Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients

Renske H Olie; Rachelle R K Hensgens; Petal A H M Wijnen; Leo F Veenstra; Bianca T A de Greef; Minka J A Vries; Paola E J van der Meijden; Jurriën M Ten Berg; Hugo Ten Cate; Otto Bekers; Yvonne M C Henskens

doi:10.3390/jcm10173992

Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients

J Clin Med. 2021 Sep 3;10(17):3992. doi: 10.3390/jcm10173992.

Authors

Renske H Olie^{1

2

3}, Rachelle R K Hensgens^{1

4}, Petal A H M Wijnen⁴, Leo F Veenstra⁵, Bianca T A de Greef⁶, Minka J A Vries², Paola E J van der Meijden^{2

3}, Jurriën M Ten Berg^{5

7}, Hugo Ten Cate^{1

2

3}, Otto Bekers⁴, Yvonne M C Henskens^{2

4}

Affiliations

¹ Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), 6229 HX Maastricht, The Netherlands.
² Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands.
³ Thrombosis Expertise Center, Maastricht University Medical Center+ (MUMC+), 6229 HX Maastricht, The Netherlands.
⁴ Central Diagnostic Laboratory, Maastricht University Medical Center+ (MUMC+), 6229 HX Maastricht, The Netherlands.
⁵ Department of Cardiology, Maastricht University Medical Center+ (MUMC+), 6229 HX Maastricht, The Netherlands.
⁶ Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center+ (MUMC+), 6229 HX Maastricht, The Netherlands.
⁷ Department of Cardiology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.

Abstract

On-treatment platelet reactivity in clopidogrel-treated patients can be measured with several platelet function tests (PFTs). However, the agreement between different PFTs is only slight to moderate. Polymorphisms of the CYP2C19 gene have an impact on the metabolization of clopidogrel and, thereby, have an impact on on-treatment platelet reactivity. The aim of the current study is to evaluate the differential effects of the CYP2C19 genotype on three different PFTs.

Methods: From a prospective cohort study, we included patients treated with clopidogrel following percutaneous coronary intervention (PCI). One month after PCI, we simultaneously performed three different PFTs; light transmission aggregometry (LTA), VerifyNow P2Y12, and Multiplate. In whole EDTA blood, genotyping of the CYP2C19 polymorphisms was performed.

Results: We included 308 patients treated with clopidogrel in combination with aspirin (69.5%) and/or anticoagulants (33.8%) and, based on CYP2C19 genotyping, classified them as either extensive (36.4%), rapid (34.7%), intermediate (26.0%), or poor metabolizers (2.9%). On-treatment platelet reactivity as measured by LTA and VerifyNow is significantly affected by CYP2C19 metabolizer status (p < 0.01); as metabolizer status changes from rapid, via extensive and intermediate, to poor, the mean platelet reactivity increases accordingly (p < 0.01). On the contrary, for Multiplate, no such ordering of metabolizer groups was found (p = 0.10).

Conclusions: For VerifyNow and LTA, the on-treatment platelet reactivity in clopidogrel-treated patients correlates well with the underlying CYP2C19 polymorphism. For Multiplate, no major effect of genetic background could be shown, and effects of other (patient-related) variables prevail. Thus, besides differences in test principles and the influence of patient-related factors, the disagreement between PFTs is partly explained by differential effects of the CYP2C19 genotype.

Keywords: CYP2C19; clopidogrel; pharmacogenetics; platelet activation; platelet function test.