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A genetic polymorphism in P2RY1 impacts response to clopidogrel in cats with hypertrophic cardiomyopathy

Ueda Y, Li RHL, Nguyen N, et al. A genetic polymorphism in P2RY1 impacts response to clopidogrel in cats with hypertrophic cardiomyopathy. Sci Reports 2021 111. 2021;11(1):1-13. doi:10.1038/s41598-021-91372-3
https://pubmed.ncbi.nlm.nih.gov/34131167/

Aortic thromboembolism is an often fatal condition in cats that is most commonly a consequence of hypertrophic cardiomyopathy. The risk of thromboembolism may be decreased with antiplatelet drugs such as clopidogrel. Clopidogrel binds to the platelet receptor P2Y12 to prevent platelet clumping and decrease the risk of clots. However, clopidogrel is not consistently effective and resistance has been described in all species tested. The prevalence of resistance in cats has been reported as 15-50%. This is a result of multiple factors including variation in the CYP2C enzyme, variations in the P2Y12 receptor, and sex of the animal. Multiple mutations in the P2Y receptor genes in cats have been previously described.
The purpose of this study was to determine the association of known variants in the platelet ADP receptors and cytochrome 450 enzymes in cats and determine their association with resistance to clopidogrel effect as assayed by multiple methods.
51 cats with HCM were enrolled and 49 completed the study. The mean age was 6.5 years, with 35 males and 14 females enrolled (this mimics most data, as male cats are overrepresented for HCM). Samples were tested before initiation of therapy and after 10-14 days of clopidogrel (the maximal effect is usually reached by 4 days post-initiation). Cats were treated with a standard oral dose of 18.75mg per cat every 24 hours.
The frequencies of the known SNPs in the P2RY1, P2RY12, and CYP2C41 genes were determined and found to follow a Hardy-Weinberg equilibrium.

Concentrations of clopidogrel and its active and inactive metabolites were assessed. Platelet function was assessed by whole blood aggregometry using the Multiplate system, and flow cytometry to measure phosphorylation of P-VASP and P-selectin.

The authors found that concentrations of clopidogrel and its active metabolite did not correlate with the degree of platelet function inhibition. Genotype was not associated with concentrations of clopidogrel or its active metabolite.

Significant variability in P-VASP expression was seen that was not correlated significantly with clopidogrel use or genotype, leading the authors to posit that P-VASP expression may not be an ideal test of clopidogrel effect. P-selectin expression was also not influenced by genotype, however, it was inhibited by clopidogrel. This suggests that clopidogrel may have modes of action unrelated to inhibition of the P2Y12 receptor, or that other pathways are at play.

In most cats, the standard dose of clopidogrel inhibited platelet function by both aggregometry and flow cytometry. However, in cats with mutations to the P2Y12 receptor, clopidogrel effect was absent or diminished. Specifically, the mutation P2RY1:A236G was associated with significant resistance to clopidogrel even after multivariate regression. Interestingly, clopidogrel does not bind to the P2Y1 receptor, and so the mutation in this gene may not directly influence clopidogrel binding, but other downstream effects of P2Y12 inhibition. It was not established if this P2Y1 mutation increased the risk of thrombosis in cats.

The authors suggest that variations in the P2Y receptors on platelet surfaces may play a significant role in resistance to clopidogrel, and in fact that this may be a more prominent determining factor in clopidogrel resistance than variations in CYP enzymes.

There were several limitations to this paper. Among them were the relatively small sample size, especially when adjusting for specific mutations and other subgroups. The study was limited to cats with HCM, which, while the most common use of clopidogrel is not the only indication for its use. A limited number of SNPs were assessed, and it is possible that other mutations in the P2Y gene or other genes could affect clopidogrel responsiveness.
Overall, this study serves to demonstrate the importance of monitoring clopidogrel effect in cats. While widespread genetic testing is likely not practical, several methods of platelet function analysis (ie impedance and optical aggregometry, PlateletWorks, the Platelet Function Analyzer, etc) are able to readily distinguish clopidogrel effect. Outside of variation in the P2Y12 receptor, polymorphisms in the cytochrome P450 system that metabolizes clopridogrel to its active metabolite also affect resistance to this drug. Variations in body weight, sex, and ability to administer medication may also affect efficacy.

See Also
Hogan, D. F. et al. Secondary prevention of cardiogenic arterial thromboembolism in the cat: the double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). J. Vet. Cardiol. 17(1), 306–317. https://doi.org/10.1016/j.jvc.2015.10.004 (2015).

Teuber, M. & Mischke, R. Influence of a low dosage of clopidogrel on platelet function in cats as measured by the platelet function analyser PFA-100 and the multiplate analyser. Res Vet Sci 109, 149–156. https://doi.org/10.1016/j.rvsc.2016.09.011 (2016).

Lee, P. M., Faus, M. C. L. & Court, M. H. High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism. J. Vet. Pharmacol. Ther. 42, 16–25. https://doi.org/10.1111/jvp.12717 (2019).

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