Abstract
Horses with inflammatory and infectious disorders are often treated with injectable heparin anticoagulants to prevent thrombotic complications. In humans, a new class of direct oral acting anticoagulants (DOAC) appear as effective as heparin, while eliminating the need for daily injections. Our study in horses evaluated apixaban, a newly approved DOAC for human thromboprophylaxis targeting activated factor X (Xa). Our goals were to: (1) Determine pharmacokinetics and pharmacodynamics of apixaban after oral (PO) and intravenous (IV) administration in horses; (2) Detect any inhibitory effects of apixaban on ex vivo Equid herpesvirus type 1 (EHV-1)-induced platelet activation, and (3) Compare an anti-Xa bioactivity assay with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) for measuring apixaban concentrations. In a blinded placebo-controlled cross-over study, five horses received a single dose (0.2 mg/kg) of apixaban or placebo PO or IV. Blood was collected before and at 3 (IV) or 15 (PO) min, 30 and 45 min, and 1, 2, 3, 4, 6, 8, and 24 h after dosing for measuring apixaban UPLC-MS concentrations and anti-Xa activity. Pharmacodynamic response was measured in a dilute prothrombin time (dPT) assay. Flow cytometric EHV-1-induced platelet P-selectin expression and clinical pathologic safety testing were performed at baseline, 2 and 24 h and baseline and 24 h, respectively. We found no detectable apixaban in plasma PO administration. After IV administration, plasma apixaban levels followed a two-compartment model, with concentrations peaking at 3 min and decreasing to undetectable levels by 8 h. The elimination half-life was 1.3 ± 0.2 h, with high protein binding (92–99%). The dPT showed no relationship to apixaban UPLC-MS concentration and apixaban did not inhibit EHV-1-induced platelet activation after IV dosing. Apixaban anti-Xa activity showed excellent correlation to UPLC-MS (r2 = 0.9997). Our results demonstrate that apixaban has no apparent clinical utility as an anticoagulant for horses due to poor oral availability.
Highlights
Inherited and acquired diseases can cause abnormal hemostasis in horses, leading to either insufficient or excessive coagulation or fibrinolysis, resulting in hemorrhage or thrombosis [1]
The mean ± standard deviation (SD) plasma concentration of apixaban peaked at 733 ± 136 ng/mL at 3 min and decreased to undetectable levels by 8 h in all horses
The results of our study show that a single oral dose of apixaban at 0.2 mg/kg was not absorbed by horses
Summary
Inherited and acquired diseases can cause abnormal hemostasis in horses, leading to either insufficient or excessive coagulation or fibrinolysis, resulting in hemorrhage or thrombosis [1]. The virus infects endothelial cells, resulting in vasculitis and thrombi, with associated ischemic and inflammatory lesions in the central nervous system and placenta [9, 10]. We and others have shown that EHV-1 is associated with a hypercoagulable state in horses, as seen by increased D-dimer concentrations in experimentally infected horses [11] and the ability of the virus to upregulate tissue factor on monocytes [12] and generate thrombin, leading to platelet activation, ex vivo [12]
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