P2RY1 and P2RY12 polymorphisms and on-aspirin platelet reactivity in patients with coronary artery disease.
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SUBMITTER: Timur AA
PROVIDER: S-EPMC3419334 | biostudies-literature | 2012 Oct
REPOSITORIES: biostudies-literature
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Project description:Previous studies have illustrated the link between high on-aspirin platelet reactivity (HAPR) with increasing thrombotic risks. The aim of our study was to investigate relative risk factors of HAPR in elderly patients with coronary artery disease.Elderly, hospitalized coronary artery disease patients on regular aspirin treatment were enrolled from January 2014 to September 2016. Medical records of each patient were collected, including demographic information, cardiovascular risk factors, concomitant drugs and routine biological parameters. Arachidonic acid (AA, 0.5 mg/mL) and adenosine diphosphate (ADP, 5 µmol/L) induced platelet aggregation were measured via light transmission assay (LTA) to evaluate antiplatelet responses, referred as LTA-AA and LTA-ADP.A total of 275 elderly patients were included, with mean age of 77.2±8.1 years, and males accounted for 81.8%. HAPR was defined as LTA-AA in the upper quartile of the enrolled population. HAPR patients tended to have lower renal function (P=0.052). Higher serum uric acid (SUA) level, as well as lower platelet count, hemoglobin and hematocrit were observed in HAPR patients, with a higher proportion of diuretics use (P<0.05). Multivariate analysis revealed that SUA (OR: 1.004, 95% CI: 1.000-1.007, P=0.048), platelet count (OR: 0.994, 95% CI: 0.989-1.000, P=0.045), hematocrit (OR: 0.921, 95% CI: 0.864-0.981, P=0.011) and concomitant P2Y12 receptor inhibitors use (OR: 1.965, 95% CI: 1.075-3.592, P=0.028) were correlated with HAPR. Spearman's correlation analysis demonstrated an inverse association of LTA-AA with hematocrit (r=-0.234, P<0.001), hemoglobin (r=-0.209, P<0.001) and estimated glomerular filtration rate (r=-0.132, P=0.031).SUA, platelet count, hematocrit and P2Y12 receptor inhibitors use were independently correlated with HAPR. These parameters might provide novel therapeutic targets for optimizing antiplatelet therapy.
| S-EPMC5557114 | biostudies-literature
Project description:Background:The mechanisms behind residual platelet reactivity (RPR) despite aspirin treatment are not established. It has been shown that coronary artery disease (CAD) patients with high on-aspirin RPR have elevated levels of von Willebrand factor (vWF). ADAMTS13 is a metalloprotease cleaving ultra large vWF multimers into less active fragments.Our aim was to investigate whether ADAMTS13 and vWF/ADAMTS13 ratio were associated with high RPR, and further with clinical endpoints after 2 years. Methods:Stable aspirin-treated CAD patients (n?=?999) from the ASCET trial. RPR was assessed by PFA-100. ADAMTS13 antigen and activity were analysed using chromogenic assays. Endpoints were a composite of acute myocardial infarction, stroke and death. Results:The number of patients with high RPR was 258 (25.8%). Their serum thromboxane B2 (TxB2) levels were low, indicating inhibition of COX-1. They had significantly lower levels of ADAMTS13 antigen compared to patients with low RPR (517 vs 544 ng/mL, p?=?0.001) and significantly lower ADAMTS13 activity (0.99 vs 1.04 IU/mL, p?=?0.020). The differences were more pronounced when relating RPR to ratios of vWF/ADAMTS13 antigen and vWF/ADAMTS13 activity (p?<?0.001, both). We found an inverse correlation between vWF and ADAMTS13 antigen (r?=?-0.14, p?<?0.001) and ADAMTS13 activity (r?=?-0.11, p?<?0.001). No correlations between TxB2 and ADAMTS13 antigen or activity, were observed, implying that ADAMTS13 is not involved in TxB2 production. Patients who experienced endpoints (n?=?73) had higher vWF level (113 vs 105%, p?=?0.032) and vWF/ADAMTS13 antigen ratio (0.23 vs 0.20, p?=?0.012) compared to patients without. When dichotomizing vWF/ADAMTS13 antigen at median level we observed that patients above median had higher risk for suffering endpoints, with an adjusted OR of 1.86 (95% CI 1.45, 2.82). Conclusion:These results indicate that ADAMTS13 is of importance for RPR, and that it in combination with vWF also is associated with clinical endpoints in stable CAD patients on aspirin. Trial registration:Clinicaltrials.gov NCT00222261. Registered 13.09.2005. Retrospectively registered.
