4954 citations retrieved, 12 studies involving 16 296 patients with acute coronary syndrome and/or stent deployment using platelet ADP-P2Y12 receptor inhibitors were included for meta-analysis. Pooled analysis revealed that PRU values of current smokers were 25.70 lower than nonsmokers (95% CI -38.81 to -12.60, p = 0.0001), getting better effects of antiplatelet treatment. In the smoking extent subgroup analysis, patients smoking >10 cigarettes/day shown about 46.49 lower of PRU values than patients smoking <10 cigarettes/day ( p < 0.00001). Racial subgroup analyses found that smokers had increased platelet inhibition in the Caucasian population. Further, pooled analysis of ADP-IPA values for 1658 patients from five studies showed a significantly lower residual platelet reactivity in current smokers compared to that in nonsmokers (MD = -4.19; 95% CI -6.55 to -1.83; p = 0.0005). This systematic review and meta-analysis suggested that smokers have increased platelet inhibition and lower aggregation in response to clopidogrel than nonsmokers. These residual platelet reactivity observations may help to explain differential clinical outcomes in smokers vs. nonsmokers in large scale clinical trials.

Cardiovascular diseases, including acute coronary syndromes, are a major cause of death among tobacco smokers. Epidemiological studies have demonstrated that long‑term prognosis is worse in smokers with acute coronary syndromes than in nonsmokers. However, some studies have suggested that clopidogrel‑treated active smokers have better in‑hospital and short‑term follow‑up outcomes, a phenomenon regarded as the smoker's paradox. The smoker's paradox may be due to enhanced platelet response to clopidogrel therapy in active smokers as compared with nonsmokers caused by hepatic cytochrome P450 activation resulting in an increased generation of clopidogrel active metabolite. Another paradox has been reported after smoking cessation. Smoking cessation in clopidogrel‑treated patients after percutaneous coronary intervention is associated with increased platelet reactivity and a greater risk of high platelet reactivity. The smoking cessation paradox may increase the risk of thrombotic complications in patients treated with clopidogrel. More potent P2Y12 inhibitors may be considered in selected patients who stopped smoking after percutaneous coronary intervention. Further studies are required to determine the optimal antiplatelet strategy for stented patients who effectively quit smoking during clopidogrel treatment. The aim of this review is to discuss the risk of smoking and the potential elevated thrombotic risk related to smoking cessation.

There are clinical scenarios where the balance between the risk of ischemic and bleeding events leads to the clinical decision to reverse the antiplatelet effect of P2Y 12 receptor inhibitors. These scenarios comprise emergency situations such as active severe bleeding, urgent procedures with presumed high bleeding risk, or major trauma with (anticipated) bleeding. Supplementation of platelets has been investigated in ex vivo as well as in in vivo studies. These studies indicate that the inhibition of adenosine diphosphate-induced aggregation by the irreversibly binding thienopyridine derivatives clopidogrel and prasugrel can be reversed by administration of platelet concentrates. Supplementation of platelets in patients on prasugrel is more effective if this can be transfused > 6 hours after last dosing. Studies on the reversal effect obtained by administration of platelet concentrates in patients on ticagrelor show conflicting results. Experimental data suggest that administration of serum albumin might increase the reversal effect. A monoclonal antibody fragment (PB2452) for neutralizing ticagrelor is currently in clinical development. A recently published first in man study shows that reversal of platelet inhibition occurs within 5 minutes after start of administration and the effect is maintained for 20 to 24 hours after a 16-hour infusion which is by far the most effective approach for reversal of ticagrelor., Competing Interests: D.T. reports lecture fees from Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi and fees for advisory board activities from Bayer, Boehringer Ingelheim, and Daiichi Sankyo. D.A. reports lecture fees from Astra Zeneca, Bayer, Boehringer Ingelheim, Pfizer, and MSD Pharma. K.S. reports personal fees from Bayer. D.S. reports grants and personal fees from Sanofi Aventis, Roche Diagnostics, and Daiichi Sankyo; personal fees from Bayer, Pfizer, and Haemonetics S.A. All the other authors have no conflict of interest