Clopidogrel Resistance Research Articles (Page 1)

Evategrel (CG-0255) is world’s first thioether prodrug relying only on carboxylesterases for metabolizing to its active metabolite, which is identical to clopidogrel’s active metabolite H4 generated through CYP metabolism. Through a fast, consistent, and one-step hydrolytic bioactivation, evategrel was designed to overcome major issues of clopidogrel: resistance, relatively weak potency, slow onset of action, and lack of intravenous (IV) formulation for emergency settings. Evategrel is also the first P2Y12 inhibitor that can be formulated for both IV and oral administration. US Phase I results were reported previously. These follow up pilot and bridging trials were carried out in healthy volunteers to further assess safety, pharmacokinetics (PK), and pharmacodynamics (PD: Inhibition of Platelet Aggregation, IPA, measured by VerifyNow). For the pilot IV study, evategrel was given by IV bolus on day 1, followed by switching to clopidogrel on either day 2 or 3, depending on evategrel doses. Clopidogrel treatment continued until day 7, cangrelor was used for comparison. For the oral study, a loading dose of 4 or 8 mg was given on day 1, followed by 0.5 or 1 mg maintenance dose from days 2 to 7. Clopidogrel and prasugrel were used for comparison. Bridging studies in China were dose escalation trials. Evategrel is safe and well tolerated. PK analysis shows fast and consistent conversion to H4 with minimal interpersonal variation. PD results indicate that evategrel is potent with fast onset of action: ≤ 15 min for IV and ≤ 30 min for oral dosing. There is excellent IPA-dose linearity, ~100% IPA is achieved at highest doses while at lower 2 mg dose, evategrel’s IPA is ~40%, similar to that of 300 mg clopidogrel. Comparing with clopidogrel, the interpersonal variation of IPA is much smaller. No significant bleeding events were observed among 128 subjects given evategrel single or multiple doses, including 79 (62%) subjects whose maximal IPA is high, ranging from 80 – 100%. In conclusion, data from all the trials indicate that evategrel indeed overcomes clopidogrel resistance and is highly potent with fast onset, excellent dose linearity, and no drug-drug interactions observed. No significant bleeding or other adverse events were observed. IV bolus is convenient for emergency and surgical settings. Orally evategrel’s IPA at very low doses matches or greatly surpasses that of clopidogrel. Evategrel fills unmet medical needs and will truly benefit patients.

Discovery of a novel and potent antiplatelet thiol prodrug CG-0255.

BackgroundThe patient-associated prevalence of Clopidogrel (CPG)-and Aspirin (ASS)-nonresponse is not well understood and varies depending on the patient population. The influence of responder status for platelet inhibition in patients eligible for carotid artery stenting (CAS) on post-interventional cerebral ischemia is unknown.MethodsWe conducted a retrospective, mono-center analysis of all patients with response-test undergoing elective CAS between 2010 and 2024 and available MRI before and after CAS. Study groups were formed according to ASS- and CPG-response. Cerebral ischemia patterns were compared between study groups in univariate analysis and patient-associated co-morbidities were tested for association with drug resistance or infarction frequency.ResultsIn total, 50/68 (73.5%) of patients showed adequate response to ASS and CPG. Non-response to CPG was higher than to ASS (clopidogrel resistance rate: 14.8%, aspirin resistance rate: 9.2%). All patients with non-response were bridged with GP IIb/IIIa antagonist tirofiban during CAS. Under these conditions, the responder status did not influence post-interventional cerebral infarction patterns.ConclusionAntiplatelet non-response, especially for CPG, is very frequent in patients undergoing CAS. When bridging patients with tirofiban during intervention, responder status had no influence on post-interventional cerebral infarction patterns.

