Platelet Activation and Clopidogrel Effects on ADP‐Induced Platelet Activation in Cats with or without the A31P Mutation in MYBPC3

Abstract

BackgroundClopidogrel is commonly prescribed to cats with perceived increased risk of thromboembolic events, but little information exists regarding its antiplatelet effects.ObjectiveTo determine effects of clopidogrel on platelet responsiveness in cats with or without the A31P mutation in the MYBPC3 gene. A secondary aim was to characterize variability in feline platelet responses to clopidogrel.AnimalsFourteen healthy cats from a Maine Coon/outbred mixed Domestic cat colony: 8 cats homozygous for A31P mutation in the MYPBC3 gene and 6 wild‐type cats without the A31P mutation.MethodsEx vivo study. All cats received clopidogrel (18.75 mg PO q24h) for 14 days. Before and after clopidogrel treatment, adenosine diphosphate (ADP)‐induced P‐selectin expression was evaluated. ADP‐ and thrombin‐induced platelet aggregation was measured by optical aggregometry (OA). Platelet pVASP and ADP receptor response index (ARRI) were measured by Western blot analysis.ResultsPlatelet activation from cats with the A31P mutation was significantly (P = .0095) increased [35.55% (18.58–48.55) to 58.90% (24.85–69.90)], in response to ADP. Clopidogrel treatment attenuated ADP‐induced P‐selectin expression and platelet aggregation. ADP‐ and PGE 1‐treated platelets had a similar level of pVASP as PGE 1‐treated platelets after clopidogrel treatment. Clopidogrel administration resulted in significantly lower ARRI [24.13% (12.46–35.50) to 11.30% (−7.383 to 23.27)] (P = .017). Two of 13 cats were nonresponders based on OA and flow cytometry.Conclusion and Clinical ImportanceClopidogrel is effective at attenuating platelet activation and aggregation in some cats. Cats with A31P mutation had increased platelet activation relative to the variable response seen in wild‐type cats.

American College of Veterinary Emergency and Critical Care (ACVECC) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines: Small animal

“…In cats, 8 studies (LOE 1–4, Good–Poor) suggest clopidogrel is effective in cats . Three studies (LOE 1–4, Good–Poor) suggest in vivo efficacy against provoked arterial thrombosis .…”

Assessment of P2Y12 Inhibition by Clopidogrel in Feline Platelets Using Flow Cytometry Quantification of Vasodilator-Stimulated Phosphoprotein Phosphorylation

“…The authors had previously evaluated P-VASP in feline platelets using Western blot analysis. Although a significant increase in P-VASP was found in response to clopidogrel therapy, interindividual variability was extremely high (11). In addition, protein analysis by Western blot only yielded semi-quantitative results that were subjected to high inter-operator variability.…”

High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

“…Many mechanisms are thought to cause clopidogrel response variability in people including body weight, sex, and variable metabolism of clopidogrel primarily due to gene polymorphisms affecting the CYP2C subfamily of CYP450 (Backman et al., ; Li et al., ; Shuldiner et al., ; Simon et al., ). Clopidogrel response variability also exists in cats (Hogan et al., ; Li, Stern, Ho, Tablin, & Harris, ; Teuber & Mischke, ). The cause for variable clopidogrel response in cats is currently unknown.…”