Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation.
Dabigatran is one of the new oral anticoagulants (NOACs) increasingly used for stroke prevention. Although specific antidotes are under development, coagulation factor concentrates are the only available options for the management of severe bleeding. In this study, the authors compared 6 coagulation factor concentrates (two 3-factor PCCs, two 4-factor PCCs, activated PCC and factor VIIa) for their ability to reduce bleeding induced by overdose of dabigatran in a rat-tail bleeding model. The secondary objective was to assess in vitro thrombin generation in response to increasing concentrations of each factor concentrate in human plasma spiked with dabigatran.
On the one hand, the authors observed that clinically relevant doses of the 6 coagulation factor concentrates significantly reduced bleeding time in rats that received excessive doses of dabigatran. However, factor VIIa administration was only effective at supra-therapeutic level. Interestingly, although dabigatran prolonged coagulation parameters in rats, administration of factor concentrates did not significantly affect the coagulation assays.
On the other hand, in vitro thrombin generation was decreased by dabigatran in a concentration-dependent manner. Addition of 3-factor, 4-factor and activated PCC restored thrombin generation while factor VIIa had no effect.
The authors conclude that whereas coagulation factor concentrates reduced bleeding induced by dabigatran in this animal model, standard coagulation assays did not consistently predict this effect. This is another non-human trial assessing the effect of factors concentrates on bleeding induced by NOAC (see the recent review by Lee FM et al. Thromb Res 2014;133:705-713). Currently, we only have limited experience with the management of severe bleeding in patients treated with NOACs. The results of these animal studies should be interpreted with caution until we have sufficient experience with the benefit-to-risk balance of the different factor concentrates.
– David Faraoni
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