| S-EPMC5700557 | biostudies-literature
Project description:Patients with stable coronary artery disease on single-antiplatelet therapy with aspirin are still at risk for atherothrombotic events, and high on-aspirin residual platelet reactivity (RPR) has been suggested as a risk factor.In this randomized trial, the association between platelet function determined by the PFA100 platelet function analyzer system (Siemens Healthcare Diagnostics, Germany) and clinical outcome in 1001 patients, all on single-antiplatelet therapy with aspirin (160 mg/d) was studied. Patients were randomized to continue with aspirin 160 mg/d or change to clopidogrel 75 mg/d. A composite end point of death, myocardial infarction, ischemic stroke, and unstable angina was used. At 2-year follow-up, 106 primary end points were registered. The prevalence of high RPR was 25.9%. High on-aspirin RPR did not significantly influence the primary end point in the aspirin group (13.3% versus 9.9%, P=0.31). However, in post hoc analysis, patients with von Willebrand factor levels or platelet count below median values and high on-aspirin RPR had a statistically significant higher end point rate than that of patients with low RPR (20% versus 7.5%, P=0.014, and 18.2% versus 10.8%, P=0.039, respectively). The composite end point rate in patients with high on-aspirin RPR treated with clopidogrel was not different from that of patients treated with aspirin (7.6% versus 13.3%, P=0.16).In stable, aspirin-treated patients with coronary artery disease, high on-aspirin RPR did not relate to clinical outcome and did not identify a group responsive to clopidogrel. Post hoc subgroup analysis raised the possibility that high on-aspirin RPR might be predictive in patients with low von Willebrand factor or platelet count, but these findings will require confirmation in future studies.URL: http://www.clinicaltrials.gov Unique identifier: NCT00222261. (J Am Heart Assoc. 2012;1:e000703 doi: 10.1161/JAHA.112.000703.).
| S-EPMC3487336 | biostudies-literature
Project description:AimsDepression and anxiety are linked to coronary events but the mechanism(s) remains unclear. We investigated the associations of depression and anxiety with serotonin-mediated platelet hyperactivity in coronary artery disease (CAD) patients in a cross-sectional study.Methods and resultsThree months after an acute coronary event, stable CAD patients (n = 83) on aspirin and clopidogrel were evaluated for depression (beck depression inventory) and anxiety (hospital anxiety and depression scale), and their platelet reactivity was measured (optical aggregometry and flow cytometric fibrinogen binding in response to adenosine diphosphate (ADP = 5 microM) and two serotonin + epinephrine doses [5HT:E (L) = 4 microM + 4 microM and 5HT:E (H) = 10 microM + 4 microM]. Platelet reactivity was significantly higher in depressed and anxious than in depressed only or non-depressed-and-non-anxious patients. Aggregation (mean +/- SE) was 41.9 +/- 2.6% vs. 32.2 +/- 2.6% vs. 30.4 +/- 3.7% with 5HT:E (L) and 46.9 +/- 2.7% vs. 35.6 +/- 2.7% vs. 31.7 +/- 3.8% with 5HT:E (H) (P < 0.05 for both). Differences in ADP aggregations were not significant, perhaps because of clopidogrel therapy. Flow cytometry findings were similar. In a multivariate linear regression model adjusted for age, body mass index, and each other, anxiety symptoms independently predicted all 5HT:E-mediated platelet reactivity measures, whereas depression predicted none.ConclusionAnxiety is associated with elevated serotonin-mediated platelet reactivity in stable CAD patients and symptoms of anxiety show strong, independent correlations with platelet function.
| S-EPMC2895160 | biostudies-literature
Project description:In patients with acute coronary syndrome, high platelet reactivity (PR) is associated with an increased risk of secondary thrombotic events. However, in patients undergoing elective percutaneous coronary intervention (PCI), no association between high PR and outcome has been demonstrated. At present, the relation of PR and clinical symptoms is unknown. To examine the association of PR with clinical indication for diagnostic angiography (stable or unstable coronary artery disease [CAD]), taking into account the influence of P2Y12 inhibitors. A platelet function score (PFS) was determined in 195 patients by quantifying fibrinogen binding and P-selectin expression with flow cytometry. We evaluated the PFS with clinical presentation of stable or unstable CAD, angiographic severity of CAD, and the incidence of cardiovascular events during 2 years of follow-up. All data were analyzed stratified by P2Y12 inhibitor use (long-term and preprocedural versus none). Surprisingly, among non-P2Y12 inhibitor users, the PFS was lower in patients with unstable CAD compared with stable CAD (5.6?±?1.8 vs. 7.4?±?1.6; p?=?0.001). Angiographic CAD severity showed no relation with PFS. The SYNTAX score tended to be inversely related with PFS: low PFS, 13.2 (IQR, 11.9-19.1); median PFS, 10.0 (IQR, 5.0-14.0); and high PFS, 8.0 (IQR, 5.0-13.0), without significance (p?=?0.304). Patients with low PFSs required more re-PCIs than those with median and high PFSs (11.1 vs. 4.7 vs. 0.0%, p?=?0.004). This association was modified for patients using P2Y12 inhibitors. Among patients without P2Y12 inhibitors undergoing coronary angiography, presentation of unstable CAD is independently associated with lower PR.
