Clinical Focus Review Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M.

, Editor

Four-factor Prothrombin Complex Concentrate Use for

Bleeding Management in Adult Trauma
Lidia Mora, M.D., Marc Maegele, M.D., Ph.D., Oliver Grottke, M.D., Ph.D., M.Sc., Andreas Koster, M.D., Philipp Stein, M.D.,
Jerrold H. Levy, M.D., Gabor Erdoes, M.D., Ph.D.

T rauma remains a leading cause of death in adults,

despite advancements in emergency medical care.1
Despite advances in understanding the underlying patho-
TIC (and associated mortality6) and to measure (vitamin
K–dependent) clotting factor levels. However, these tests
are inadequate for assessing the overall response of the
physiology, leading to reductions in mortality rates, up to hemostatic system because they cannot measure circulat-
35% of severe trauma patients still present with coagulop- ing clot initiators or inhibitors involved in the termination
athy upon hospital admission.2 Exsanguination remains a phase. To overcome this limitation, thrombin generation
leading cause of death in these patients, accounting for up assays have been developed to assess components of all
to 14.6% of fatalities due to severe bleeding.3 Bleeding and three phases of hemostasis.7 In vivo, thrombin genera-
hemorrhagic shock contribute to trauma-induced coagu- tion potential can be assessed by measuring the throm-
lopathy (TIC), influenced by factors including the nature of bin–antithrombin complex and prothrombin fragments
the injury and the type of resuscitation.4 1 + 2 (F1 + 2), whereas in vitro thrombin generation assays
Hemostasis is based on the potential of the blood to assess the endogenous capacity of the total hemostatic
produce thrombin (thrombin generation) and the down- potential.8 The in vivo and in vitro assays are therefore not
stream effects of thrombin on coagulation, anticoagulation, identical and must be used and interpreted in a differen-
fibrinolysis, and the vascular endothelium.5 According to tiated manner. Thrombin generation is most sensitive to
the cell-based concept of coagulation, hemostasis begins prothrombin levels (increased thrombin generation) and
with the initiation phase, which is characterized by the antithrombin levels (decreased thrombin generation) but
involvement of tissue factors and phospholipids and leads can also be perturbed by hemodilution, coagulation fac-
to the initial production of small amounts of thrombin. tor consumption, shock-induced systemic acidosis, and
The production of thrombin activates platelets, factor V, hypothermia.9
and factor VIII and leads to the second phase (propagation Patients with severe trauma and coagulopathy often
phase) of coagulation. In this phase, thrombin production present with reduced levels of factors V, VII, and X and
increases rapidly and forms a hemostatic plug. Hemostasis fibrinogen early after injury.10–13 Data on reduced activity
concludes with the termination phase, in which various of coagulation factors after severe injury are inconsistent.
inhibitory mechanisms regulate the amount and duration Further, decreased concentrations of procoagulant factors
of thrombin production and prevent excessive clot forma- are not necessarily associated with a lower rate of throm-
tion. Conventional coagulation tests such as prothrombin bin generation expressed in some analyses. Trauma patients
time (PT) have been used to identify patients at risk of can present with decreased procoagulants but increased

This article has been selected for the Anesthesiology CME Program (www.asahq.org/JCME2025FEB). Learning objectives and disclosure and ordering information can be found in
the CME section at the front of this issue. This article is featured in “This Month in Anesthesiology,” page A1. Peter Nagele, M.D., M.Sc., served as Handling Editor for this article.
Submitted for publication July 6, 2024. Accepted for publication September 11, 2024. Published online first on October 30, 2024.
Lidia Mora, M.D.: Department of Anesthesiology, Intensive Care and Pain Clinic, Vall d’Hebron Trauma, Rehabilitation and Burns Hospital, Autonomous University of Barcelona,
Barcelona, Spain.
Marc Maegele, M.D., Ph.D.: Department for Trauma and Orthopedic Surgery, Cologne–Merheim Medical Center, Witten/Herdecke University, Campus Cologne–Merheim, Cologne,
Germany.
Oliver Grottke, M.D., Ph.D., M.Sc.: Department of Anesthesiology, Rhenish–Westphalian Technical University, Aachen University Hospital, Aachen, Germany.
Andreas Koster, M.D.: Clinic for Anesthesiology and Interdisciplinary Intensive Care Medicine, Sana Heart Center Cottbus, Cottbus, Germany; Ruhr University of Bochum, Bochum,
Germany.
Philipp Stein, M.D.: Division of Anesthesiology, Hospital Linth, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Jerrold H. Levy, M.D.: Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, North Carolina.
Gabor Erdoes, M.D., Ph.D.: Department of Anesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists. This is an open-access article distributed
under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work
provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Anesthesiology 2025; 142:351–63. DOI:
10.1097/ALN.0000000000005230
The article processing charge was funded by the University of Bern, Bern, Switzerland.

