Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation.
BACKGROUND
Dabigatran is a potent oral anticoagulant. Like any anticoagulant, there is an increased risk of bleeding associated with its use, and reversal may be needed in cases of severe bleeding.


METHODS
In this study, six coagulation factor concentrates (CFCs) were tested for their ability to reduce bleeding induced by oral dabigatran etexilate (30 mg/kg) in a rat-tail bleeding model (n = 5 to 8 per group): three-factor (Profilnine [Grifols Biologicals Inc., Los Angeles, CA] and Bebulin [Baxter BioScience, Westlake Village, CA]) and four-factor prothrombin complex concentrates (Beriplex [CSL Behring, Marburg, Germany] and Octaplex [Octapharma AG, Lachen, Switzerland]), activated prothrombin complex concentrate (Factor Eight Inhibitor Bypassing Activity; Baxter AG, Vienna, Austria), and recombinant factor VIIa (NovoSeven; NovoNordisk, Bagsværd, Denmark). The effect of CFCs on prolongation of coagulation assays was measured. Thrombin generation after administration of each CFC was compared in vitro using human plasma (n = 5) spiked with dabigatran in concentrations corresponding to median peak (200 ng/ml) and supratherapeutic values (600 and 1,000 ng/ml).


RESULTS
Dabigatran resulted in an approximately three-fold increase in bleeding time, consistent with supratherapeutic dabigatran plasma levels. Beriplex (35 and 50 IU/kg), Octaplex (40 IU/kg), Profilnine (50 IU/kg), Bebulin (60 IU/kg), Factor Eight Inhibitor Bypassing Activity (100 U/kg), and NovoSeven (500 μg/kg) significantly decreased this prolonged bleeding time over 30 min (P < 0.001). The coagulation assays were prolonged three- to eight-fold over baseline (P = 0.01). None of the CFCs produced a consistent change in these assays that was predictive of reduced bleeding. Thrombin generation reversal was dependent on the concentration of dabigatran and each CFC; normalization occurred at the lower concentration of dabigatran with most CFCs, but not at higher concentrations.


CONCLUSIONS
In this animal model, bleeding induced by high doses of dabigatran can be reduced by CFCs. However, routine coagulation assays do not predict this effect.
From the Department of CardioMetabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany (J.v.R., J.S., M.K.-E.); and Department of Global Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany (A.C.).
Joanne
J
van Ryn
Johanna
J
Schurer
Monika
M
Kink-Eiband
Andreas
A
Clemens
D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity*; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D001779:Blood Coagulation Factors / Q000494:pharmacology / Q000627:therapeutic use*; D000069604:Dabigatran; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000139:chemically induced* / Q000188:drug therapy*; D006801:Humans; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013623:Tail / Q000098:blood supply; D016896:Treatment Outcome
D001562:Benzimidazoles; D001779:Blood Coagulation Factors; D011725:Pyridines; D000069604:Dabigatran