Acute coronary syndrome (ACS) is a leading cause of death, and clopidogrel resistance remains a major challenge in its treatment. This study aims to determine the impact of CYP2C19 genetic variants on clopidogrel resistance (CR) and major adverse cardiovascular events (MACEs) in Vietnamese patients undergoing percutaneous coronary intervention (PCI). We carried out a descriptive cross-sectional study, supplemented by a prospective longitudinal follow-up, on 113 ACS patients undergoing PCI with drug-eluting stent implantation at the Department of Cardiology, Military Hospital 103, from January 2015 to May 2018. We excluded patients with a decreased platelet count (< 100 × 10^9/L), a decreased estimated glomerular filtration rate (< 15 mL/min), ongoing bleeding, coagulation disorders, planned or recent surgery, or a coexisting malignancy. CR was defined as platelet aggregation ≥ 46%. The Amplification Refractory Mutation System (ARMS)-PCR was used to determine the CYP2C19 genotype and phenotype. Causes leading to patient readmission, such as angina, recurrent acute myocardial infarction, stroke, or death within 30 days, were recorded as MACEs. The rate of CR was 29.9% (33/113 patients), and the incidence of MACEs was 15.9% (18/113 patients). The frequencies of CYP2C192 and CYP2C193 polymorphisms, as well as the PM CYP2C19 phenotype, were higher in the CR and MACE groups compared to those without these characteristics (p = 0.24, 0.006, and < 0.001, respectively). The PM CYP2C19 phenotype was predictive of 30-day MACEs in ACS patients undergoing PCI with stent implantation (p < 0.001). Our findings demonstrate a strong association between CYP2C19 PM phenotypes and increased risks of both clopidogrel resistance and 30-day MACEs in Vietnamese ACS patients undergoing PCI. These results underscore the clinical significance of CYP2C19 genotyping in optimizing antiplatelet therapy and enhancing outcomes in this patient population. PM CYP2C19 phenotypes were associated with an increased risk of CR and MACEs in Vietnamese patients undergoing PCI with stent implantation.

Association Between Clopidogrel Resistance and CYP2C19 Polymorphism and Hypomethylation in Patients From South East Asia With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis

Improved platelet inhibition with ticagrelor when compared to clopidogrel in peripheral artery disease patients.

ABSTRACT Background Clopidogrel and aspirin are widely used antiplatelet agents. Although clopidogrel resistance is more prevalent in Asian populations, a Korean study suggested that clopidogrel was superior to aspirin in patients who completed standard dual antiplatelet therapy following percutaneous coronary intervention. However, the comparative effectiveness of clopidogrel versus aspirin in populations with lower levels of clopidogrel resistance remains to be further investigated. Methods This study included 1,007 participants from NHANES 1999–2018 who were receiving aspirin or clopidogrel monotherapy. Cox proportional hazards regression and Kaplan-Meier survival analyses were used to compare the risks of mortality between the two groups. Sensitivity analyses were conducted by excluding individuals who died within the first 6 months of follow-up. Results Across all Cox models, clopidogrel use was associated with significantly higher risks of all-cause mortality (Model 1, HR1.47, 95%CI 1.20–1.79, p < .01; Model 2, HR1.25, 95%CI 1.02–1.54, p = .03; Model 3, HR 1.33, 95%CI 1.08–1.64, p = .01; Model 4, HR1.31, 95%CI 1.06–1.63, p = .01), stroke and cardiac mortality (Model 1, HR1.76, 95%CI 1.27–2.43, p < .01; Model 2, HR1.41, 95%CI 1.01–1.97, p = .04; Model 3, HR 1.54, 95%CI 1.10–2.17, p = .01; Model 4, HR1.47, 95%CI 1.03–2.08, p = .03) compared with aspirin. These associations remained consistent in sensitivity analyses. Kaplan-Meier survival curves also indicated higher risks of all-cause mortality, stroke and cardiac mortality in the clopidogrel group relative to the aspirin group. Conclusion In this community-based population, clopidogrel monotherapy was associated with higher risks of all-cause mortality, stroke and cardiac mortality compared with aspirin.

Clopidogrel is extensively utilized for the prevention and treatment of cardiovascular, cerebrovascular, and other arterial circulation disorders attributed to platelet hyperaggregation. Nevertheless, its antiplatelet efficacy displays substantial individual variability and unpredictability. Our aim was to develop a machine learning model based on clinical data, incorporating various laboratory indicators, to predict the risk of clopidogrel resistance in clinical patients. This study included 1592 cardiovascular disease patients treated with clopidogrel. Potential predictive variables included age, sex, hematological, coagulation, biochemical parameters, and CYP2C19 genetic polymorphisms. Lasso regression and multivariable logistic regression were used for variable selection. Modeling was performed using Logistic Regression, LGBM Classifier, Random Forest Classifier, and SVC machine learning models, followed by model comparison, to ultimately construct the clopidogrel resistance risk prediction model. The clopidogrel resistance rate increased year by year from 2020 to 2022, but decreased slightly in 2023. There was a significant difference in clopidogrel resistance rate among different years (χ2 = 49.969, P = 0.000). Predictive variables included white blood cell count, hemoglobin level, platelet count, fibrinogen, triglycerides, D-Dimer, mean platelet volume, prothrombin time ratio, uric acid, glycated hemoglobin, and apolipoprotein B. The Random Forest Classifier machine learning method yielded a CR risk prediction model with AUC = 0.8730 and accuracy = 0.8033, demonstrating good predictive capability for identifying the risk of clopidogrel resistance after clinical use of clopidogrel. This study developed a highly predictive clopidogrel resistance risk prediction model, which can assist in clinical decision-making for better treatment strategies.