to declare., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: High on-treatment platelet reactivity (HTPR) has been suggested as a risk factor for patients with ischemic vascular disease. We explored a predictive model of platelet reactivity to clopidogrel and the relationship with clinical outcomes., Methods: A total of 441 patients were included. Platelet reactivity was measured by light transmittance aggregometry after receiving dual antiplatelet therapy. HTPR was defined by the consensus cutoff of maximal platelet aggregation >46% by light transmittance aggregometry. CYP2C19 loss-of-function polymorphisms were identified by DNA microarray analysis. The data were compared by binary logistic regression to find the risk factors. The primary endpoint was major adverse clinical events (MACEs), and patients were followed for a median time of 29 months. Survival curves were constructed with Kaplan-Meier estimates and compared by log-rank tests between the patients with HTPR and non-HTPR., Results: The rate of HTPR was 17.2%. Logistic regression identified the following predictors of HTPR: age, therapy regimen, body mass index, diabetes history, CYP2C192, or CYP2C193 variant. The area under the curve of receiver operating characteristic for the HTPR predictive model was 0.793 (95% confidence interval: 0.738-0.848). Kaplan-Meier analysis showed that patients with HTPR had a higher incidence of MACE than those with non-HTPR (21.1% vs. 9.9%; χ = 7.572, P = 0.010)., Conclusions: Our results suggest that advanced age, higher body mass index, treatment with regular dual antiplatelet therapy, diabetes, and CYP2C192 or CYP2C193 carriers are significantly associated with HTPR to clopidogrel. The predictive model of HTPR has useful discrimination and good calibration and may predict long-term MACE.

Objectives: This study was to evaluate platelet reactivity over time among patients with chronic kidney disease (CKD) receiving standard dose of clopidogrel after percutaneous coronary intervention (PCI). The effect of CYP2C19 loss-of-function genotypes on platelet reactivity was also determined., Methods: Patients with CKD (n = 138) on maintenance dose of clopidogrel after PCI were enrolled. Platelet reactivity was assessed by measuring P2Y 12 reaction units (PRU) with VerifyNow P2Y 12 assay, and platelet reactivity index (PRI) with flow cytometric using vasodilator-stimulated phosphoprotein (VASP) at baseline and 2 weeks later, respectively. The genotypes of CYP2C19 were also measured concurrently., Results: The proportion of patients with high platelet reactivity (HPR) ranged from 23.2% to 59.4%, and almost 1 in 5 patients had a dual conversion between HPR and non-HPR status. Patients carrying CYP2C19 loss-of-function genotypes showed a higher platelet reactivity than non-carriers, but with an undetermined HPR status between the first and second visits. The individual switch of HPR to non-HPR status existed in both loss-of-function genotype carriers and non-carriers., Conclusions: HPR conversions occur in a significant proportion of CKD patients with maintenance doses of clopidogrel treatment post-PCI, and this conversion was not confined to CYP2C19 loss-of-function genotype carriers. Risk stratification for treatment adjustment in personalized antiplatelet therapy should be investigated in future research., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Platelet activation contributes to organs failure in inflammation and plays an important role in endotoxemia. Clopidogrel inhibits platelet aggregation and activation. However, the role of clopidogrel in modulating inflammatory progression of endotoxemia remains largely unexplored. Therefore, we investigated the role of clopidogrel on the activation of platelet and leukocytes in lipopolysaccharide (LPS)-induced inflammation in mice. Animals were treated with clopidogrel or vehicle before LPS induction. The expression of neutrophil-platelet aggregates and platelet activation and tissue factor was determined. Immunofluorescence was used to analyze platelet-leukocyte interactions and tissue factor (TF) expression on leukocytes. Clopidogrel pretreatment markedly decreased lung damage, inhibited platelet-neutrophil aggregates and TF expression. In addition, clopidogrel reduced thrombocytopenia and affected the number of circulating white blood cell in endotoxemia mice. Moreover, clopidogrel also reduced platelet shedding of CD40L and CD62P in endotoxemic mice. Taken together, clopidogrel played an important role through reducing platelet activation and inflammatory process in endotoxemia., (© 2018 Wiley Periodicals, Inc.)

