Cholestatic liver injury as a side-effect of dabigatran and the use of coagulation tests in dabigatran intoxication and after reversal by idarucizumab in bleeding and sepsis

Abstract

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.

Keywords:

• Antidotes
• blood coagulation tests
• dabigatran
• chemical and drug induced liver injury
• sepsis
• haemorrhage
• anticoagulants
• activated partial thromboplastin time
• blood coagulation
• prothrombin time
• international normalized ratio
• thrombin time

Disclosure statement

There are no conflicts of interest related directly to this manuscript. Conflicts of interest not directly related to this manuscript: W.J. Comuth has received research support from the European Society of Cardiology Working Group on Thrombosis, Siemens Healthcare, Diagnostica Stago and ANIARA; advisory board- and/or speaker fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer and Astra-Zeneca; she is principal investigator for studies conducted by Thrombosis Research Institute, Boehringer Ingelheim and Janssen-Cilag A/S. A.-M. B. Münster has received speaker fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer and Merck Sharp & Dohme Corporation (MSD). A.M. Haase, L.Ø. Henriksen, J. Malczynski and D. van de Kerkhof have no conflicts of interest.