Title: Role of Prothrombin Complex Concentrate in Transfusion Protocols
Author: Kenichi A. Tanaka, M.D., M.Sc.
Affiliation: Professor, Department of Anaesthesiology, University of Pittsburgh Medical
Center, Pittsburgh, Pennsylvania, USA
Email: tanakak@upmc.edu
Haemostasis is a natural defence mechanism against vascular injury and haemorrhage (1), and it
consists of multiple phases involving both cellular and humoral elements of coagulation (2). In
the presence of coagulopathy after major trauma and surgery, haemostasis management becomes
a major challenge for anesthesiologists and intensivists (3-6). The haemostatic defect in
perioperative patients is often multifactorial, and the coagulation status can change for the worse
in a short period of time. It is thus important to address this problem with comprehensive clinical
assessments of coagulopathy, and timely administration of haemostatic therapy (6-9).
Transfusion of plasma and platelets has been the mainstay haemostatic therapy for many decades.
However, the timing of transfusion is difficult to control particularly because blood components
and laboratory test results are often unavailable in a timely fashion. Delayed decision and
administration of transfusion can exacerbate coagulopathy, and potentially affect clinical
outcomes. However, premature and overzealous uses of haemostatic agents can be equally
harmful to the patients (10). For a number of hereditary coagulation factor deficiency, plasmaderived or recombinant factor concentrate is available to replace the deficient factor(s) without
using plasma (11). The FDA has recently approved the concentrate of vitamin K dependent
factors for the management of bleeding in patients treated with vitamin K antagonists (e.g.,
warfarin)(12). When managing perioperative bleeding, these factor concentrates can be more
effective than allogeneic plasma, but inappropriate uses can be costly, and associated with
worsening haemorrhage or thromboembolic complications. The goals of this lecture are to review
current limitations of plasma transfusion, and discuss the roles of prothrombin complex
concentrate (PCC) as a perioperative therapy for haemostasis.
Human Plasma-derived PCC
Acute reversal of warfarin using plasma has been a difficult and time-consuming task in case of
bleeding complications or emergency surgery (13, 14). Clinical availability of PCC overcomes
some of the major issues of perioperative plasma transfusion. PCCs contain the standardized
amounts of lyophilized, human plasma-derived vitamin K dependent factors; FII (prothrombin),
FVII, FIX and FX. There are also various amounts of protein C, protein S, protein Z, heparin or
antithrombin in different PCCs (15). PCCs were historically indicated for FIX replacement in
haemophilia B, and the potency of each vial is shown in the dose of FIX (international unit [IU]).
Two commercial PCC products are mainly indicated for the reversal of warfarin anticoagulation.
Kcentra (CSL Behring, Marburg, Germany) has been recently approved by the FDA, and
Octaplex (Octapharma, Hoboken, NJ) is expected to be approved soon. Cofact is another PCC
product available in some European countries (Note: these PCCs have been clinically available
for years in European countries; Table 1)(16, 17). These two PCCs are different from Bebulin
(Baxter, Westlake Village, CA) and Profilnine (Grifols, Los Angels, CA) with low amounts of
FVII relative to FII, FIX, and FX (Note: they are referred as a 3-factor PCC; Table 1). The use of
4-factor PCC is preferred under these circumstances because additional sources of FVII are less
likely to be required (i.e., plasma transfusion, or 1-2 mg of rFVIIa)(18).
Table 1. Prothrombin Complex Concentrates (PCCs)
Product name
FII
FVII
FIX
FX
Protein C/S
Additive
Kcentra/Beriplex
111
57
100
150
Yes
Heparin, AT
Octaplex
98
66
100
96
Yes
Heparin
Bebulin
120
13
100
139
N.R.
Heparin
Profilnine
148
11
100
64
N.R.
No heparin
Cofact
106
48
100
103
Yes
No heparin
Note: Data in Table 1 indicate relative contents of vitamin K dependent factors for different PCCs. The percent (%)
activity of each factor is shown relative to FIX activity (based on the prescribing information for each product; actual
factor contents may vary for each vial). Manufacturers are as follows; Kcentra/Beriplex (CSL Behring, Marburg,
Germany), Octaplex (Octapharma, Lachen, Switzerland), Bebulin (Baxter, Westlake Village, CA), and Profilnine
(Grifols, Los Angels, CA), Cofact (Sanquin, Amsterdam, Netherlands). Other PCC products are also available in
different countries.
Dosing and Contraindications of PCC
The dose of 4-factor PCC is chosen according to the prolongation of international normalized
ratio (INR) of prothrombin time (Table 2). Hemostatic efficacy and pharmacological activity of
4-factor PCC compared to FFP have been shown in the multicenter prospective randomized study
of Kcentra and FFP in warfarin-treated adult patients (INR>2.0) undergoing urgent surgery or
invasive procedure (Table 2)(12). Intravenous vitamin K (5–10 mg) is administered to prevent a
rebound increase in INR over 6–8 h due to the relatively short half-life of FVII (4–6 h).
Table 2. Treatments for Acute Warfarin Reversal for the Kcentra® Study
INR
PCC Treatment (iv)
Plasma Transfusion (iv)
2.0-3.9
PCC 25 IU kg-1 + vit K 5-10 mg
Plasma 10 ml kg-1 + vit K 5-10 mg
4.0-5.9
PCC 35 IU kg-1 + vit K 5-10 mg
Plasma 12 ml kg-1 + vit K 5-10 mg
>6.0
PCC 50 IU kg-1 + vit K 5-10 mg
Plasma 15 ml kg-1 + vit K 5-10 mg
Table 2 indicates the study protocol from the Kcentra® study (19).
Protein C/S=protein C/protein S, AT = antithrombin, N.R. = not reported, Yes = contains therapeutic amounts. IU =
international unit of factor IX, vit K = vitamin K.
Clinical haemostasis over 24h was judged to be effective in 72.4% (71/98) with Kcentra, and
65.4% (68/104) with FFP transfusion (i.e., PCC was non-inferior to FFP)(19). The percentage of
cases in which INR was reduced to <1.3 after 30 min of intervention was clearly higher with
Kcentra than with FFP; 62.2% (61/98) vs. 9.6% (10/104).
Thromboembolic complication is a possible risk of PCCs. In a recent meta-analysis of 27 studies
(1032 patients) including both 3-factor and 4-factor PCCs for the reversal of vitamin K
antagonists, the overall incidence of thromboembolic complications was 1.4% (95% CI, 0.8–2.1).
The uses of PCCs were rarely the direct cause of death, but total mortality rate was 10.6%,
indicating the patients who received PCCs were often very ill.
The use of PCCs is contraindicated in the case of ongoing DIC (20). PCCs are known to increase
prothrombin and FX levels (half-lives, 40–72h) in a dose-dependent manner, and the balance of
procoagulant and anticoagulant proteins may be shifted toward hypercoagulable state. Most PCCs
contain subtherapeutic amounts of heparin and AT, although some contain therapeutic amounts of
protein C, protein S, and protein Z (15).
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