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Published on: November 8, 2024
Synergistic inhibitory effects of clopidogrel and rivaroxaban on platelet function and platelet-dependent thrombin
Sara T Lo1, Ronald H L Li2, Catherine J Georges1
1University of California Davis School of Veterinary Medicine, William R. Prichard Veterinary Medical Teaching Hospital, Davis, California, USA.
Insights
Dual antithrombotic treatment (DAT) with clopidogrel and rivaroxaban safely reduced platelet activation and thrombin generation in cats. This combination therapy proved more effective than single-drug treatments for modulating platelet response.
Area of Science:
- Veterinary Pharmacology
- Cardiovascular Research
- Thrombosis and Hemostasis
Background:
- Dual antithrombotic treatment (DAT) using clopidogrel and rivaroxaban is sometimes used in cats with hypertrophic cardiomyopathy at risk of thromboembolism.
- Previous studies have not evaluated the combined effects of clopidogrel and rivaroxaban on platelet function in cats.
Purpose of the Study:
- To evaluate the safety of DAT in healthy cats.
- To compare ex vivo platelet activation, aggregation, and thrombin generation in cats treated with clopidogrel, rivaroxaban, or DAT.
- To test the hypothesis that DAT would safely modulate platelet activation and aggregation more effectively than monotherapy.
Main Methods:
- An unblinded, nonrandomized, ex vivo crossover study was conducted on nine healthy cats.
- Cats received 7-day treatments of rivaroxaban, clopidogrel, or DAT, with washout periods in between.
- Platelet activation (P-selectin expression), platelet-dependent thrombin generation, and platelet aggregation were measured before and after each treatment.
Main Results:
- No adverse effects were observed in any treatment group.
- DAT significantly decreased platelet activation, modulated response to thrombin, and reduced thrombin generation potential compared to single agents.
- DAT and clopidogrel inhibited ADP-mediated platelet aggregation, while rivaroxaban alone increased it.
Conclusions:
- Dual antithrombotic treatment (DAT) combining clopidogrel and rivaroxaban is safe in healthy cats.
- DAT effectively decreases platelet activation, response to agonists, and thrombin generation in feline platelets.
- DAT demonstrates superior efficacy in modulating platelet function compared to monotherapy with clopidogrel or rivaroxaban.
Background:
Dual antithrombotic treatment (DAT) with clopidogrel and rivaroxaban sometimes is prescribed to cats with hypertrophic cardiomyopathy at risk of thromboembolism. To date, no studies have evaluated their combined effects on platelet function.
Objectives/Hypothesis:
Evaluate the safety of DAT in healthy cats and compare, ex vivo, platelet-dependent thrombin generation and agonist-induced platelet activation and aggregation in cats treated with clopidogrel, rivaroxaban, or DAT. We hypothesized that DAT would safely modulate agonist-induced platelet activation and aggregation more effectively than single agent treatment.
Animals:
Nine apparently healthy 1-year-old cats selected from a research colony.
Methods:
Unblinded, nonrandomized ex vivo cross-over study. All cats received 7 days of rivaroxaban (0.6 ± 0.1 mg/kg PO), clopidogrel (4.7 ± 0.8 mg/kg PO), or DAT with defined washout periods between treatments. Before and after each treatment, adenosine diphosphate (ADP)- and thrombin-induced platelet P-selectin expression was evaluated using flow cytometry to assess platelet activation. Platelet-dependent thrombin generation was measured by fluorescence assay. Platelet aggregation was assessed using whole blood impedance platelet aggregometry.
Results:
No cats exhibited adverse effects. Of the 3 treatments, only DAT significantly decreased the number of activated platelets (P = .002), modulated platelet activation in response to thrombin (P = .01), dampened thrombin generation potential (P = .01), and delayed maximum reaction velocity (P = .004) in thrombin generation. Like clopidogrel, DAT inhibited ADP-mediated platelet aggregation. However, rivaroxaban alone resulted in increased aggregation and activation in response to ADP.
Conclusion And Clinical Importance:
Treatment combining clopidogrel and rivaroxaban (DAT) safely decreases platelet activation, platelet response to agonists, and thrombin generation in feline platelets more effectively than monotherapy with either clopidogrel or rivaroxaban.
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