The Successful Reversal of Dabigatran-Induced Bleeding by Coagulation Factor Concentrates in a Rat Tail Bleeding Model Do Not Correlate with Ex Vivo Markers of Anticoagulation

Dabigatran etexilate (DE) is a prodrug, which is rapidly converted in vivo to the active moiety dabigatran, a potent, direct thrombin inhibitor. It is approved as an alternative to oral vitamin K antagonists for sustained prevention of ischemic and hemorrhagic strokes in patients with atrial fibrillation. However, as with any anticoagulant, bleeding risks are associated with its use. Thus, the effects of different coagulation factor concentrates, prothrombinase complex concentrates, activated prothrombinase complex concentrates and recombinant factor VIIa were tested for their ability to reverse bleeding of high dose oral dabigatran etexilate treatment and the corresponding systemic anticoagulation was measured.

Rats (Hann:Wistar, 220 g BW) were given 30 mg/kg DE or vehicle by gavage and 20 min later were anesthetized for surgical preparation. Catheters for i.v. administration of reversal agent and blood sampling were placed and 45 min after oral DE a reversal agent (Beriplex^®, Octaplex^®, Feiba^® and NovoSeven^®) or vehicle was administered intravenously at clinically recommended doses. Bleeding was tested at 5, 15, 30 and 120 min (n=3-6/group) post i.v. dosing. Bleeding was induced using a rat tail cut model, where standardized incisions are made in the rat tail and the time to hemostasis recorded. Blood samples were taken at the same time points as bleeding above to allow correlation between ex vivo clotting and bleeding times. Clotting was performed using aPTT, TT, PT, ECT and diluted TT on a laboratory coagulometer and dabigatran plasma levels were determined by Hemoclot. Data shown as mean±SE.

Control bleeding times in the absence of treatment were 171±10s over the 2hr experiment. Oral treatment with 30 mg/kg DE resulted in an ∼3-fold elevation in time to hemostasis (495±65 s) just prior to reversal agent administration, this correlated with supratherapeutic dabigatran plasma levels between 800–1000 ng/ml. Beriplex^® 35 U/kg, Octaplex^® 40 U/kg, Feiba^® 100 U/kg and NovoSeven^® 0.5 μg/kg all completely reversed the DE-induced prolonged bleeding time to baseline levels within 5 min of i.v. administration. This effect was maintained over the 2 hr measurement period.

All clotting tests were prolonged 3–5-fold baseline with the administered dose of DE, indicating the supratherapeutic dose used. The TT, aPTT and ECT all remained prolonged after administration of the coagulation factor concentrates, despite reversal of bleeding time. In contrast the PT was reversed to baseline levels with all coagulation factor concentrates, regardless of whether bleeding time was reversed or not. Thus all these parameters did not correlate with the bleeding outcome measurement.

This study illustrates that high doses of dabigtran that induce bleeding can be reversed by coagulation factor concentrates at clinically recommended doses in this animal model. However, the systemic coagulation parameters routinely measured clinically do not predict this reversal. This may be due to lack of predictiveness of systemic clotting on local hemostasis at the site of injury for DTIs, for instance by not taking the role of local tissue factor generation and other surface-dependent processes into account.

van Ryn:Boehringer Ingelheim: Employment. Schurer:Boehringer Ingelheim: Employment. Kink-Eiband:Boehringer Ingelheim: Employment. Clemens:Boehringer Ingelheim Pharma GmbH & Co. KG: Employment.