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Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate.

Publication ,  Journal Article
Hoffman, M; Volovyk, Z; Monroe, DM
Published in: Anesthesiology
February 2015

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.

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Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

February 2015

Volume

122

Issue

2

Start / End Page

353 / 362

Location

United States

Related Subject Headings

  • beta-Alanine
  • Thrombin
  • Thrombelastography
  • Saphenous Vein
  • Humans
  • Hemostasis
  • Hemorrhage
  • Factor VIIa
  • Dabigatran
  • Blood Coagulation Factors
 

Citation

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Hoffman, M., Volovyk, Z., & Monroe, D. M. (2015). Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate. Anesthesiology, 122(2), 353–362. https://doi.org/10.1097/ALN.0000000000000540
Hoffman, Maureane, Zoya Volovyk, and Dougald M. Monroe. “Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate.Anesthesiology 122, no. 2 (February 2015): 353–62. https://doi.org/10.1097/ALN.0000000000000540.
Hoffman, Maureane, et al. “Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate.Anesthesiology, vol. 122, no. 2, Feb. 2015, pp. 353–62. Pubmed, doi:10.1097/ALN.0000000000000540.

Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

February 2015

Volume

122

Issue

2

Start / End Page

353 / 362

Location

United States

Related Subject Headings

  • beta-Alanine
  • Thrombin
  • Thrombelastography
  • Saphenous Vein
  • Humans
  • Hemostasis
  • Hemorrhage
  • Factor VIIa
  • Dabigatran
  • Blood Coagulation Factors