A nesthesiology, V 142 • NO 2 February 2025 351

 Clinical Focus Review

thrombin generation biomarkers compared to those with- affecting clinical outcomes and the risk of thromboembo-
out injury or TIC. In addition, certain procoagulant micro- lism. The study highlights the importance of treating each
particles can enhance thrombin generation, despite a lack PCC as a distinct agent, with individualized safety and effi-
of procoagulant factors.7 In trauma patients, peak thrombin cacy profiles, and advises caution when substituting prod-
generation was higher than in healthy individuals, despite ucts. These data are crucial for selecting PCCs, especially
prolonged standard coagulation tests. Trauma patients when neutralizing new oral anticoagulants.19
exhibit 2.5-fold higher average plasma thrombin genera- This review explores studies on the use of 4F-PCC for
tion capacity on hospital admission than uninjured individ- trauma-related bleeding in adults, focusing on its indica-
uals.14 However, 17% of severely injured patients showed tions, monitoring, and management strategies aimed at
low thrombin generation capacity and peak concentra- optimizing patient outcomes. Although plasma’s undeni-
tion, leading to a fourfold increase in 30-day mortality.14 able benefits, such as blood volume expansion, glycocalyx
Hemostatic resuscitation approaches to restoring thrombin protection,20 and replacement of coagulation factors, are
generation in trauma vary with massive bleeding and focus acknowledged, a detailed comparative evaluation of plasma
on fresh frozen plasma (FFP) to replace soluble coagulation versus 4F-PCC in the management of traumatic hemor-
factor deficiency and restore hemostasis. However, in vitro rhagic shock is beyond the scope of this discussion.
and clinical studies suggest inefficient thrombin genera-
tion recovery after FFP transfusion alone.15,16 Holcomb et
al.3 reported on a large randomized clinical trial in which Pharmacology of Four-factor Prothrombin
hemorrhagic traumatic shock resuscitation was driven by Complex Concentrate
fixed ratios of blood products. Although this method has The coagulation activity (measured in IU/ml) of lyophilized
been widely shown to be effective, no significant differ- 4F-PCC is based on factor IX content, although the con-
ences in morbidity or mortality were observed with higher centrations of other factors vary between products, as well
FFP ratios in cases of severe trauma and major bleeding. as other anticoagulant proteins such as protein C, protein S,
Conversely, first-line treatment with four-factor prothrom- and variable amounts of heparin (0.2 to 0.5 IU per IU of
bin complex concentrate (4F-PCC), as part of a coagula- factor IX), antithrombin III, and human albumin, which are
tion factor concentrate-based hemostatic approach guided not therapeutic.This gives the various products on the mar-
by viscoelastic point-of-care (POC) coagulation moni- ket a certain specificity in terms of their activity, without
toring to reversing TIC, rapidly restores clot strength and any major differences in their efficacy.21 Three-factor pro-
reduces the need for allogeneic blood products. However, thrombin complex concentrate (3F-PCC; e.g., Profilnine
it is important to note that this evidence is derived from SD, Grifols Biologicals Inc., USA) contains factors II, IX,
a small clinical trial and carries certain limitations.17 One and X and a relatively low concentration of factor VII (less
advantage of 4F-PCC over FFP is its ability to deliver high than or equal to 175 IU per 500 IU PCC). In contrast,
doses of vitamin K–dependent clotting factors to restore 4F-PCC (in Europe: e.g., Beriplex, CSL Behring; Octaplex,
hemostasis more effectively and faster. The availability of Octapharma; in the United States: Kcentra, CSL Behring,
a resource that can be rapidly and easily administered in approved by the Food and Drug Administration for the
austere environments with limited access, especially when urgent reversal of anticoagulation by vitamin K antago-
prolonged transfers to medical centers are expected, would nist therapy in adult patients with acute major bleeding or
be highly valuable and appreciated. The 4F-PCC com- need for urgent surgery/invasive procedures), includes a
pound undergoes a viral pathogen inactivation process high concentration of factor VII (180 to 500 IU per 500 IU
during manufacturing, which enhances its biologic safety. PCC),21 affecting the extrinsic, tissue-factor induced coag-
Additionally, some formulations can be stored at room tem- ulation pathway. 4F-PCC also contains antithrombotic pro-
perature, are easily reconstituted, and can be administered teins C and S, small amounts of heparin (0.2 to 0.5 IU per
intravenously, making them particularly advantageous in IU factor IX), antithrombin III, and human albumin.21–24
emergency situations in which rapid resolution of trauma- Modern 4F-PCC is the primary treatment option for the
induced coagulopathy is critical. However, the efficacy emergent reversal of coagulopathy associated with vitamin
and safety of 4F-PCC in treating TIC remain uncertain, K antagonists (VKAs).21,25,26 In healthy individuals, factor
without consensus on indications, timing, adjunct trans- II (prothrombin) exhibits an elimination half-life of 60 h.
fusion therapies, and dosage regimens.18 In addition, in a The other procoagulant factors have a half-life of approx-
study examining commercially available PCC, notable dif- imately 40 h, whereas the antithrombotic proteins are
ferences were found in their composition and functional eliminated in greater than 50 h.22 A recent review of post-
activity, despite being standardized based on FIX antigen marketing pharmacovigilance safety report analyses showed
levels. The research revealed variations in protein content, that treatment with 4F-PCC across multiple indications
the presence of additives such as heparin and antithrom- was associated with few adverse reactions and a low rate
bin, and the ability to generate thrombin.These differences, of thrombotic events, confirming a positive safety profile
influenced by heparin, antithrombin, and other proteins, for 4F-PCC.27 However, rapid administration of 4F-PCC,
affect the hemostatic properties of the PCCs, potentially combined with the prolonged half-life of prothrombin and