Previous studies have reported that various factors affect ADP-induced platelet reactivity during clopidogrel therapy. The aim of this study was to determine whether clinical and laboratory variables for platelet reactivity during dual antiplatelet therapy (DAPT) are dependent on the assay used. We enrolled 904 patients receiving DAPT following coronary intervention. Platelet reactivity was measured using three methods: the VerifyNow P2Y12 assay, multiple electrode aggregometry (MEA) ADP assay, and the light transmittance aggregometry (LTA) ADP assay at 24-48 h following coronary intervention. The VerifyNow results demonstrated a significant inverse correlation with hematocrit value (r = -0.268, p < 0.0001); however, MEA results had no such correlation with hematocrit (r = 0.044, p = 0.188). There was a positive correlation between the MEA results and platelet count (r = 0.255, p < 0.0001). LTA was weakly influenced by hematocrit (r = -0.064, p = 0.057) and platelet count (r = 0.069, p = 0.040). Gender (odds ratio 1.53, 95% CI 1.10-2.14, p = 0.013) and hematocrit (odds ratio 0.91,95% CI 0.88-0.94, p < 0.0001) were the independent variables for HPR by VerifyNow. Smoking (odds ratio 0.38, 95% CI 0.16-0.94, p = 0.036) and platelet count (odds ratio 1.01, 95% CI 1.00-1.01, p < 0.0001) were independent factors for HPR when using the MEA assay, whereas platelet count (odds ratio 1.00, 95% CI 1.00-1.01, p = 0.006) was identified as the only independent variable for HPR when using LTA. The incidence of HPR and the influencing variables involved are dependent on the platelet function test used.

CD34 + cells expressing KDR (CD34 + /KDR + ) represent a small proportion of circulating progenitor cells that have the capacity to interact with platelets and to differentiate into mature endothelial cells, thus contributing to vascular homeostasis and regeneration as well as to re-endothelialization. We investigated the levels of CD34 + and CD34 + /KDR + progenitor cells as well as their interaction with platelets in acute coronary syndrome (ACS) patients before the initiation (baseline) of their treatment with a P2Y 12 receptor antagonist, and at 5-days post-treatment (follow-up). Sixty-seven consecutive ACS patients and thirty healthy subjects (controls) participated in the study. On admission, all patients received 325 mg aspirin, followed by 100 mg/day and then were loaded either with 600 mg clopidogrel or 180 mg ticagrelor, followed by 75 mg/day (n = 36) or 90 mg × 2/day (n = 31), respectively. The levels of circulating CD34 + and CD34 + /KDR + progenitor cells, as well as their interaction with platelets, were determined by flow cytometry, before and after activation with ADP, in vitro. The circulating levels of CD34 + and CD34 + /KDR + cells in both patient groups at baseline were lower compared with controls while they were significantly increased at 5-days of follow-up in both groups, this increase being more pronounced in the ticagrelor group. The platelet/CD34 + (CD61 + /CD34 + ) conjugates were higher at baseline and reduced at follow-up while the platelet/KDR + (CD61 + /KDR + ) conjugates were lower at baseline and increased at follow-up, both changes being more pronounced in the ticagrelor group. ADP activation of control samples significantly increased the KDR expression by CD34 + cells and the CD61 + /KDR + conjugates, these parameters being unaffected in patients at baseline but increased at follow-up. Short-term dual antiplatelet therapy in ACS patients restores the low platelet/KDR + conjugates and CD34 + cell levels and improves the low membrane expression levels of KDR in these cells, an effect being more pronounced in ticagrelor-treated patients. This may represent a pleiotropic effect of antiplatelet therapy towards vascular endothelial regeneration.

