Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model.
BACKGROUND
New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.


METHODS
Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.


RESULTS
Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.


CONCLUSIONS
In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.
Oliver
O
Grottke
Joanne
J
van Ryn
Henri M H
HM
Spronk
Rolf
R
Rossaint
D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001562:Benzimidazoles / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000097:blood / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D000069604:Dabigatran; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000494:pharmacology*; D065427:Factor Xa Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D008099:Liver / Q000293:injuries; D011725:Pyridines / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D013916:Thrombelastography / Q000379:methods; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000097:blood
D000931:Antidotes; D001562:Benzimidazoles; D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D007140:Immunoglobulin Fab Fragments; D011725:Pyridines; D011994:Recombinant Proteins; D015091:beta-Alanine; C025667:prothrombin complex concentrates; C103587:recombinant FVIIa; D015942:Factor VIIa; D000069604:Dabigatran