| S-EPMC5114132 | biostudies-literature
Project description:The purpose of this study was to determine if an incomplete response to or inadequate antiplatelet effect of aspirin, or both, contribute to saphenous vein graft (SVG) occlusion after coronary artery bypass graft (CABG) surgery.Thrombosis is the predominant cause of early SVG occlusion. Aspirin, which inhibits cyclooxygenase-1 activity and thromboxane generation in platelets, reduces early SVG occlusion by one-half.Aspirin responsiveness and platelet reactivity were characterized 3 days and 6 months after coronary artery bypass graft surgery in 229 subjects receiving aspirin monotherapy by platelet aggregation to arachidonic acid, adenosine diphosphate, collagen and epinephrine, Platelet Function Analyzer-100 (Siemens Healthcare Diagnostics, Newark, Delaware) closure time (CT) using collagen/epinephrine agonist cartridge and collagen/adenosine diphosphate (CADP) agonist cartridge, VerifyNow Aspirin assay (Accumetrics, Inc., San Diego, California), and urine levels of 11-dehydro-thromboxane B(2) (UTXB(2)). SVG patency was determined 6 months after surgery by computed tomography coronary angiography.Inhibited arachidonic acid-induced platelet aggregation, indicative of aspirin-mediated cyclooxygenase-1 suppression, occurred in 95% and >99% of subjects 3 days and 6 months after surgery, respectively. Despite this, 73% and 31% of subjects at these times had elevated UTXB(2). Among tested parameters, only UTXB(2) and CADP CT measured 6 months after surgery correlated with outcome. By multivariate analysis, CADP CT of ?88 s (odds ratio: 2.85, p = 0.006), target vessel diameter of ?1.5 mm (odds ratio: 2.38, p = 0.01), and UTXB(2) of ?450 pg/mg creatinine (odds ratio: 2.59, p = 0.015) correlated with SVG occlusion. CADP CT and UTXB(2) in combination further identified subjects at particularly high and low risk for SVG occlusion.Aspirin-insensitive thromboxane generation measured by UTXB(2) and shear-dependent platelet hyper-reactivity measured by Platelet Function Analyzer-100 CADP CT are novel independent risk factors for early SVG thrombosis after coronary artery bypass graft surgery.
| S-EPMC3089948 | biostudies-literature
Project description:BackgroundHyperglycaemia may attenuate the antiplatelet effect of aspirin and thereby increase the risk of cardiovascular events. We investigated the influence of increased haemoglobin A1c (HbA1c) levels on platelet aggregation and turnover in a large cohort of patients with coronary artery disease (CAD) with type 2 diabetes, prediabetes or no diabetes.MethodsIn this observational study, we included 865 stable CAD patients on 75 mg aspirin as mono-therapy of whom 242 patients had type 2 diabetes and were receiving antidiabetic drugs. Among 623 patients without diabetes, we classified 303 patients with prediabetes (HbA1c ≥5.7-6.4% [39-47 mmol/mol]) naive to antidiabetic drugs. Platelet aggregation was evaluated by the Multiplate Analyzer using arachidonic acid and collagen and by the VerifyNow Aspirin. Platelet turnover was evaluated by immature platelets using flow cytometry and platelet activation by soluble P-selectin.ResultsCAD patients with type 2 diabetes had higher platelet aggregation (all p-values <0.01), platelet turnover (immature platelet count, p<0.01) and platelet activation (p<0.001) than patients without diabetes. CAD patients with prediabetes had increased platelet aggregation (p = 0.02) and platelet count (p = 0.02) compared with patients without diabetes. Increased levels of HbA1c correlated positively with increased platelet aggregation using arachidonic acid (r = 0.19, p<0.0001), collagen (r = 0.10, p<0.01) and VerifyNow (r = 0.15, p<0.0001), and with platelet count (r = 0.08, p = 0.01), immature platelet count (r = 0.11, p<0.001) and soluble P-selectin (r = 0.15, p<0.0001). These associations were mainly evident in non-diabetic and prediabetic CAD patients.ConclusionsCAD patients with prediabetes and diabetes may have attenuated antiplatelet effect of aspirin compared with CAD patients without diabetes. This may be related to increased platelet count in patients with prediabetes. Increased levels of HbA1c correlated positively, though weakly, with increased platelet aggregation, platelet turnover and platelet activation.
