Related Experiment Video
Updated: Jun 6, 2025
Microfluidics in Assessing Platelet Function
Published on: November 8, 2024
Randomized evaluation of the loss-of-function carboxylesterase 1 (CES1) G143E variant on clopidogrel and ticagrelor
Joshua P Lewis1, Kathleen A Ryan1, Elizabeth A Streeten1
1Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Insights
The CES1 G143E gene variant significantly affects clopidogrel
Area of Science:
- Pharmacogenomics
- Cardiovascular Medicine
- Platelet Biology
Background:
- Antiplatelet therapy is crucial for managing coronary artery disease.
- Carboxylesterase 1 (CES1) metabolizes clopidogrel.
- A loss-of-function CES1 G143E mutation impacts clopidogrel efficacy.
Purpose of the Study:
- To investigate the effect of CES1 G143E genotype on platelet aggregation inhibition (IPA) with clopidogrel versus ticagrelor.
- To determine if ticagrelor's pharmacodynamics are influenced by the CES1 G143E variant.
Main Methods:
- Prospective randomized crossover study in 50 patients with coronary artery disease.
- Patients received clopidogrel (75 mg/day) and ticagrelor (180 mg/day) for 7 days each.
- Stratification by CES1 G143E genotype (34 GG, 16 GE) and measurement of IPA using various agonists.
Main Results:
- CES1 G143E significantly altered on-clopidogrel IPA (71.6% in carriers vs. 48.0% in non-carriers, p=3.8x10⁻⁵).
- Similar genotype-dependent effects were seen with arachidonic acid, epinephrine, and collagen stimulation.
- No significant association between CES1 G143E and IPA was observed with ticagrelor.
Conclusions:
- The CES1 G143E genotype substantially modifies platelet aggregation in response to clopidogrel.
- Ticagrelor's pharmacodynamics are not affected by the CES1 G143E genotype.
- Ticagrelor may offer more consistent platelet inhibition in patients with CES1 G143E variants.
Abstract:
Antiplatelet therapy with a P2Y12 receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss-of-function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on-clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by CES1 G143E genotype (N = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate-stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E-allele carriers vs. non-carriers, respectively, p = 3.8 × 10-5). Similar significant effects on platelet aggregation were also noted between 143E-allele carriers versus non-carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, p = 0.04), epinephrine (44.4 vs. 18.8%, p = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, p = 3.7 × 10-3). In contrast, no relationship between CES1 G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on-clopidogrel platelet aggregation is substantially modified by CES1 G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response-modifying alleles in CES1.
