Partial Reversal of Dabigatran Effect by a Prothrombin Complex Concentrate in a Model of Thrombin Generation
Dabigatran etexilate (Pradaxa) is a prodrug that is metabolised to a small molecule direct thrombin inhibitor. It has some more desirable charactersitics than warfarin for long-term anticoagulation of patients with atrial fibrillation, particularly the fact that it does not routinely need laboratory monitoring. However, it has the drawback that it is not readily reversable. While the package insert suggests administration of fresh frozen plasma or recombinant FVIIa as “antidotes”, there is no good theoretical or experimental basis to support this recommendation. Several sutdies have suggested that prothrombin complex concentrates (PCCs) can partially reverse the effects of dabigatran on laboratory assays. However, there is still much controversy over the potential of PPCs to reverse dabigatran anti-coagulation. The goal of our studies was to assess the effects of a 4-component PCC (Beriplex, CSL-Behring) on parameters of thrombin generation in PRP and a cell-based model. This allow us to use varying levels of dabigatran and varying levels of PCC, a cell-associated source of tissue factor (TF), fresh platelets, and either plasma or plasma levels of coagulation factors. Thrombin generation was assessed continuously using a fluorogenic thrombin substrate in a fluorescent plate reader. Dabigatran (Selleck Chemicals) was dissolved in DMSO and added to the test plasma at concentrations from 189–944 ng/mL. Beriplex was added to test plasma at concentrations from 0.25 FIX units/mL to 2.0 FIX units/mL. As others have reported for conventional calibrated automated thrombogram (CAT) assays, we found that dabigatran prolonged the lag before onset of thrombin generation. It also progressively depressed the rate and peak level of thrombin production. We found that the addition of Beriplex increased the rate and peak level of thrombin generation in a dose-dependent manner, but had little effect on the lag. This effect was seen at all levels of dabigatran tested, with a level of 1 U/mL restoring the rate and peak levels of thrombin generation, as well as the area-under-the-curve, to normal levels. The addition of FIX alone at 1 U/mL had no significant effect on thrombin generation in the presence of dabigatran. The effects of Beriplex were similar, though not identical, to the pattern seen when prothrombin alone was added to this model. Thus, we hypothesize that Beriplex has its dominant effect on reversal of dabigatran effects by a prothrombin-mediated mechanism. This increases the burst of platelet surface thrombin generation. However, this unactivated PCC does not reverse the inhibitory effect of dabigatran on the amplification phase of hemostasis as reflected in the lag time before the onset of thrombin generation. Thus, Beriplex corrects some, but not all, parameters all of thrombin generation affected by dabigatran in this model.
Hoffman: CSL Behring: Research Funding.
Hoffman, MR; Volovyk, Z; Monroe, DM
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