Abstract
Specific antagonists have been developed for the reversal of direct oral anticoagulants (DOAC). We investigated the impact of these reversal agents on the plasma concentration and visco-elastic test results of dabigatran and factor Xa inhibitors. After baseline measurements of dabigatran, the plasma concentration, and the visco-elastic ClotPro® ecarin clotting time (ECA-CT), we added the reversal agent Idarucizumab in vitro and these two analyses were repeated. Likewise, the baseline plasma concentration of apixaban, edoxaban, and rivaroxaban as well as ClotPro® Russell’s viper venom test clotting time (RVV-CT) were measured and reanalyzed following Andexanet alfa spiking. We analyzed fifty blood samples from 37 patients and 10 healthy volunteers. Idarucizumab decreased the measured dabigatran plasma concentration from 323.9 ± 185.4 ng/mL to 5.9 ± 2.3 ng/mL and ECA-CT from 706.2 ± 344.6 s to 70.6 ± 20.2 s, (all, p < 0.001). Andexanet alfa decreased the apixaban concentration from 165.1 ± 65.5 ng/mL to 9.8 ± 8.1 ng/mL, edoxaban from 152.4 ± 79.0 ng/mL to 36.4 ± 19.2 ng/mL, and rivaroxaban from 153.2 ± 111.8 ng/mL to 18.1 ± 9.1 ng/mL (all p < 0.001). Andexanet alfa shortened the RVV-CT of patients with apixaban from 239.2 ± 71.7 s to 151.1 ± 30.2 s, edoxaban from 288.2 ± 65.0 s to 122.7 ± 37.1 s, and rivaroxaban from 225.9 ± 49.3 s to 103.7 ± 12.1 s (all p < 0.001). In vitro spiking of dabigatran-containing blood with Idarucizumab substantially reduced the plasma concentration and ecarin-test clotting time. Andexanet alfa lowered the concentration of the investigated factor Xa-inhibitors but did not normalize the RVV-CT. In healthy volunteers’ blood, Idarucizumab spiking had no impact on ECA-CT. Andexanet alfa spiking of non-anticoagulated blood prolonged RVV-CT (p = 0.001), potentially as a consequence of a competitive antagonism with human factor Xa.
Highlights
We investigated the impact of the direct oral anticoagulants (DOAC)-specific reversal agents Idarucizumab and Andexanet alfa on both the plasma concentration and visco-elastic parameter clotting time
The current study revealed that Idarucizumab spiking returned the dabigatran plasma concentration to values
In vitro monitoring of the reversal effect of DOAC-specific antagonists was feasible with both measurement of the DOAC plasma concentration using the chromogenic test and with the DOAC-specific assays
Summary
Direct oral anticoagulants (DOACs) are increasingly prescribed for stroke prevention in patients with non-valvular atrial fibrillation or as prophylaxis and treatment of thromboembolic events [1,2]. Phase III studies revealed a higher efficacy and an equivalent or lower rate of spontaneous bleeding events compared to vitamin K antagonists [3,4,5,6]. Similar findings have been reported for anticoagulated trauma patients on DOACs [7,8,9,10,11]. DOAC specific reversal agents have been approved, which considerably facilitate bleeding management in emergency scenarios. A modified and catalytically inactive recombinant human factor Xa molecule, competitively inhibits the activity of apixaban and rivaroxaban [14], but has not been yet approved for edoxaban due to the lack of data
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