title: Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate.
abstract: BACKGROUND
  The oral thrombin inhibitor dabigatran has the drawbacks that it does not have a validated antidote. Data from animal studies and plasma coagulation assays suggest that prothrombin complex concentrate (PCC) or recombinant factor VIIa (FVIIa) might reverse dabigatran anticoagulation.
  
  
  METHODS
  Cellular elements make a significant contribution to hemostasis. Our goals were to (1) test the hypothesis that both FVIIa and a 4-factor PCC improve parameters of thrombin generation in the presence of dabigatran in a cell-based model; and (2) determine whether results in a cell-based model correlate with hemostasis in vivo.
  
  
  RESULTS
  PCC reversed dabigatran effects on the rate, peak, and total amount of thrombin but did not shorten the lag (n = 6 experiments in triplicate). By contrast, FVIIa shortened the lag, increased the rate and peak, but did not improve total thrombin (n = 6). Effects of PCC were seen at both therapeutic and markedly supratherapeutic dabigatran levels, whereas beneficial effects of FVIIa decreased as the dabigatran level increased. The PCC effect was reproduced by adding prothrombin, factor X, and factor IX. At therapeutic dabigatran levels, both PCC and FVIIa normalized hemostasis time in a mouse saphenous vein bleeding model.
  
  
  CONCLUSIONS
  A cell-based model reflects the effects on thrombin generation of clinically relevant levels of FVIIa and PCC in the presence of dabigatran. Enhancing the rate of thrombin generation and peak thrombin level appear to correlate best with hemostasis in vivo. The ineffectiveness of FVIIa at supratherapeutic dabigatran levels may explain conflicting reports of its efficacy in dabigatran reversal.
authors.affiliation: From the Division of Hematology/Oncology, Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Maureane
authors.initials: M
authors.lastname: Hoffman
authors.forename: Zoya
authors.initials: Z
authors.lastname: Volovyk
authors.forename: Dougald M
authors.initials: DM
authors.lastname: Monroe
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology*; D001562:Benzimidazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D000069604:Dabigatran; D015942:Factor VIIa / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D012501:Saphenous Vein / Q000473:pathology; D013916:Thrombelastography; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D001779:Blood Coagulation Factors; D015091:beta-Alanine; C025667:prothrombin complex concentrates; D015942:Factor VIIa; D013917:Thrombin; D000069604:Dabigatran