Synergistic inhibitory effects of clopidogrel and rivaroxaban on platelet function and platelet‐dependent thrombin generation in cats

• Published in: Journal of veterinary internal medicine Vol. 37; no. 4; pp. 1390 - 1400
• Main Authors: Lo, Sara T., Li, Ronald H. L., Georges, Catherine J., Nguyen, Nghi, Chen, Cheyenne K., Stuhlmann, Claire, Oldach, Maureen Sigmund, Rivas, Victor Noel, Fousse, Samantha, Harris, Samantha P., Stern, Joshua A.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-07-2023; Wiley
• Subjects: Adenosine diphosphate; Anticoagulants; Biochemistry; Blood clots; Blood platelets; cardiology; Cardiomyopathy; cardiovascular; Cardiovascular disease; clopidogrel resistance; factor Xa inhibitor; Flow cytometry; Heart failure; hypertrophic cardiomyopathy; Mortality; Plasma; Proteins; saddle thrombus; SMALL ANIMAL; Thromboembolism; Thrombosis; United States > US; Maine; thromboembolism; saddle thrombus; hypertrophic cardiomyopathy; factor Xa inhibitor; cardiovascular; clopidogrel resistance; cardiology
• ISSN: 0891-6640; 1939-1676
• DOI: 10.1111/jvim.16727

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.