We aimed to evaluate the prevalence of clopidogrel resistance in hypercoagulable dogs using the Platelet Function Analyzer-200 (PFA-200) P2Y cartridge; further, we aimed to assess the utility of hematocrit (HCT), platelet count (PLT), prothrombin time (PT), activated partial thromboplastin time (aPTT), thromboelastography (TEG) parameters, and D-dimer level as indicators of clopidogrel efficacy. Forty healthy dogs underwent single measurements of P2Y closure time (CT), HCT, PLT, PT, aPTT, TEG parameters, and D-dimer levels, while thirty hypercoagulable dogs underwent two measurements of these parameters before and after clopidogrel treatment. The reference interval for P2Y CT in healthy dogs was 40.0-141.5 s, with a mean of 63.9 ± 26.82 s. Hypercoagulable dogs showed a mean baseline P2Y CT of 77.4 ± 37.6 s. Moreover, 23 (76.67%) and 7 (23.33%) showed responsiveness and resistance to the initial clopidogrel dose, respectively. The mean P2Y CT of the clopidogrel-resistant group after clopidogrel administration was 182.71 ± 78.43 s. Increasing the maintenance dose successfully overcame clopidogrel resistance in these seven dogs. Among the assessed parameters, only D-dimer levels showed a significant decrease in the clopidogrel-responder group (p < 0.05), suggesting its potential utility in evaluating responsiveness. In conclusion, the PFA-200 P2Y cartridge effectively detects clopidogrel resistance in dogs and can guide therapeutic adjustments such as dose escalation.

Clopidogrel is the drug of choice for coronary syndromes, which is used to reduce the incidence of recurrent myocardial infarctions. However, in clinical practice, resistance to this drug reaches 45%. Clinical, demographic, and genetic factors make a significant contribution to its development, since carriage of the CYP2C19 allele with reduced function (CYP2C19*2, CYP2C19*3) is associated with a lower level of the active metabolite of clopidogrel, decreased platelet inhibition, and a higher incidence of cardiovascular events.

Graft Thrombosis after Revascularization Due to CYP2C19 Polymorphism and Clopidogrel Resistance: A Rare Case Report

BackgroundClopidogrel plays an important role in the treatment of acute ischemic strokes (AIS) through antiplatelet activity. However, some patients have clopidogrel resistance (CR), which could lead to stroke recurrence and bleeding. This study aimed to explore associated factors of CR and establish a diagnostic nomogram for predicting the probability of CR in AIS patients.MethodsThis retrospective study involved 692 AIS patients from the Second Affiliated Hospital of Guangzhou Medical University, treated with clopidogrel (75 mg/day for 5 ± 2 days) after admission. Platelet reactivity was evaluated using thromboelastography to measure the ADP-induced platelet inhibition ratio (ADP-PIR). Patients were classified into CR (ADP-PIR < 30%) and non-clopidogrel resistance (NCR) groups. Group comparison, followed by least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression, was used to identify key predictors of CR. A diagnostic nomogram was developed and its performance was validated using bootstrap resampling.Results16.76% of 692 patients experienced CR after AIS. Beta blocker use (OR: 0.47, 95% CI: 0.22–1.03, P = 0.058) and apolipoprotein A1 (OR: 0.17, 95% CI: 0.07–0.46, P < 0.001) were identified as protective factors, while unstable carotid plaque (OR: 10.65, 95% CI: 4.18–27.13, P < 0.001), high apolipoprotein B levels (OR: 2.35, 95% CI: 1.23–4.51, P = 0.01), and proton pump inhibitors use (OR: 2.09, 95% CI: 1.32–3.31, P = 0.002) were risk factors. Our nomogram effectively validated these factors, showing strong discrimination and clinical utility in diagnosing CR probability.ConclusionsWe identified several significant CR predictors and further developed a diagnostic nomogram of CR to help clinicians choose antiplatelet drugs.Trial retrospectively registrationTrial Retrospectively registration = ChiCTR2300073944.Data: 2023-7-25. The present study was approved by the Ethics Committee of the Second Affiliated Hospital of Guangzhou Medical University.