352 A nesthesiology 2025; 142:351–63 Mora et al.

 Prothrombin Complex Concentrate in Trauma

the imbalance of pro- and anticoagulant proteins, raised for guiding and monitoring 4F-PCC therapy.41 Thrombin
concerns about thromboembolic complications. Risk fac- generation assays have been investigated in patients whose
tors for thrombosis should be considered to increase the anticoagulation has been reversed due to bleeding, includ-
safety of 4F-PCC.28 Indeed, massive acute thromboembo- ing those treated with VKAs or factor Xa inhibitors. In
lism shortly after 3F- and 4F-PCC administration has been VKA-treated patients, thrombin generation assay parame-
reported.29,30 In a preclinical safety study with 15 healthy ters returned to normal values post–4F-PCC administration,
volunteers, the infusion of 50 IU/kg of 4F-PCC did not whereas in factor Xa inhibitor–treated patients, thrombin
result in clinical evidence of thrombosis.Transient elevation generation assay parameters remained above the normal
of the thrombogenic markers F1 and 2 was observed 15 min range after receiving a mean dose of 49 IU/kg of 4F-PCC.42
postinfusion, subsiding after 3 h and returning to baseline by Although these results are promising and might support
24 h, with no changes in plasma D-dimer concentrations.22 thrombin generation assay use in bleeding patients, thrombin
Although 4F-PCC has been used in Europe for decades, generation assays require platelet-poor plasma and meticu-
safety data from prospective randomized clinical studies are lous execution, which limit their routine use in emergency
limited to two recent larger studies from the same group settings where precision is crucial and time is of the essence.
from the United States, comparing 4F-PCC versus FFP for To date, none of the thrombin generation assays have been
urgent VKA reversal.31,32 An integrated safety analysis from applied in bleeding trauma patients, and therefore, they can-
these studies showed thromboembolic events in 7.3% of not be considered routine in this setting.43
the 4F-PCC group and 7.1% of the FFP group.33,34 The Coagulation therapy in clinical trauma settings is primar-
observational REVERSAL study analyzed data from two ily guided by conventional coagulation assays or viscoelas-
large healthcare systems in Southern California from 2008 tic POC assays, as potential surrogate markers of thrombin
to 2020.35 In the 1,119 patients who received 4F-PCC for generation.44–47 In the Early Administration of Prothrombin
the urgent reversal of VKA therapy, matched 1:1 to those Concentrate Complex in Patients With Acute Hemorrhage
treated with FFP, the 45-day risk of thromboembolic events Following Severe Trauma (PROCOAG) multisite random-
was 3.4% versus 4.1% in the FFP group (adjusted hazard ized clinical trial, the PT ratio (prothrombin time/laboratory
ratio, 0.76; 95% CI, 0.49 to 1.16; P = 0.25).35 In a porcine normal reference value) was used to delineate trauma-related
model of coagulopathy with liver injury treated with 50 coagulation factor deficiency. Acute traumatic coagulopathy
IU/kg PCC, 44% of the animals developed disseminated was defined by a PT ratio greater than 1.2, whereas severe
intravascular coagulation and other thromboembolic com- acute traumatic coagulopathy was characterized by a PT ratio
plications, especially when 4F-PCC was coadministered exceeding 1.5.48 A systematic review and meta-analysis of 23
with fibrinogen concentrate.36 Adding antithrombin III mostly observational studies indicated that a dose of 20 to
seemed to reduce this risk.37 In another animal model com- 30 IU/kg of 4F-PCC for TIC was typically initiated when
paring the thrombogenic potential of 4F-PCC, activated coagulation analysis showed an INR of greater than or equal
PCC, and recombinant activated factor VII, 4F-PCC was to 1.5 or a clotting time (CT) longer than 80 s in the extrin-
found to have the lowest risk, making it more suitable for sically activated thromboelastometry (EXTEM) assay after
reversing coagulopathy in bleeding patients.38 administering fibrinogen concentrate. This approach did not
significantly reduce mortality or increase venous thrombo-
embolism.24 Current practices in large European trauma cen-
Monitoring of Four-factor Prothrombin Complex ters and European recommendations (e.g., European Trauma
Concentrate Effects Guidelines)47 for managing trauma patients with major bleed-
Effective monitoring of 4F-PCC therapy is essential to max- ing favor a coagulation factor concentrate-based management
imize its benefits and minimize potential risk, such as throm- strategy.49,50 European guidelines state that after administer-
boembolic events. Conventional coagulation tests, such as ing sufficient amounts of fibrinogen concentrate to achieve a
PT and international normalized ratio (INR), are partially fibrinogen level greater than 1.5 g/l, the EXTEM CT should
useful for detecting coagulation factor deficiencies. Although be normalized using 4F-PCC if it remains prolonged. Data
INR is standardized for monitoring VKA therapy and can from two prospective studies in warfarin-treated individuals
guide 4F-PCC administration, PT is a test that may not pro- showed a strong correlation between reduced thrombin gen-
vide immediate results. Moreover, both PT and INR can be eration, INR, and CT prolongation in the EXTEM assay.51,52
influenced by various factors and may not fully reflect the These findings imply that EXTEM CT is more sensitive to
complexities of TIC or the rapid fluctuations in plasma coag- coagulation factors II, X, and VII deficiencies than assays acti-
ulation factor levels after 4F-PCC administration.39 However, vated via the intrinsic contact pathway. Therefore, EXTEM
when measured with certain point-of-care devices, these tests CT could serve as a monitoring tool for 4F-PCC in trauma
have proven to be useful.40 Thrombin generation assays, using cases with deficiency in extrinsic pathway coagulation fac-
the calibrated automated thrombogram method, could offer tors. Figure 1 provides a visual summary of a clinical mon-
a suitable alternative, although it does not provide a quick itoring and management approach for 4F-PCC based on
result either, and it is not widely available for clinical use, nor surrogate markers of thrombin generation.

