Abstract 11955: Successful Reversal of Dabigatran-Induced Bleeding by 3-Factor Coagulation Concentrates in a Rat Tail Bleeding Model: Lack of Correlation with ex vivo Markers of Anticoagulation
Dabigatran etexilate (DE) is rapidly converted in vivo to the active moiety dabigatran, a potent, direct thrombin inhibitor. It is approved as an alternative to warfarin for prevention of ischemic and hemorrhagic strokes in patients with atrial fibrillation. However bleeding risks can be associated with its use. Preclinical data show 4-factor prothrombinase complex concentrates (PCC) can reverse dabigatran-induced bleeding, but effects of a 3-factor PCC are unknown. Thus 3-factor PCCs were tested for their ability to reverse bleeding of high dose oral DE treatment and systemic anticoagulation. Rats were given 30 mg/kg DE or vehicle orally. Bebulin®, Profilnine® or vehicle i.v. was given 45 min following DE. Bleeding was tested 5, 15, 30 and 120 min (n=4) post i.v. dosing using a rat tail cut model (standardized incisions are made in the rat tail) and the time to hemostasis recorded. Blood samples were taken at the same time points to allow correlation between ex vivo clotting and bleeding times. Clotting was performed using aPTT, PT, ECT. Diluted TT (dTT) was used to determine dabigatran plasma levels (Hemoclot®). Data shown as mean±SE. Control bleeding times were ∼165±9 s over 2hrs. Oral treatment with 30 mg/kg DE resulted in an ∼2.8-fold elevation in bleeding time (470±42 s) just prior to reversal agent administration, this correlated with dabigatran plasma levels ∼800 ng/ml. Bebulin® and Profilnine® completely reversed the DE-induced prolonged bleeding time to baseline levels (p < 0.001) within 5 min of i.v. administration. This effect was maintained over 30 min, but was not different from dabigatran after 2 hrs (p>0.05). Clotting tests were prolonged 3-5-fold over baseline with the high dose DE. The aPTT, PT and ECT all remained prolonged after administration of the PCCs, despite reversal of bleeding time. Thus high doses of dabigtran that induce bleeding can be reversed by 3-factor PCCs at clinically recommended doses in this animal model. However, systemic coagulation parameters routinely measured clinically do not predict this reversal. Thus systemic clotting may not be predictive of local hemostasis at the site of injury for DTIs, i.e. by not taking the role of local tissue factor generation and other surface-dependent processes into account.
- © 2012 by American Heart Association, Inc.