Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model

Abstract

Summary. Background: One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation. Objectives: This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran‐associated bleeding diathesis. Methods: Anesthetized rabbits were treated with 0.4 mg kg−1 dabigatran followed by PCC doses of 20, 35 or 50 IU kg−1 or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined. Results: From an initial mean of 29 mL, blood loss progressively declined by 5.44 mL with a 95% confidence interval (CI) of 2.21–8.67 mL per 10 IU kg−1 increment in PCC dose (P = 0.002). At a PCC dose of 50 IU kg−1 blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7 min (P < 0.001). The rate of hemostasis was nearly trebled with each 10 IU kg−1 increment in PCC dose (rate ratio, 2.89; CI, 1.64–5.09). Conclusions: In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted.

Translational Insights into Traumatic Brain Injury Occurring during Dabigatran or Warfarin Anticoagulation

“…In experimental studies, diminished bleeding times have been observed in the absence of measurable parameter changes after PCC administration. 12,25 In our third experimental series, the application of PCC 30 minutes after TBI for anticoagulation reversal did not prevent the development of larger bleeding volumes in some of the mice with excess dabigatran levels as compared with saline injections. Apart from an incomplete anticoagulation reversal, another explanation might be that the PCC injection occurred at a time that was too late to substantially change the hemorrhage volume after 24 hours.…”

Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents

“…Human studies (dabigatrantreated healthy volunteers) PCC No reduction in blood loss after tail transection in mice [44] Reduced intracranial hematoma expansion and 24-hr mortality in mice [45] Reduced blood loss following kidney incision in rabbits [46] Reduced bleeding time, but not coagulation tests in rat tail transection model [18] Corrected some TG indices [25] Corrected PT, aPTT, TT and some TG indices [13] No correction of Hemoclot assay [13] No correction of aPTT, ECT, TT [9] aPCC No reduction in blood loss after tail transection in mice [44] Reduced bleeding time, but not coagulation tests in rat tail transection model [18] Corrected some TG indices [25] Corrected PT, aPTT and some TG indices [13] [23],…”

Novel Oral Anticoagulants: Efficacy, Laboratory Measurement, and Approaches to Emergent Reversal

“…28 In contrast, a study of dabigatran-associated bleeding in a rabbit model showed that treatment with the 4-factor PCC reduced blood loss and improved bleeding time. 29 Abbreviations: FEIBA, factor eight inhibitor bypass activity; FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa. a The use of FFP, platelets, or cryoprecipitate may be indicated owing to blood loss, but these therapies would not be expected to be helpful as monotherapy in the reversal of the novel oral anticoagulants.…”