Background: Elevated mean platelet volume (MPV) and immature platelet fraction (IPF) are predictive for vascular risk. Both can be associated with residual platelet reactivity. We aimed to explore associations among platelet characteristics and responder status in stroke patients on clopidogrel., Methods: Blood samples from 46 patients and 15 healthy subjects were analyzed for platelet count, MPV, IPF, large cell ratio (LCR) and high-fluorsecent immature platelet fraction (H-IPF). As a novelty, not only whole blood, but upper and lower half blood samples after 1-hour gravity sedimentation were analyzed. Platelet aggregometry was used for the whole blood and separated samples to explore area under the curve (AUC) in patients and controls., Results: The AUC of the whole blood showed significant differences compared to the upper and lower samples separated after 1-hour sedimentation in patients and controls (p < 0.001 and p = 0.005 respectively). Remarkably, AUC measured in the upper samples in 59% of patients on clopidogrel were exceeding the therapeutic range suggesting that ascending platelets exert aggregation in the presence of ADP. This observation was associated with increased MPV and LCR in the upper samples (both p = 0.04). Patients on clopidogrel were characterized as responders and non-responders and the percentage of H-IPF was significantly higher among non-responders compared to controls in the upper samples (p = 0.04)., Conclusions: The modified platelet function test may help to stratify patients with high residual platelet reactivity.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor is a mainstay of the prevention of stent thrombosis following percutaneous coronary intervention (PCI). In the 2015 European guidelines for the management of acute coronary syndrome (ACS), prasugrel (PRA) and ticagrelor (TICA) combined with aspirin are recommended as first-line therapy. Clopidogrel (CLO) is recommended as an alternative medication for patients with contradictions to these new drugs. This single-center study analyzed the platelet function of 809 ACS patients undergoing PCI and treatment with DAPT. The platelet response to ADP was determined using Multiplate® analyzer at a median of 3 days after PCI in 254 patients treated with PRA (loading dose [LD] 60 mg, 10 mg qd), 162 patients receiving TICA (LD 180 mg, D 90 mg bid), and 393 CLO-treated patients (LD 600 mg, 75 mg qd). An aggregation >468 arbitrary units (AU)*min was defined as "high on-treatment platelet reactivity" (HPR), <188 AU*min as "low on-treatment platelet reactivity" (LPR). Platelet response in PRA-treated patients was lower compared to CLO or TICA (median; interquartile range: PRA 220 [163-275] AU*min vs. CLO 268 [186-387] AU*min, p < 0.001 vs. TICA 245 [190-320] AU*min, p = 0.001). Only 1.6% of PRA patients were stratified as HPR and 34.6% as LPR, while in the TICA group 1.9% fulfilled the criteria of HPR and 24.1% criteria of LPR. Sixteen percent of CLO patients were stratified as HPR and 26.2% as LPR. In a real-world cohort of ACS patients following PCI, PRA results in more potent inhibition of platelet function compared to CLO and TICA. TICA achieves a consistent antiplatelet effect with reduced rates of HPR and LPR in relation to CLO.