Mora et al. A nesthesiology 2025; 142:351–63 353

 Clinical Focus Review

Fig. 1. Clinical monitoring and management approach for four-factor prothrombin complex concentrate (4F-PCC) as an option for trauma
bleeding resuscitation strategy. ACT, activated clotting time (in seconds); α, alpha angle; A5, amplitude at 5 min after CT (in mm); CT, clotting
time, in seconds; CK, citrated kaolin test; CRT, citrated rapid TEG test; DOAC, direct oral anticoagulants; EXTEM, extrinsically activated throm-
boelastometry assay; FIBTEM, fibrin-based extrinsically activated test with tissue factor and the platelet inhibitor cytochalasin D; FFP, fresh fro-
zen plasma; INR, international normalized ratio; IU, international unit; PT, prothrombin time; R, reaction time (in min), VKA, vitamin K antagonist.

Clinical Evidence for Prothrombin Complex show that it is more effective than FFP. As a result, it
Concentrate in Trauma is widely recognized as a validated and highly effective
therapeutic option.31,32,56,57 The noninferiority of fixed-
Evidence specifically supporting the clinical use of 4F-PCC
dose versus tailored-dose 4F-PCC has not been defin-
for trauma-related bleeding is currently lacking, because
itively demonstrated,58 with some studies indicating
systematic reviews often fail to differentiate between the
effectiveness and safety for both.59–61 Despite the phar-
effects of 3F- and 4F-PCC compounds. Additionally, due
macologic differences and the heterogeneity in study
to the limited availability of 3F-PCC, obtaining robust
designs and outcomes, meta-analyses comparing 3F- and
data for this compound in the future seems unlikely.24,53–55
4F-PCC have generally concluded that 4F-PCC is more
The main trauma-related pathophysiologic conditions that
effective in achieving target INR levels, with a similar
might benefit from 4F-PCC are summarized in figure 2.
safety profile.23 4F-PCC has also been investigated for the
The use of 4F-PCC for trauma-related bleeding, aside from
reversal of direct oral anticoagulants (DOACs) in cases
VKA reversal, is considered off-label in the United States.
of DOAC-related bleeding and nonbleeding situations.
However, in Europe, it is an on-label treatment when
In this entity, it is considered a possible aid to counter-
trauma-induced coagulopathy is accompanied by impaired
act, if not completely reverse, its effect.25,62–68 Low-dose
thrombin generation.21,47
4F-PCC (25 IU/kg) has been proposed as a cost-effec-
tive alternative to high-dose 4F-PCC (50 IU/kg) for the
Prothrombin Complex Concentrate for Anticoagulant acute reversal of factor Xa inhibitors, providing effective
Reversal hemostasis without increasing the risk of thromboem-
4F-PCC is well established for its on-label use in emer- bolic events or in-hospital mortality.63 A recent qualitative
gency reversal of VKA,21,25,26 and studies consistently review suggests that both low and high doses of 4F-PCC

354 A nesthesiology 2025; 142:351–63 Mora et al.

 Prothrombin Complex Concentrate in Trauma

Fig. 2. Key trauma-related pathophysiologic conditions that may benefit from four-factor prothrombin complex concentrate (4F-PCC). +,
good evidence available; −, less evidence available.