Background: Prior use of antiplatelet agents is associated with reduced severity in patients with ischemic stroke. However, clopidogrel resistance, which is characterized by a suboptimal platelet response to clopidogrel, diminishes the drug’s efficacy. This study aimed to investigate the impact of clopidogrel resistance on stroke severity in patients receiving clopidogrel. Methods: A total of 116 patients who developed acute ischemic stroke while on clopidogrel, presented to two hospitals within 72 h of symptom onset, and underwent clopidogrel resistance testing using the VerifyNow assay were enrolled. The relationship between the VerifyNow parameters and stroke severity was analyzed using correlation and multivariable regression analyses. Results: Among the VerifyNow parameters, percent inhibition showed a significant inverse correlation with National Institutes of Health Stroke Scale (NIHSS) score at admission (r = -0.387, p &lt; 0.001), whereas the P2Y12 reaction unit (PRU) exhibited a significant positive correlation (r = 0.207, p = 0.028). Multivariable analysis confirmed a significant inverse relationship between percent inhibition and NIHSS score at admission (B = -0.107, 95% confidence interval = -0.163 to -0.051; p &lt; 0.001). However, PRU was not significantly associated with NIHSS score at admission in the multivariable analysis. Conclusions: Clopidogrel resistance, particularly lower percent inhibition, was associated with greater stroke severity in patients receiving clopidogrel.

Compare TEG parameters between clopidogrel-resistant and clopidogrel-non-resistant groups. Graft or stent thrombosis affects 1 in 5 patients within six months post-revascularization and is a leading cause of amputation in the elderly. Clopidogrel resistance occurs in 5-44% of patients. This prospective observational study evaluated patients with PAD undergoing revascularization and taking clopidogrel between 2022 and 2024. Whole blood samples were analyzed using thromboelastography (TEG) and VerifyNow testing. Patients were categorized based on their clopidogrel response: clopidogrel-resistant (>180 P2Y12 Reaction Units (PRU)) and non-resistant (<180 PRU). Fisher's exact and Wilcoxon tests were used to compare the groups for categorical and continuous variables, respectively. Spearman's correlation coefficient was used to determine the relationship between platelet function and clopidogrel response (VerifyNow). Fifty-three patients were analyzed, 70% were male, and 23% were clopidogrel-resistant. Clopidogrel-resistant exhibited higher platelet reactivity (PRU 224.2 vs. 74.9, P<0.0001), faster clot formation (1.14min vs. 1.22min, P<0.0001), clot strength (ADP-MA 54.9mm vs. 39.8mm, P<0.0001), and reduced clot lysis (0.97min vs. 0.69min, P=0.0005) compared to non-resistant. Additionally, these patients showed a higher percentage of platelet aggregation (74.0% vs. 44.0%, P<0.0001) and a lower platelet inhibition (26.0% vs. 56.0%, P<0.0001), indicating a diminished response to clopidogrel and an increased risk of thrombosis. Clopidogrel-resistant group exhibited faster clot formation, greater clot strength, and higher platelet aggregation. Incorporating TEG into clinical practice could help identify patients at risk of inadequate clopidogrel response.

Background: Clopidogrel (CLOP) has been used as an antiplatelet medication for many years to treat strokes; however, CLOP resistance may increase the risk of stroke recurrence. The poor metabolism of CLOP, which leads to resistance, is thought to be caused by the CYP2C19 (C-19) loss of function (LoF) polymorphism. It was impossible to draw firm conclusions from earlier research since the data were so inconsistent and diverse. Aim: The current study was conducted to gather conclusive data from an updated meta-analysis about the relationship between C-19LoF(C-19-LoF) polymorphism and coronary artery (CA) events in individuals using CLOP. Methodology: Electronic databases PubMed, EMBASE, SciHub, and Google Scholar were used to extract data till November 2024. RevMan 5 software was used for the analysis of extracted data. Results: Out of 7582 articles, we used 90 carefully selected to conduct our meta-analysis, which comprised 52,748 patients with CA disease undergoing CLOP medication. Conclusion: Our results indicate that CA events and composite events are significantly more common in individuals with one or more C-19-LoF alleles worldwide than in those without these alleles, particularly in Asian populations. The C-19-LoF alleles put the entire population at risk for composite events and recurrent CA events, especially Asians on CLOP, according to our meta-analysis. For people with poor or intermediate metabolic activity, more study is needed on alternate antiplatelet treatments.

