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Direct oral anticoagulants (DOAC) are increasingly common, with bleeding events associated with elevated plasma concentrations. Rotational thromboelastometry (ROTEM), a point-of-care tool for assessing secondary hemostasis, has demonstrated a correlation with increasing concentrations of DOAC. However, previous studies have only partially explored this relationship. The primary aim in the current study was to investigate the impact of increasing rivaroxaban concentrations on clotting time (CT) in the EXTEM assay. The secondary aims were to investigate the impact of increasing rivaroxaban concentrations on clot formation time (CFT) and α-angle (AA) and to investigate the impact of increasing concentrations of dabigatran and apixaban on CT, CFT and AA. Blood from 12 healthy volunteers was spiked to anticipated concentrations of rivaroxaban, dabigatran and apixaban at 0, 50, 100, 200, 500 and 1000 µg/L each. Blood with these varying concentrations was analyzed in four different ROTEM assays and CT, CFT and AA were extracted. CT increased linearly with increasing concentrations of all three DOACs. Rivaroxaban and dabigatran spiked blood showed an increase in CT-EXTEM for the 200-1000µg/L concentrations, compared to baseline, and apixaban for the 500-1000 µg/L concentrations. CFT and AA were affected only in supratherapeutic concentrations for all tested DOACs and primarily in the INTEM assay. Among the tested DOACs, apixaban demonstrated the least impact on CT across all assays. In conclusion, ROTEM-derived CT measurements can serve as surrogate markers for DOAC concentrations.

In this study, we evaluated the in vitro stability of direct oral anticoagulants (DOACs) in blood samples of 57 patients under different storage conditions using functional coagulation assays. We determined the analyte concentrations (1) immediately after blood collection (baseline); (2) after storage of citrated whole blood (agitated) at room temperature and citrated plasma at room temperature and at 4 °C for 4, 8, and 24 h, respectively; and (3) after storage of citrated plasma at -20 °C for 30, 60, and 90 days. According to the concept of acceptable change limits (ACL), analytes were considered stable if the mean relative analyte recovery at a given time was >78%. The mean baseline values (range) of dabigatran, rivaroxaban, apixaban, and edoxaban were 115 ng/mL (62-217), 129 ng/mL (31-215), 156 ng/mL (49-362), and 101 ng/mL (33-283), respectively. After applying the analyte stability limit, all four DOACs were stable for 24 h at room temperature and at 4 °C. The mean recovery after 24 h was 102-111% for dabigatran, 88-97% for rivaroxaban, 95-98% for apixaban, and 90-96% for edoxaban. When plasma samples were stored at -20 °C, the mean percentage deviation after 90 days for all four DOACs was ≤10%, even after three freeze-thaw cycles. Thus, for the correct determination of DOAC plasma concentrations, blood samples do not have to be analyzed immediately and can be stored at room temperature for up to 24 h before analysis. In clinical practice, blood sample transport and storage for DOAC measurements appear to be unproblematic.

Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily) or rivaroxaban (10 or 15 mg once daily) at one general hospital. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.

Idarucizumab, an antidote specific for dabigatran, became available recently. Dabigatran is not associated with increased risk of hepatotoxicity in comparison with warfarin, but it is seen as a rare side-effect. Cases of cholestatic liver injury due to dabigatran have not been reported previously. We present a case of severe gastro-intestinal bleeding with underlying dabigatran intoxication in a patient with renal failure and the effect of reversal of dabigatran using idaruzicumab on coagulation assays. International normalized ratio (INR) and activated partial thromboplastin time (APTT) results were elevated in a setting of sepsis, possibly due to liver failure. INR and APTT can be elevated if sepsis is complicated by disseminated intravascular coagulation (DIC) or liver failure, making it challenging to determine dabigatrans contribution to their prolongation. A rebound effect after administration of idarucizumab and slow elimination of dabigatran due to reduced kidney function could be detected using the Hemoclot ® diluted thrombin time (dTT) in this situation, in contrast to with non-dilutional assays. Before admission, cholestatic liver injury started shortly after initiation of dabigatran etexilate therapy. As no other cause was found, this liver injury was likely to be drug-induced. Bleeding cessated promptly after administration of idarucizumab in dabigatran intoxication. In conclusion, the anticoagulant effect of dabigatran can be measured by Hemoclot ® dTT in sepsis and cholestatic liver injury was seen as a possible rare side-effect of dabigatran treatment.

Context: An overdose of oral anticoagulants represents a challenging scenario for emergency physicians. Dabigatran, an oral direct thrombin inhibitor, is increasingly used in place of warfarin. The lack of an antidote is a concern in patients who overdose on dabigatran, even though the drug can be eliminated with hemodialysis. Idarucizumab is an antibody fragment that binds dabigatran with high affinity. It reverses the anticoagulant effect of dabigatran within minutes and is approved for the reversal of dabigatran during emergency situations., Case Details: We describe the use of idarucizumab in the management of a 68-year-old woman who was taking dabigatran 150 mg twice daily and ingested 125 capsules. Despite gastric lavage and administration of activated charcoal within two hours of drug intake, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) remained prolonged. The administration of 5 g of intravenous idarucizumab promptly and completely reversed the anticoagulant activity of dabigatran as assessed by routine and specific coagulation assays (aPTT from to 75 to 26 s, PT from 26 to 11 s and diluted thrombin time from 92 to 27 s). The initially planned emergency hemodialysis was canceled., Discussion: This case highlights the potential use of idarucizumab for the management of massive dabigatran overdoses.