Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model.
BACKGROUND
One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation.


OBJECTIVE
This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran-associated bleeding diathesis.


METHODS
Anesthetized rabbits were treated with 0.4 mg kg(-1) dabigatran followed by PCC doses of 20, 35 or 50 IU kg(-1) or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined.


RESULTS
From an initial mean of 29 mL, blood loss progressively declined by 5.44 mL with a 95% confidence interval (CI) of 2.21-8.67 mL per 10 IU kg(-1) increment in PCC dose (P = 0.002). At a PCC dose of 50 IU kg(-1) blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7 min (P < 0.001). The rate of hemostasis was nearly trebled with each 10 IU kg(-1) increment in PCC dose (rate ratio, 2.89; CI, 1.64-5.09).


CONCLUSIONS
In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted.
CSL Behring GmbH, Marburg Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. ingo.pragst@cslbehring.com
I
I
Pragst
S H
SH
Zeitler
B
B
Doerr
F J
FJ
Kaspereit
E
E
Herzog
G
G
Dickneite
J
J
van Ryn
D000818:Animals; D000925:Anticoagulants / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D001562:Benzimidazoles / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D000069604:Dabigatran; D004338:Drug Combinations; D005164:Factor IX / Q000494:pharmacology*; D005167:Factor VII / Q000494:pharmacology*; D005170:Factor X / Q000494:pharmacology*; D005260:Female; D023421:Models, Animal; D010919:Placebos; D011516:Prothrombin / Q000494:pharmacology*; D011817:Rabbits; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology
D000925:Anticoagulants; D001562:Benzimidazoles; D004338:Drug Combinations; D010919:Placebos; C525441:factor IX, factor VII, factor X, prothrombin drug combination; D015091:beta-Alanine; D005167:Factor VII; D011516:Prothrombin; D005164:Factor IX; D005170:Factor X; D000069604:Dabigatran