may offer similar clinical effectiveness and safety.68 Meta- with dabigatran, with idarucizumab being preferred
analyses have compared andexanet alfa with PCC for for urgent reversal. However, 4F-PCC may be valuable
urgent reversal of anti-factor Xa–associated bleeding.64,65 when the anticoagulant is unknown or idarucizumab is
Although there are concerns about comparing the dif- unavailable. Studies have observed benefits from com-
ferent types of PCC (3F, 4F, and activated) due to their bining minimum doses of different reversal agents.70 The
pharmacologic differences and lack of uniformity, the use of activated PCC is neither widespread nor recom-
included studies do not show significant differences in mended for the trauma patient with bleeding,38 and a
efficacy or thromboembolic risk profiles between PCC few nonrandomized studies on DOAC reversal with
and andexanet alfa. Observational data, however, suggest activated PCC have provided questionable results regard-
that andexanet alfa may be associated with lower in- ing its safety, particularly in terms of thrombotic effects.71
hospital and 30-day mortality compared to 4F-PCC.66
An in vitro study on thrombin generation indicated that
4F-PCC normalized values in the presence of low or Prothrombin Complex Concentrate in Intracranial
narrow range factor Xa inhibitor concentrations (less Bleeding
than 75 ng/ml).67 A recent experimental study in healthy Numerous investigations have focused on intracerebral
adults evaluated the ex vivo reversal capacity of andexanet hemorrhage and traumatic brain injury to prevent fur-
alfa, 4F-PCC, and activated PCC in rivaroxaban-antico- ther hemorrhagic progression in anticoagulated patients
agulated blood at different plasma concentrations using receiving oral anticoagulants including VKAs and DOACs.
conventional coagulation assays, thrombin generation Despite the heterogeneity of study designs, the use of
assay, and viscoelastic tests. This study concluded that 4F-PCCs for intracerebral hemorrhage in anticoagulated
high-dose 4F-PCC showed similar efficacy to andexanet patients is reported with favorable outcomes in terms of
alfa when simulating in vivo thrombogenicity potential INR reversal for VKA-treated patients as well as 30-day
under arterial flow conditions.69 In experimental set- mortality and thromboembolic events in oral anticoagulated
tings, both idarucizumab and PCC have demonstrated patients.72–80 A propensity score–weighted analysis of patients
effectiveness in reversing traumatic bleeding associated with apixaban- or rivaroxaban-associated intracerebral