Background Platelets play a role in promoting inflammatory responses under several disease conditions. Platelets are activated in hypertensive patients. However, the mechanisms responsible for platelet-mediating vascular inflammation are unknown. The present study investigated the role of platelets in promoting vascular inflammation following angiotensin II (Ang II ) stimulation, and the efficacy of antiplatelet intervention. Methods and Results Within a mouse model of Ang II infusion (490 ng/kg per min), we measured the portion of P-selectin-positive platelets and platelet-monocyte (P-M) binding in blood samples, and platelet accumulation and P-M binding in vessels under Ang II stimulation at days 1, 3, and 7. We tested the efficacy of clopidogrel (15 mg/kg per day, followed by 5 mg/kg per day) on Ang II -induced platelet activation, P-M binding, vascular platelet accumulation, as well as vascular inflammation and remodeling at day 7 or 14. Clopidogrel reduced platelet vascular deposition (28.7±2.4% versus 18.3±2.9%), suppressed inflammatory cell infiltration (3.6±0.8×10 4 /vessel versus 2.3±1.2×10 4 /vessel) and oxidative stress, and attenuated vascular remodeling and dysfunction (55.0±5.5% versus 84.0±6.0%) following Ang II stimulation at day 7 or 14. Clopidogrel suppressed Ang II -induced P-M binding both at circulating (13.4±3.3% versus 5.9±2.7%) and regional (33.4±4.3% versus 11.9±2.7%) levels. Conclusions Platelets play a critical role in vascular inflammation under Ang II stimulation, with a marked promotion of P-M binding as an important mechanism. Clopidogrel prevented vascular inflammation in Ang II -infused mice.

P2Y 12 receptor antagonists are a class of drugs that act on platelet P2Y 12 receptors and inhibit adenosine diphosphate-induced platelet aggregation. As a thienopyridine antiplatelet agent which is approved by the US Food and Drug Administration for the treatment of cardiovascular diseases, currently, clopidogrel was once considered to be the most safe and effective antiplatelet drug in the P2Y 12 receptor antagonists, however, it has become increasingly clear that clopidogrel does not satisfactorily inhibit the platelets of approximately one-third of patients. This is in part due to clopidogrel is a prodrug and reliance on multiple cytochrome P450 enzymes for conversion into its active metabolite. Prasugrel and ticagrelor reduces the risk of adverse cardiovascular events compared to clopidogrel in acute coronary syndromes patients, however, the cardiovascular benefit of both drugs is counter-balanced by increased rates of spontaneous bleeding. Unlike clopidogrel, which is a prodrug, cangrelor is an active drug not requiring metabolic conversion, despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as breathlessness. DV-127 was synthesized by using three generations of thienopyridine P2Y 12 receptor antagonists as research models, using high resolution mass spectrometry, selective deuteration, and 2,7-position replacement groups technologies in order to maximize cardiovascular benefit while minimizing adverse effects on hemostasis. Our results show that although the dose of DV-127 is greatly reduced, it can achieve similar anticoagulant and antiplatelet effects as clopidogrel, and DV-127 can more strongly inhibit the release of α-granules even though the inhibitory effect of dense granules is similar to clopidogrel., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Hepatitis B virus (HBV) infection has been reported to down-regulate the expression of CYP2C19 gene, which may decrease the bioactivation of clopidogrel into active metabolites. We aimed to evaluate the impact of HBV infection on platelet response to clopidogrel in patients undergoing coronary stent implantation., Methods: A total of 1805 patients who had received coronary stent implantation and taken aspirin 100 mg in combination with clopidogrel 75 mg daily ≥5 days were consecutively recruited. The serologic identifications for HBV, platelet aggregations in response to arachidonic acid (PL AA ) and adenosine diphosphate (PL ADP ), as well as ABCB1, CYP2C19, CYP3A5, PON1 and P2RY12 genotypes were determined. Clopidogrel low response (CLR) was defined as PL ADP  > 40%., Results: Among the recruited subjects, 102 patients showed hepatitis B surface antigen (HBsAg) positive and 1703 patients negative. PL ADP was significantly higher in HBsAg positive group than that in HBsAg negative group [38 (24-48) % vs. 29 (20-39) %, p < 0.001] while the difference of PL AA was not statistically significant (p = 0.329). The incidence of CLR was significantly higher in HBsAg positive group compared with that in HBsAg negative group (43.1% vs. 23.4%, p < 0.001). After adjusted for CYP2C19 genotype and known risk factors, HBsAg positive patients exhibited a significantly higher risk of CLR (adjusted odds ratio: 2.81, 95% confidence interval: 1.73 to 4.58, p < 0.001)., Conclusions: HBV infection is an independent risk factor of CLR, in addition to CYP2C19 gene mutations. (Pharmacogenetic and Pharmacokinetic Study of Clopidogrel; NCT01968499)., (Copyright © 2018. Published by Elsevier Ltd.)

