Evaluation of point‐of‐care coagulation tests as alternatives to anti‐Xa activity for monitoring the anticoagulant effects of rivaroxaban in healthy dogs

Lynch, Alex; Ruterbories, Laura; Griffith, Emily H.; Hanel, Rita M.; Stablein, Alyssa P; Brooks, Marjory B.

doi:10.1111/vec.13011

Cited by 7 publications

(17 citation statements)

References 31 publications

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“…While these assays provide pharmacodynamic information on apixaban's anticoagulant action, they are not suited to gauge clinical efficacy for thromboprophylaxis or as treatment for dogs with overt thrombosis. Similar to other investigations of DOACs in dogs ( 17 , 49 , 50 ), we used TEG to assess the effect of apixaban on global hemostasis. We used a 1:50,000 TF dilution for assay activation in order to produce a sensitive assay.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs

et al. 2021

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Thrombosis is common in critically ill dogs and causes considerable morbidity and mortality. The direct factor Xa inhibitor apixaban is safe, efficacious, and convenient in humans. This study aimed to determine the pharmacokinetics (PK), bioactivity, protein binding, and bioavailability of apixaban following intravenous (IV) and oral (PO) administration to healthy dogs. Six healthy, adult, mixed-breed dogs were administered apixaban 0.18 mg/kg IV and then following a minimum 2-week washout period administered apixaban 0.2 mg/kg PO. Dogs were monitored using an apixaban-calibrated anti-Xa bioassay, prothrombin time (PT) and activated partial thromboplastin time (aPTT) and tissue-factor thromboelastography (TF-TEG). Plasma apixaban concentrations were measured using liquid chromatography-tandem mass spectrometry. Concentration-time plots were constructed, and PK modeling performed using compartmental methods. Administration of IV and PO apixaban was well-tolerated. Following IV administration, mean half-life was 4.1 h, and volume of distribution was 177 ml/kg. Apixaban was highly protein bound (98.6%). Apixaban concentrations and anti-Xa activity were highly correlated (R2 0.994, P < 0.0001). Intravenous apixaban significantly prolonged PT at time points up to 1 h, and aPTT at time points up to 0.25 h post-administration. Coagulation times were positively correlated with apixaban concentrations (PT R2 0.599, P < 0.0001; aPTT R2 0.430, P < 0.0001) and TF-TEG R-time was significantly prolonged 0.25 h post-administration. Following oral administration, mean bioavailability was 28.4%, lag time was 2 h, time to Cmax was 5 h and the apparent elimination half-life was 3.1 h. Oral apixaban significantly prolonged PT at 4, 6, and 8 h but aPTT and TF-TEG were not consistently affected by oral apixaban. Apixaban concentrations are best monitored using anti-Xa activity. Future studies should determine PK and bioactivity of other doses using commercial tablets and following multidose administration and establish safe, effective dosing ranges in sick dogs.

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Section: Discussionmentioning

confidence: 99%

“…This might have increased the potential for influence by pre-analytical factors. Others have used higher TF concentrations including 1:100 ( 17 , 50 ) and 1:3,700 ( 49 ). The PROVETS guidelines ( 36 ) recommend using both a 1:3,600 and a 1:50,000 TF concentration for small animals.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs

et al. 2021

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“…Thrombin generation assays have been evaluated in dogs 13,14 and are decreased following heparin and rivaroxaban administration. [15][16][17] Rodent models demonstrate reduced TG following clopidogrel administration as well, 18 but clopidogrel inconsistently attenuates TG in people. [19][20][21][22] There is currently a knowledge gap regarding the impact of pharmacologic platelet inhibition on TG assays in dogs.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a thrombin generation assay in dogs administered clopidogrel

