Is platelet responsiveness to clopidogrel attenuated in overweight or obese patients and why? A reverse translational study in mice

Abstract

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.

Impact of the ABCD‐GENE Score on Clopidogrel Clinical Effectiveness after PCI: A Multi‐Site, Real‐World Investigation

“…Diabetes is also associated with significantly reduced clopidogrel active metabolite formation and increased platelet reactivity 20,21 . Although the mechanism underlying these effects remains unclear, suppression of hepatic CYP2C expression and activity in the setting of chronic inflammatory conditions (such as advanced age, obesity, CKD, and diabetes) could contribute to reduced clopidogrel active metabolite formation 48–50 . The ABCD‐GENE score combines these independent risk factors for clopidogrel nonresponse.…”

“…20,21 Although the mechanism underlying these effects remains unclear, suppression of hepatic CYP2C expression and activity in the setting of chronic inflammatory conditions (such as advanced age, obesity, CKD, and diabetes) could contribute to reduced clopidogrel active metabolite formation. [48][49][50] The ABCD-GENE score combines these independent risk factors for clopidogrel nonresponse. With the increasing uptake of CYP2C19 testing in clinical practice, 34 the ABCD-GENE score represents a feasible means of more precisely predicting clopidogrel response following PCI.…”

Precision antiplatelet therapy

“…Obese patients appear to generate less clopidogrel active metabolites and display-reduced platelet inhibition as compared to lean subjects [ 83 ]. Mice with high-fat diet-induced obesity show reduced metabolic activation of clopidogrel and higher CES-1 activity, leading to reduced platelet responsiveness to the drug [ 84 ].…”

Analysis of Factors of High and Low Platelet Residual Reactivity During Clopidogel Treatment in the Subacute Period of Myocardial Infarction

“…В литературе есть работы, демонстрирующие связь между избыточной массой тела либо ожирением и ВОРТ на клопидогрел у пациентов c ОКС после ЧКВ [7,8], есть работы, в которых такой связи обнаружено не было [9], есть работы, в которых показана связь ожирения с сердечно-сосудистыми тромботическими осложнениями у пациентов, перенесших ЧКВ [10]. Механизмы, объясняющие ВОРТ на клопидогрел у пациентов с ожирением, многообразны: хроническое воспаление, вызванное висцеральным ожирением, повышенный оборот тромбоцитов, повышенное воздействие АДФ, нарушение синтеза и действия циклических нуклеотидов в тромбоцитах, увеличение цитозольного кальция и снижение активности CYP3A4 (цитохрома Р450), участвующего в метаболизме клопидогрела [11][12][13].…”