ObjectiveTo analyze the relationship between in-stent restenosis (ISR) following carotid artery stenting (CAS) and platelet clopidogrel reactivity confirmed by the P2Y12 reaction unit (PRU) and inhibition rate (IR).MethodsWe retrospectively analyzed...

ABSTRACTBackgroundClopidogrel response varies significantly among individuals due to multiple influencing factors. This study aimed to investigate the associations between P2RY12 gene variants, non‐genetic factors, and platelet aggregation in patients undergoing clopidogrel therapy and percutaneous coronary intervention.MethodsWe conducted a cross‐sectional descriptive study involving 171 patients who successfully underwent coronary artery stenting and were treated with clopidogrel at two military hospitals in Vietnam. Platelet aggregation was assessed using the light transmission aggregometry (LTA) method, with clopidogrel resistance (CR) defined as maximal platelet aggregation > 50%. P2RY12 genetic polymorphisms (C34T‐rs6785930 and G52T‐rs6809699) were genotyped using Sanger sequencing.ResultsThe allele frequencies were 74.56% (C) and 25.44% (T) for P2RY12 C34T, and 88.30% (G) and 11.70% (T) for P2RY12 G52T. Platelet aggregation progressively increased across the GG, GT, and TT genotypes of P2RY12 G52T (p = 0.03), with patients carrying the TT genotype exhibiting significantly higher platelet aggregation compared to other genotypes (p = 0.01). Among non‐genetic factors, proton pump inhibitor (PPI) intake was associated with a significant increase in platelet aggregation (p = 0.03). The prevalence of clopidogrel resistance (CR) was 43.86%. Multivariate logistic regression analysis identified the T allele of P2RY12 C34T, reduced estimated glomerular filtration rate (eGFR), and PPI intake as significant risk factors for CR (OR = 2.24, 2.49, 4.01; p = 0.02, 0.049, 0.01, respectively).ConclusionsThe T allele of P2RY12 C34T was associated with an increased risk of CR. Among non‐genetic factors, PPI intake significantly elevated platelet aggregation and, along with reduced eGFR, contributed to a higher risk of CR.

Introduction: Cerebrovascular and cardiovascular diseases are major causes of global mortality, with significant impact in India. Clopidogrel, an antiplatelet prodrug, requires activation by CYP enzymes to inhibit platelet activation. Clopidogrel resistance, affecting 4-30% of patients, is often due to CYP2C19 gene variations, among other factors. This study explores genetic variants associated with clopidogrel resistance to improve personalized therapy for thrombotic conditions. Objective: To evaluate the relationship between CYP2C19 polymorphisms and recurrent thrombotic events in patients treated with clopidogrel for coronary artery disease and stroke. Methods: An ambispective observational study at a tertiary hospital over six months included 114 adults on clopidogrel for various ischemic conditions. Exclusion criteria were pregnancy, lactation, intracerebral hemorrhage, atrial fibrillation, left ventricular clot, and cardioembolic stroke. Data were collected from medical records. CYP2C19 2 and CYP2C19 3 polymorphisms were analyzed using PCR and gel electrophoresis. Statistical analysis was conducted with chi-square tests in IBM SPSS version 20.0 (p&lt;0.05). Results: The study included 114 participants (71.9% males, mean age 64.7 ± 10.9 years). Significant associations were found between recurrent ischemic events and hypertension (p=0.001), diabetes (p=0.033), and smoking (p=0.001). Of the 114 patients, 72 (63.2%) were positive for CYP2C19* 2, with 61 (84.7%) experiencing recurrent events (p=0.005). CYP2C19* 3 positivity was observed in 20 (17.5%) patients, with 9 (45%) having recurrent events (p=0.401). All 12 patients who underwent PCI had recurrent thrombotic events (p=0.000), with 7 (58.3%) having CYP2C19 polymorphisms—5 with CYP2C19* 2 and 2 with CYP2C19* 3. Medication adherence was not significantly linked to recurrence (p=0.063). The findings suggest a potential association between CYP2C19*2 and recurrent thrombotic events. Conclusion: This study highlights a significant association between CYP2C192 polymorphism and recurrent thrombotic events in clopidogrel-treated patients, indicating that genetic screening may help identify clopidogrel resistance. No significant association was found with CYP2C193. Smoking, hypertension, and diabetes were significant risk factors for recurrent ischemic events. The high prevalence of CYP2C19 polymorphisms among PCI patients with recurrent thrombotic events suggests the potential benefit of genetic screening in clinical practice.

