E Editorial
Factor Concentrates for Perioperative Bleeding:
Old Drugs with New Approaches
Ian J. Welsby, BSc, MBBS, FRCA (Eng), and Jerrold H. Levy, MD, FAHA, FCCM
B
leeding and coagulopathy are major concerns for
clinicians in the perioperative and trauma setting.
Although blood product transfusions are the mainstay
of therapy, they are clearly associated with multiple risks
and require crossmatching, blood bank storage, and inven-
tory management that is labor-intensive and complicated
by potential availability and delay in delivery. Factor con-
centrates such as fibrinogen or prothrombin complex con-
centrates (PCCs) are increasingly evolving as a replacement
for allogeneic blood products.13 Literature and guidelines
describe the perioperative use of PCCs for the urgent rever-
sal of vitamin K antagonist anticoagulants (i.e., warfarin).2,4
A growing body of literature also reports the off-label appli-
cation of PCCs for reversing direct oral anticoagulants, apix-
aban, dabigatran, rivaroxaban, and edoxaban.57 PCCs can
be rapidly deployed, do not require crossmatching, and are
highly purified to prevent infectious disease transmission.
In the current edition of Anesthesia & Analgesia, Ortmann
et al.8 present a retrospective series of patients undergoing
pulmonary thromboendarterectomy treated with either
PCCs or fresh-frozen plasma (FFP), comparing postopera-
tive blood loss and clinical outcomes. The PCC group bled
significantly less than the FFP group, despite the inclusion
of more surgically complex patients and those with more
pronounced pretreatment coagulopathy (higher baseline
international normalized ratio, lower postcardiopulmonary
bypass platelet counts, and higher partial thromboplastin
times). Despite this, there were no differences in clinical
outcomes reported (intensive care unit or hospital length
of stay or other complications) between the PCC and the
FFP groups either before or after adjustment for treatment
group selection bias using a propensity score constructed
from pretreatment laboratory values. Transfusions of plate-
lets and cryoprecipitate were still required for both the
FFP and the PCC groups, an expected finding considering
From the Department of Anesthesiology and Critical Care, Duke University
School of Medicine, Durham, North Carolina.
Accepted for publication March 25, 2015.
Funding: NIH R01 HL121232-01 (IJW).
Conflict of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Jerrold H. Levy, MD, FAHA, FCCM, Department
of Anesthesiology and Critical Care, Duke University Medical Center, 2301
Erwin Rd., 5691H HAFS, Box 3094, Durham, NC 27710. Address e-mail to
Jerrold.levy@duke.edu.
Copyright 2015 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000806
4 www.anesthesia-analgesia.org July 2015 Volume 121 Number 1
Copyright 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
the complex coagulopathy after circulatory arrest and the
absence of platelets or fibrinogen in PCC preparations.
This study illustrates some important considerations
regarding the potential perioperative use of PCCs in cardiac
surgery. The current U.S. Food and Drug Administration
indication for the 4-component PCC indication for Kcentra
(CSL Behring, Marburg, Germany) is the urgent reversal
of warfarin anticoagulation for acute major bleeding or
the need for an urgent surgery/invasive procedure. There
are other 3-component PCC products available that have
high levels of factor IX and were previously approved for
the treatment of patients with hemophilia B. An increasing
number of reports in the literature described the use of these
agents off-label for bleeding in high-risk patients including
for patients undergoing cardiac surgery. Regardless, the
correction of warfarin anticoagulation is faster and more
efficient with PCCs than FFP.9 We could also postulate a
benefit from more rapid restoration of hemostasis in high-
risk patients who are bleeding in a perioperative setting.
An additional advantage of PCCs is in the setting of right
ventricular failure, as the volume of PCCs required to rap-
idly restore adequate clotting factor levels is far less than the
volume of FFP.
The purpose of administering PCCs or FFP was to
restore clotting factor levels and, therefore, thrombin gen-
eration. The low incidence of postoperative thromboembo-
lism in the current study is encouraging and consistent with
the findings of Sarode et al.,9 but further studies are needed
to determine the prothrombotic safety of PCCs in this set-
ting. The levels of prothrombin/factor II are linearly related
to thrombin generation and are reduced to approximately
50% after separation from cardiopulmonary bypass after
major cardiac surgery.10 Although thought to be sufficiently
hemostatic, subsequent blood loss or hemodilution may
critically reduce factor II levels to approximately 25%30%,
a level expected with a therapeutic international normal-
ized ratio of 2.53. Regarding dosing, 1 unit of PCC/kg of
ideal body weight increases factor levels by approximately
1%. Therefore, the dose of PCC used in the current study
and the 2030 units/kg in previous reports11 seem reason-
able and unlikely to overcorrect hemostatic factor levels and
lead to a prothrombotic state,11 which is thought to result
from an excess of factor II.
In summary, perioperative PCCs may present an alter-
native to plasma/FFP in some patients with bleeding after
complex cardiac surgery or trauma, with possible advan-
tages that need to be determined by prospective studies. All
transfusion factors and factor concentrates pose potential
 Factor Concentrates for Perioperative Bleeding
risks, and their administration should be determined by
risk versus benefit consideration. We believe that factor
concentrates represent important therapies for major bleed-
ing, and our current work is exploring their use in clinical
settings. However, additional randomized and controlled
studies are needed to better define their application in the
complex milieu of perioperative bleeding. E
DISCLOSURES
Name: Ian J. Welsby BSc, MBBS, FRCA (Eng),
Contribution: The author helped write the manuscript.
Attestation: Ian J. Welsby approved the final manuscript.
Conflicts of Interest: Ian J. Welsby has received grant support
from CSL Behring and Terumo BCT for investigator initiated
trials.
Name: Jerrold H. Levy, MD, FAHA, FCCM.
Contribution: The author helped write the manuscript.
Attestation: Jerrold H. Levy approved the final manuscript.
Conflicts of Interest: Jerrold H. Levy serves on steering
committees for CSL Behring, Grifols, and Janssen.
This manuscript was handled by: Charles W. Hogue, Jr., MD.
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