Efficacy of direct oral anticoagulants in plasma from patients with liver cirrhosis at high thrombotic risk

Objective Liver cirrhosis (LC) is a complex pathology which confers a prothrombotic state. The anticoagulation of LC-patients remains challenging because of the unknown efficacy of heparins and direct oral anticoagulants (DOACs), monitoring difficulty (particularly for coumarins), and alterations in drug metabolism. Among DOACs, apixaban and dabigatran seem to have the most adequate metabolic profile for LC-patients. We aimed to analyse the in vitro efficacy of these two anticoagulants in LC-patients at high thrombotic risk.

Material and Methods We included 22 LC-patients identified as prothrombotic using ex vivo thrombin generation (ST Genesia with ThromboScreen reagents, Stago, Asnières-sur-Seine, France) and nine healthy donors. Plasma samples were spiked with either Owren’s veronal buffer, apixaban, or dabigatran solutions (final target concentrations: 50, 150 ng/ml; additional concentration of 300 ng/ml for dabigatran). We have chosen these concentrations because they represent peak and through levels observed in clinical studies of a therapeutic anticoagulation with both drugs. After spiking, apixaban and dabigatran concentrations were verified and ex vivo thrombin generation were analysed using ST Genesia with DrugScreen reagents (Stago). Ratios for velocity index and peak height assessed without and with anticoagulants were calculated, and compared between LC-patients and healthy donors for each target concentration using Mann-Whitney test.

Results Ratios for velocity index and peak height according to apixaban and dabigatran concentrations are presented in Fig. 1. At a target concentration of 150 ng/ml (roughly representing peak levels for both DOACs), in apixaban treated samples the peak height ratio was slightly but significantly higher [median 0.74 (LC, red) vs. 0.60 (control, blue), p-value 0.0329] and the velocity index ratio significantly higher (0.42 vs. 0.27, p-value 0.0076) in LC-plasma compared to controls. With dabigatran, both ratios were significantly lower (0.58 vs. 0.80, p-value <0.0001; 0.51 vs. 0.94, p-value <0.0001) in the LC-group compared to controls.

Conclusion We demonstrated a slightly lower anticoagulant efficacy of apixaban and a clearly higher efficacy of dabigatran in LC compared to control plasma. Based on these preliminary data and on DOACs metabolism, apixaban appears to be the safest DOAC for LC-patients.

Abb 1. Ratios for velocity index and peak height according to apixaban (A, B) and dabigatran (C, D) concentrations in patients with liver cirrhosis (red) and healthy donors (blue). The lines represent the linear regression lines. PH, peak height; VI, velocity index.

Publication History

Article published online:
18 June 2021