Objectives: The objective of the study was to ascertain adverse events (major adverse cardiac and limb events) events in patients of established peripheral arterial disease (PAD), on clopidogrel and aspirin antiplatelet therapy. Patients and Methods: Patients aged 18 years or over, with PAD were screened for participation in the study. Patients were considered to have symptomatic PAD if they met either of two criteria: a history of intermittent claudication, rest pain, or tissue loss of presumed atherosclerotic origin, with either ankle–brachial index &lt;0.85, previous leg amputation, peripheral vascular surgery, or percutaneous intervention; or angiographic or computed tomographic imaging of significant lower-extremity occlusive atherosclerotic disease. The patients took clopidogrel and aspirin at a dose ≥75 mg/day for at least 4 weeks before enrolment. Those with contraindications to antiplatelet usage were excluded from the study. Blood was used as genotyping material. Patient samples were genotyped for clopidogrel resistance (CR)-associated single-nucleotide polymorphism (SNPs) using Illumina Global Screening Array Ver 3 Bead Chip. Illumina Infinium Genotyping Assay protocol was implemented. Intensities of the beads’ fluorescence were detected using iScan Reader (Illumina Inc). Aspirin resistance (AR) was determined with the whole blood, point of care, turbidimetric cartridge-based method, platelet aggregation, and VerifyNow P2Y12 assay, and results were reported in platelet reactivity units (PRU), at a cutoff of 550 PRU. Results: The mean age was 58.4 (12.6) years with 90% males. The mean body mass index was 22.57 (3.54) kg/m2. The cohort comprised 58.9% smokers, 42% alcoholics, 33.5% diabetics, and 63% hypertensives. Limited efficacy of clopidogrel was observed in 52.38% of patients with loss of function (LOF) variations in the CYP2C19 gene. The mean duration of follow-up was 13.4 (4.7) months. Subjects with CYP2C19 LOF alleles showed more complications (39%) and the relationship between the LOF variation in the CYP2C19 gene and the adverse clinical outcomes (major adverse cardiac events [MACE] and major adverse limb events [MALE]) was found to be statistically significant (P = 0.11). CR and AR were found in 147 (50.3%) and 69 (23%) patients, respectively. Resistance to both the antiplatelets was found in 41 (14%) patients. Conclusion: In this largest observational study, the use of dual antiplatelet therapy in the Indian population with PAD on the MACE and MALE events was higher in the patients with CYP2C19 LOF alleles. The study found a statistically significant relationship between genetic testing results and clinical outcomes.

Clopidogrel, an anti-platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data. We conducted a genome-wide association study (GWAS), including local ancestry adjustment, in 141 AA on clopidogrel to identify genetic associations with high on-treatment platelet reactivity (HTPR), with validation of genome-wide significant and suggestive loci in an independent cohort of AA clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional analysis. We performed differential gene expression (DGE) analysis in whole blood to identify transcriptomic predictors of response, followed by functional validation in MEG-01 cells. GWAS identified one signal on Chromosome 7 as significantly associated with increasing risk of HTPR. The lead single-nucleotide polymorphism (SNP), rs7807369, within thrombospondin 7A (THSD7A) was associated with an increased risk of HTPR (odds ratio (OR) = 4.02, P = 4.56 × 10-9). Higher THSD7A gene expression was associated with HTPR in an independent cohort of clopidogrel-treated patients (P = 0.004) and carrying a risk allele showed increased gene expression in primary human endothelial cells. Notably, the CYP2C19*2 variants showed no association with clopidogrel response in the discovery or MVP cohorts. DGE analysis identified an association with decreased LAIR1 and AP3B2 expression to HTPR. LAIR1 knockdown in MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. In summary, these findings suggest that other variants and genes outside of CYP2C19 star alleles play an important role in clopidogrel response in AA.