Abstract Number: PB0789
Meeting: ISTH 2022 Congress
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=51.28.5y) and “old” (mean age=73.62.3y) 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.
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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