Essentials Procoagulant platelets can be detected using GSAO in human whole blood. Stable coronary artery disease is associated with a heightened procoagulant platelet response. Agonist-induced procoagulant platelet response is not inhibited by aspirin alone. Collagen plus thrombin induced procoagulant platelet response is partially resistant to clopidogrel., Summary: Background Procoagulant platelets are a subset of highly activated platelets with a critical role in thrombin generation. Evaluation of their clinical utility in thrombotic disorders, such as coronary artery disease (CAD), has been thwarted by the lack of a sensitive and specific whole blood assay. Objectives We developed a novel assay, utilizing the cell death marker, GSAO [(4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid], and the platelet activation marker, P-selectin, to identify procoagulant platelets in whole blood by flow cytometry. Patients/Methods Using this assay, we characterized the procoagulant platelet population in healthy controls and a cohort of patients undergoing elective coronary angiography. Results In patients with CAD, compared with patients without CAD, there was a heightened procoagulant platelet response to thrombin (25.2% vs. 12.2%), adenosine diphosphate (ADP) (7.8% vs. 2.7%) and thrombin plus collagen (27.2% vs. 18.3%). The heightened procoagulant platelet potential in CAD patients was not associated with other markers of platelet function, including aggregation, dense granule release and activation of α 2b β 3 integrin. Although dual antiplatelet therapy (DAPT) was associated with partial suppression of procoagulant platelets, this inhibitory effect on a patient level could not be predicted by aggregation response to ADP and was not fully suppressed by clopidogrel. Conclusions We report for the first time that procoagulant platelets can be efficiently detected in a few microliters of whole blood using the cell death marker, GSAO, and the platelet activation marker, P-selectin. A heightened procoagulant platelet response may provide insight into the thrombotic risk of CAD and help identify a novel target for antiplatelet therapies in CAD., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity., Summary: Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8 + T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity., (© 2018 International Society on Thrombosis and Haemostasis.)

Background: Prasugrel has been shown to provide more potency and less variability than clopidogrel, but its potential temporal variability has not been described.Methods and Results:We conducted a prospective open-label study, evaluating platelet reactivity overtime in acute coronary syndrome (ACS) patients on aspirin and clopidogrel (n=60) or prasugrel (n=61), after a percutaneous coronary intervention (PCI). Blood samples were taken at discharge and at 3 and 6 months. Platelet function tests included VerifyNow (VN-P2Y12), and Multiplate Aggregometry (MEA). By means of VN-P2Y12, prasugrel patients displayed significantly (P<0.001) higher platelet inhibition than clopidogrel patients over time, although there were not significant differences using MEA. Prasugrel patients showed higher platelet inhibition at baseline than at 3 months (59.3±8.1 vs. 105.0±49.2; P<0.001), without significant change at 6 months (107.9±72.0; P=0.919 vs. 3 months). Clopidogrel patients showed a similar trend (160.1±65.1, 184.8±62.7 and 185.0±53.3; baseline vs. 3 months P=0.060; 3 months vs. 6 months P=0.974). High platelet reactivity (HPR) was shown in 16.3% prasugrel patients, with no patient consistently remaining in HPR over time. HPR was detected in 36.6% of the clopidogrel patients, being consistently observed in 15.0% of them. Low platelet reactivity (LPR) was detected in 60.5% prasugrel and 9.8% clopidogrel patients., Conclusions: Prasugrel patients showed less temporal variation than patients on clopidogrel in terms of HPR. In contrast, higher variability in LPR was detected in prasugrel patients for up to 6 months' follow-up.