Mora et al. A nesthesiology 2025; 142:351–63 355

 Clinical Focus Review

hemorrhage found that andexanet alfa demonstrated A systematic analysis demonstrated an association
superior hemostatic efficacy and survival compared to between the use of PCC in addition to FFP and reduced
4F-PCC.72 However, this effect was not observed in ret- mortality in trauma-related bleeding in patients not taking
rospective cohorts of similar patients.76,77 Other system- anticoagulants (odds ratio, 0.64; 95% CI, 0.46 to 0.88; P
atic reviews, lacking randomized clinical trials, have failed = 0.007; I2 = 0%), although the pooled analysis was con-
to demonstrate significant differences in the effectiveness founded by heterogeneity and lack of included clinical tri-
of DOAC reversal in cases of intracerebral hemorrhage.75 als.53 Another meta-analysis showed that combining PCC
However, a recent randomized controlled trial involving 530 with FFP decreased the need for allogenic blood transfu-
patients with intracerebral hemorrhage on factor Xa inhib- sions, improved survival rates, and led to successful clini-
itors found that andexanet alfa resulted in better control of cal outcomes without increasing thromboembolic events
hematoma expansion (67% vs. 53.1%; adjusted difference, compared to FFP alone in TIC patients.54 However, a later
13.4; 95% CI, 4.6 to 22.2; P = 0.003) compared to usual systematic review concluded that the use of PCC was not
care, which included PCC, emphasizing that both groups definitively associated with reduced mortality (odds ratio,
achieved effective hemostasis. Nevertheless, andexanet alfa 0.94; 95% CI, 0.60 to 1.45; I2 64%).24 Despite potential biases
was associated with an increased incidence of thrombotic in study selection, adjusted analyses indicate a better associ-
events (10.3% vs. 5.6%; adjusted difference, 4.6; 95% CI, ation between PCC use and reduced mortality in trauma
0.1 to 9.2; P = 0.048), including ischemic stroke (6.5% vs. patients (odds ratio, 0.68; 95% CI, 0.51 to 0.90; I2 0%),
1.5%).80 In cases of mild traumatic brain injury, the use of emphasizing the need for better discrimination in assessing
4F-PCC for factor Xa inhibitor–associated intracerebral outcomes to optimize TIC treatments.55 The heterogeneity
hemorrhage did not affect the incidence or degree of hem- observed in the systematic reviews of the use of 4F-PCC in
orrhage progression and did not result in an increased rate traumatic hemorrhage have failed to find significant differ-
of thromboembolic events based on retrospective observa- ences in the cases in which the inclusion of patients with
tional data.73 The efficacy of 4F-PCC in reversing factor Xa penetrating versus blunt trauma was distinguished.24
inhibitor–related intracerebral hemorrhage was comparable Robust evidence for clinical use of PCC in severe
to its efficacy in warfarin-related intracerebral hemorrhage, trauma and the risk of massive transfusion comes from the
as demonstrated in a meta-analysis74 and a subsequent mul- PROCOAG trial,48 despite some methodologic limitations.
