Johanna Schurer

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 &mgr;g/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.

EVALUATION OF A SPECIFIC ANTIDOTE TO DABIGATRAN: IN VITRO PROPERTIES, PHARMACOKINETICS AND REVERSAL OF DABIGATRAN ETEXILATE–INDUCED BLEEDING IN RATS

The new oral anticoagulants have demonstrated efficacy and safety in preventing stroke in patients with atrial fibrillation; however, one feature they all share is the lack of a specific antidote in cases of emergency. A humanized antibody fragment (Fab) against dabigatran is currently in

DIFFERENTIAL EFFECTS OF DABIGATRAN ETEXILATE AND TICAGRELOR ON BLEEDING AS ASSESSED BY WASHED BLOOD AND SHED BLOOD TESTS IN HEALTHY SUBJECTS

The most frequent side effect associated with long term anticoagulant and antiplatelet therapy is bleeding. It has been attempted with different methods to assess blood loss in healthy volunteers (HV). The feasibility of two alternative methods for the assessment of bleeding due to anticoagulation