Journal of Anesthesia

, Volume 30, Issue 3, pp 369–376 | Cite as

Computational simulation and comparison of prothrombin complex concentrate dosing schemes for warfarin reversal in cardiac surgery

  • Kenichi A. TanakaEmail author
  • Michael A. Mazzeffi
  • Erik R. Strauss
  • Fania Szlam
  • Nina A. Guzzetta
Original Article



Prothrombin complex concentrate (PCC) is increasingly used for acute warfarin reversal. We hypothesized that computational modeling of thrombin generation (TG) could be used to optimize the timing and dose of PCC during hemodilution induced by cardiopulmonary bypass (CPB).


Thrombin generation patterns were modeled in anticoagulated patients (n = 59) using a published computational model. Four dosing schemes were evaluated including single full dose (median, 41.2 IU/kg) of PCC before or after CPB, ½-dose before and after CPB, or 1/3-dose before CPB plus 2/3-dose after CPB. Hemodilution was modeled as 40 or 60 % dilution of factors from baseline. The lag time (s) of TG, and peak thrombin level (nM) were evaluated.


Prolonged lag time, and reduced peak TG were due to low vitamin K-dependent (VKD) factors, and pre-CPB PCC dose-dependently restored TG to near-normal or normal range. After 40 % dilution, TG parameters were similar among 4 regimens at the end of therapy. The recovery of VKD factors was less when PCC was given before CPB after 60 % dilution, but TG parameters were considered hemostatically effective (>200 nM) with any regimen. Withholding the full dose of PCC until post-CPB resulted in severely depressed TG peak (median, 47 nM) after 60 % dilution, and some supra-normal TG peaks after treatment.


Pre-CPB administration of full or divided doses of PCC prevents extremely low TG peak during surgery, and maintains hemostatic TG peaks in both 40 and 60 % hemodilution models. Although PCC’s hemostatic activity appears to be highest using the full dose after CPB, hypercoagulability may develop in some cases.


Vitamin K antagonist Thrombin generation Prothrombin complex concentrate Cardiopulmonary bypass Hemodilution 



We thank Dr. A. D. Szlam (City College of New York, New York, NY) and Dr. Varner (Cornell University, Ithaca, NY) for their help with the computational analysis, and Dr. F. Kursten (Octapharma, Vienna) for providing coagulation factor data.

Compliance with ethical standards

Conflict of interest

MAM, ERS, FS, and NAG have no conflict of interest relating to this study. KAT has previously served as a consultant for Octapharma (Hoboken, NJ, USA) in a project unrelated to the current study. Octapharma was not involved in study design, data analysis, or manuscript preparation.


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Copyright information

© Japanese Society of Anesthesiologists 2016

Authors and Affiliations

  • Kenichi A. Tanaka
    • 1
    Email author
  • Michael A. Mazzeffi
    • 1
  • Erik R. Strauss
    • 1
  • Fania Szlam
    • 2
  • Nina A. Guzzetta
    • 3
  1. 1.Department of AnesthesiologyUniversity of Maryland Medical CenterBaltimoreUSA
  2. 2.Department of AnesthesiologyEmory University School of MedicineAtlantaUSA
  3. 3.Department of AnesthesiologyEmory University School of Medicine, Children’s Healthcare of AtlantaAtlantaUSA

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