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Is platelet responsiveness to clopidogrel attenuated in overweight or obese patients and why? A reverse translational
Li-Ping Jiang1, Jin-Zi Ji1, Peng-Xin Ge1,2
1Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
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.
Insights
Obesity impairs clopidogrel's antiplatelet effect by reducing its metabolic activation and increasing platelet counts. This suggests that overweight or obese patients may require adjusted clopidogrel dosages.
Area of Science:
- Pharmacology
- Metabolic Disorders
- Hematology
Background:
- Overweight and obese individuals show reduced platelet response to clopidogrel.
- The underlying mechanisms for this diminished response are not fully understood.
Purpose of the Study:
- To investigate how obesity affects clopidogrel's metabolic activation.
- To determine the impact of obesity on platelet response to clopidogrel in patients and a mouse model.
Main Methods:
- Analysis of residual platelet reactivity in overweight/obese patients on clopidogrel.
- Utilized high-fat diet-induced obese mice to study clopidogrel metabolism and platelet activation.
- Examined gene expression related to clopidogrel activation and platelet counts in mice.
- Analyzed GEO datasets from obese patients for relevant gene pathways.
Main Results:
- Obese patients demonstrated significantly weaker antiplatelet effects from clopidogrel.
- In obese mice, reduced systemic exposure to clopidogrel's active metabolite (H4) and increased hydrolytic metabolite were observed.
- Liver enzyme alterations (down-regulated P450s, up-regulated carboxylesterase-1) impacted clopidogrel metabolism.
- Increased megakaryocyte proliferation and elevated platelet counts were noted in obese mice.
Conclusions:
- Obesity hinders clopidogrel's metabolic activation and increases platelet counts, leading to impaired drug responsiveness.
- Findings suggest a potential need for dose adjustments of clopidogrel in overweight or obese patients.
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