| S-EPMC4493028 | biostudies-literature
Project description:BackgroundThe mechanisms leading to the high on-treatment platelet reactivity in diabetes patients are not fully elucidated. The genetic factors may be associated with the diminished antiplatelet efficacy of dual antiplatelet therapy. We investigated the possible association between insulin receptor substrate-1 (IRS-1) polymorphisms and high platelet reactivity in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM).MethodsA total of 674 CAD patients with T2DM were enrolled in this study. Platelet aggregation and platelet activation were assessed with light transmission aggregometry and flow cytometry analysis, respectively. Participants were divided into high platelet reactivity (HPR) group and non-HPR group according to their maximal platelet aggregation. Genotypes were identified by polymerase chain reaction and direct sequencing of genomic DNA. The association between IRS-1 genetic variants and platelet function was assessed.ResultsThere were 233 participants in the HPR group and 441 participants in the non-HPR group. G allele frequencies of rs13431554 were 27.7 % for the HPR group and 18.6 % for the non-HPR group (p < 0.001). Adenosine diphosphate and arachidonic acid induced platelet aggregation were significantly higher in G allele carriers compared with non-carriers (56.8 ± 16.2 vs 52.0 ± 17.9 %, p < 0.01, 28.9 ± 18.6 vs 25.2 ± 17.8 %, p < 0.01, respectively). We observed that P-selectin expression and PAC-1 binding were higher in G allele carriers compared with non-carriers (40.8 ± 12.4 vs 36.2 ± 13.8, p = 0.01; 43.7 ± 15.9 vs 38.7 ± 19.9, p = 0.03, respectively).ConclusionThe G allele of rs13431554 in the IRS-1 gene was associated with a hyperreactive platelet phenotype in the CAD patients with T2DM.
| S-EPMC4804508 | biostudies-literature
Project description:Coronary artery disease (CAD) is the leading cause of human morbidity and mortality worldwide, underscoring the need to improve diagnostic strategies. Platelets play a major role, not only in the process of acute thrombosis during plaque rupture, but also in the formation of atherosclerosis itself. MicroRNAs are endogenous small non-coding RNAs that control gene expression and are expressed in a tissue and disease-specific manner. Therefore they have been proposed to be useful biomarkers. The aim of this study was to investigate whether differences in miRNA expression levels in platelets can be found (i) between patients with premature CAD and healthy controls and (ii) within healthy controls after and before aspirin and statin administration. In this case-control study we measured expression levels of platelet miRNAs using microarrays from 40 male patients with premature CAD and 40 age- and sex-matched healthy controls. Premature CAD was defined as a cardiac event before the age of 51 years. The patients were selected from the outpatient clinic of the Academic Medical Center (AMC) of Amsterdam, which is specialised in premature CAD. The control cohort was composed of 40 healthy Caucasian male volunteers, who were recruited by advertisement and who were matched with the cases for age and smoking habits. Individuals of this control cohort did not have a history of CVD, nor did they have a positive family history of CVD and they were not allowed to use any medication. Patients and controls were excluded when they suffered from diabetes. Most CAD patients use aspirin and statins as secondary prevention. The influence of these drugs on miRNA profiles is unknown. To assess the possible influence of medication on miRNA expression and to control for medication as confounding factor, we asked 27 volunteers in our control cohort to also use these drugs. We administered simvastatin 40 mg, once daily, for 6 weeks and during the last two weeks we added 100mg of acetyl salicylic acid, once daily. Blood samples including isolated platelets were collected at baseline in the absence of aspirin and statins and after six weeks of medication use. We also assessed platelet function using the Multiplate® Analyzer (Roche) in the absence of aspirin and statin use. In short, 300 µl whole blood was diluted with 300 µl 0.9% saline and stirred for 3 minutes at 37 ºC. Adenosine diphosphate (ADP) was added in a final concentration of 2.5 ?mol/L to initiate platelet aggregation. Aggregation was measured for 6 minutes and was reported in arbitrary aggregation units plotted against time. Also, the area under the aggregation curve (AUC) was measured. All samples were measured in the absence and presence of 200 ?mol/L indomethacin (20 min incubation with blood) to mimic the effect of aspirin use. We calculated the percentage reduction in AUC after incubation with indomethacin as an in vitro measure of the effect of aspirin use on whole blood platelet aggregation.
2015-06-22 | E-GEOD-59421 | biostudies-arrayexpress
Project description:Coronary artery disease (CAD) is the leading cause of human morbidity and mortality worldwide, underscoring the need to improve diagnostic strategies. Platelets play a major role, not only in the process of acute thrombosis during plaque rupture, but also in the formation of atherosclerosis itself. MicroRNAs are endogenous small non-coding RNAs that control gene expression and are expressed in a tissue and disease-specific manner. Therefore they have been proposed to be useful biomarkers. The aim of this study was to investigate whether differences in miRNA expression levels in platelets can be found (i) between patients with premature CAD and healthy controls and (ii) within healthy controls after and before aspirin and statin administration.
2015-06-22 | GSE59421 | GEO