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Impact of age on in vitro metabolism of clopidogrel: a potential explanation for high on-treatment platelet reactivity in elderly?

1Department of Biological Hematology, Pontchaillou, University Hospital of Rennes, Institut de recherche en santé, environnement et travail - IRSET, Inserm UMR_S 1085,  Univ Rennes, CHU Rennes, France, Rennes, Bretagne, France, 2Clinical Pharmacology Department, University Hospital of Saint-Etienne, INSERM, U1059, Vascular Dysfunction and Hemostasis, F-42023 Saint-Etienne, France, Saint Etienne, Rhone-Alpes, France, 3Laboratory of Clinical Pharmacology, University Hospital of Rennes, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, University of Rennes, France, Rennes, Bretagne, France, 4INSERM U1059, Jean Monnet University of Saint-Etienne, France, Saint Etienne, Bretagne, France, 5University of Rennes, France, Rennes, Bretagne, France, 6Department of Biological Hematology, Pontchaillou, University Hospital of Rennes, France, Rennes, Bretagne, France, 7Department of Biological Hematology, European Hospital Georges Pompidou, AP-HP, Innovative Therapies in Haemostasis, Paris University, INSERM U1140, Paris, France, Paris, Ile-de-France, France, 8Innovative Therapies in Haemostasis, Paris University, INSERM U1140, Paris, France, Paris, Ile-de-France, France

Abstract Number: PB0789

Meeting: ISTH 2022 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Antiplatelet Therapy

Background: High on-treatment platelet reactivity (HTPR) exits in about 30% of patients on clopidogrel and has been associated with an increased risk of cardiovascular events. Interestingly, this HTPR reaches 50% in elderly patients (≥70), but little is known on the mechanism of this resistance. One hypothesis is an age-related impaired hepatic metabolism of the prodrug clopidogrel, leading to a lower formation of its active metabolite (clopidogrel-AM).

Aims: To compare levels of clopidogrel-AM formed in vitro using “old” and “young” human liver microsomes (HLMs) and their consequences on platelet functions.

Methods: An in vitro model was developed using “young” (mean age=51.28.5y) and “old” (mean age=73.62.3y) HLMs. “Young” or “old” HLMs, in an incubation/reaction mixture, were added to a citrated platelet-rich plasma from healthy donors (1:1) in the presence or not of clopidogrel (50µM) and incubated at 37°C for 30 (T30) and 45min (T45).

Clopidogrel-AM was quantified by a validated LC MS/MS method (lower limit of quantification: 0.8 ng/mL).

Platelet aggregation was performed by light transmission aggregometry (LTA) at each incubation time.

Results: The generation of clopidogrel-AM was time-dependant and concentrations were comparable to those observed in treated patients. At T30, the mean concentration of clopidogrel-AM was significantly higher with “young” HLMs 8.56µg/L, 95%CI[5.87-11.24] than with “old” HLMs 7.64µg/L, 95%CI[5.14-10.14] (p=0.002) (n=21). Similar differences were found at T45: 11.40µg/L, 95%CI[7.57-15.22] and 10.63µg/L, 95%CI[7.10-14.15] with “young” and “old” HLMs (p=0.016), respectively(figure 1).

Despite a significant inhibition of platelet aggregation, no significant difference was found in LTA (ADP 10µM) after clopidogrel metabolism by “old” or “young” HLMs, probably due to a low sensitivity of the method to detect significant but small variations of clopidogrel-AM.

Conclusion(s): In this original model combining metabolic and functional approaches, less clopidogrel-AM was systematically produced with older HLMs. This provides support for a decreased in CYP450 activity that may contribute to HTPR in elderly patients.

Fihure 1

Concentrations -mean, SD- of clopidogrel active metabolite after metabolism by < 70 and ≥70 years old human liver microsomes after 30 minutes -T30- or 45 minutes -T45- of incubation. n=21 in each group. **: p < 0.01 ***: p < 0.001

To cite this abstract in AMA style:

PONTIS A, DELAVENNE X, VERDIER M, HODIN S, ANDRIAMAHARO A, GUERET P, NEDELEC-GAC F, GAUSSEM P, BACHELOT-LOZA C, Gouin I. Impact of age on in vitro metabolism of clopidogrel: a potential explanation for high on-treatment platelet reactivity in elderly? [abstract]. https://abstracts.isth.org/abstract/impact-of-age-on-in-vitro-metabolism-of-clopidogrel-a-potential-explanation-for-high-on-treatment-platelet-reactivity-in-elderly/. Accessed October 1, 2023.

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