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Ruterbories

et al. 2022

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Background: The antiplatelet effect of clopidogrel can vary between patients. A modified thromboelastography (TEG) protocol (TEG-Platelet Mapping assay® [TEG-PM]) can be used for clopidogrel monitoring but is not widely available. Thrombin generation (TG) assays could offer a novel alternative. The main objective of this pilot study was to assess TG assay variables (lag time, peak, endogenous thrombin potential [ETP]) in dogs before and after 7 days of clopidogrel administration, and compare with TEG-PM variables (maximum amplitude [MA]-ADP and percentage (%) inhibition). Six healthy mix-breed dogs were enrolled in this pilot study. Blood samples for platelet count, TG assays, and TEG-PM were obtained at two time points, corresponding to baseline, and after 7 days of clopidogrel administration (mean 2.3 +/- 0.3 mg/kg PO q24 hours). Data were then compared with a Student’s t-test. Results There was no significant change in TG assay variables performed on platelet poor plasma after 7 days of clopidogrel administration: lag time (Day 1: 1.8 +/- 0.2 min, Day 7: 1.8 +/- 0.2 min, P = 0.42); Peak (Day 1: 76 +/- 7 nM, Day 7: 72 +/- 10 nM, P = 0.49); and ETP (Day 1: 399 +/- 27 nM*min, Day 7: 392 +/- 32 nM*min; P = 0.49). There were significant changes in TEG MA-ADP (Day 1: 19 +/- 8 mm, Day 7: 9 +/- 6 mm, P = 0.04) and % inhibition (Day 1: 58 +/- 27, Day 7: 99 +/- 0.3, P = 0.02) however over the course of the study. Conclusions Clopidogrel administration did not lead to changes in TG assay variables performed on platelet poor plasma samples, despite concomitant changes in TEG-PM variables consistent with platelet inhibition. Thrombin generation performed on platelet poor plasma does not appear to be a useful antiplatelet monitoring tool in dogs.

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“…22 The RapidTEG assay can be used to assess hemostasis of veterinary species (dog, cat, horse) in ~15 min. 4 Studies evaluating the TEG 5000 analyzer with the RapidTEG activator in healthy dogs have shown mixed results using RapidTEG to monitor rivaroxaban therapy, 1,26 as well as results supporting using RapidTEG for monitoring unfractionated heparin therapy. 28 The TEG Functional Fibrinogen assay uses an activator that consists of tissue factor and abciximab, which binds to human platelet glycoprotein (GP) IIb/IIIa receptors, inhibiting platelet aggregation.…”

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confidence: 99%

“…27 Compared to standard plasma-based coagulation tests, such as prothrombin time and activated partial thromboplastin time, viscoelastic tests reflect more closely the in vivo cell-based model of hemostasis, 21 allowing for more accurate understanding of a patient's current coagulation status. 24,27 Viscoelastic tests serve as a valuable adjunct for individualized clinical decision-making in veterinary patients with conditions accompanied by altered hemostasis, such as trauma, 16 spontaneous hemoperitoneum, 12 disseminated intravascular coagulation, 2 sepsis, 37 immune-mediated hemolytic anemia, 15 neoplasia, 25 renal disease, 10 intestinal disease, 8 hepatic disease, 13 iatrogenic anticoagulation, 1,26,28 pyometra, 9 and pancreatitis. 32 Two of the most common benchtop viscoelastic analyzers used in veterinary medicine are the TEG 5000 Thrombelastograph (Haemonetics) and the ROTEM delta (Werfen).…”

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confidence: 99%

Comparison of assessment of coagulation in healthy dogs by the TEG 6s and TEG 5000 viscoelastic analyzers

et al. 2022

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The TEG 6s (Haemonetics) point-of-care viscoelastic analyzer is portable, compact, simple to use, and has the potential for rapid viscoelastic analysis that can guide the treatment of veterinary patients at the site of care. Although approved for use in people, the TEG 6s has yet to be evaluated for hemostatic analysis in veterinary medicine. Citrated whole blood (CWB) was collected from 27 healthy dogs. An aliquot of CWB from each dog was diluted by 33% with an isotonic crystalloid, representing an in vitro model of hemodilution. Unaltered and diluted CWB samples were analyzed using 2 TEG 6s and 6 TEG 5000 (Haemonetics) analyzers. The 6 TEG 5000 analyzers ran duplicate analyses of either unaltered or diluted samples using 1 of 3 reagents (Haemonetics): Kaolin TEG, RapidTEG, or TEG Functional Fibrinogen. Duplicate TEG 5000 analyses were averaged and compared with a single TEG 6s analysis. Lin concordance correlation coefficient and Bland–Altman plots were used to evaluate agreement of reaction time, kinetic time, alpha angle, maximum amplitude (MA), and G value (G) for samples activated with Kaolin TEG, and agreement of MA for samples activated with RapidTEG between the 2 machines. Overall, agreement between the TEG 6s and TEG 5000 analyzers was poor. Viscoelastic measurements by the TEG 6s and TEG 5000 in healthy dogs were not all interchangeable. Agreement was satisfactory only for MA and G measurements of diluted blood samples activated with Kaolin TEG, and MA measurements for both unaltered and diluted blood samples activated with RapidTEG.

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Evaluation of point‐of‐care coagulation tests as alternatives to anti‐Xa activity for monitoring the anticoagulant effects of rivaroxaban in healthy dogs

Cited by 7 publications

References 31 publications

Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs

Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs

Evaluation of a thrombin generation assay in dogs administered clopidogrel

Comparison of assessment of coagulation in healthy dogs by the TEG 6s and TEG 5000 viscoelastic analyzers

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