ticenter retrospective cohort study.78 The trial’s reliance on PT ratios to define coagulopathy,
rather than global coagulation assessments like viscoelastic
Prothrombin Complex Concentrate in Major Trauma testing, limits the generalizability of its findings. PT val-
Hemorrhage ues can indicate a deficiency in procoagulants but do not
The indication for tranexamic acid or other procoagulants, account for concurrent deficiencies in anticoagulants.90
such as 4F-PCC, in traumatic bleeding is not mutually Although PT has been used to predict early coagulopa-
exclusive but rather guided by the course of the bleeding, thy and guide plasma transfusion in trauma,40,91,92 it has not
the severity of the patient’s condition, and overall clinical been a reliable predictor of perioperative bleeding.93 The
status. Treatment should be individualized based on these PROCOAG trial hypothesized that combining 4F-PCC
factors, with ongoing monitoring as appropriate.47 Because with a ratio-based transfusion strategy (packed red blood
fibrinogen is the most commonly depleted coagulation fac- cells [PRBCs]:FFP ratio of 1:1 to 2:1) would be superior
tor in traumatic bleeding, fibrinogen concentrate or cryo- to the ratio-based strategy alone in reducing 24-h blood
precipitate is usually used more frequently and in higher product consumption. The trial included patients at risk of
amounts compared to 4F-PCC. massive transfusion, defined as those requiring at least 1 unit
The debate on the appropriateness of 4F-PCC versus of PRBC during prehospital care or within 1 h of admis-
FFP in managing traumatic hemorrhage has long been sion, an assessment of blood consumption score greater than
influenced by geographical location and resource avail- or equal to 2, or those needing 3 units or more PRBCs
ability.81–83 In cases of acquired traumatic coagulopathy, within the hour of admission or 10 units or more PRBC
4F-PCC is particularly indicated when endogenous throm- within 24 h. Of 4,313 admitted patients, 327 were random-
bin generation is significantly impaired, highlighting the ized, and 324 were analyzed (160 in placebo group and
benefit of a multimodal therapy approach to minimize 164 in the 4F-PCC group). At randomization, about two
risks and enhance efficacy.28,37,44,70,84,85 Observational stud- thirds of the patients had a PT ratio greater than 1.2, and
ies suggest that the early administration of 4F-PCC can one-quarter had a PT ratio greater than 1.5. Both groups
boost thrombin generation and reduce the need for allo- were comparable regarding the need for surgical/inter-
genic blood product transfusions.17,86,87 The combination of ventional hemorrhage control, although more patients in
FFP and 4F-PCC has not been shown to provide addi- the placebo group received tranexamic acid (86% vs. 76%)
tional protection through glycocalyx shedding.88 New data and a higher median dose of fibrinogen concentrate. The
on resuscitation of massive traumatic bleeding with plasma median 24-h blood product consumption was not signifi-
or factor concentrates are awaited.89 cantly different between the groups (12 units [5 to 19] in

356 A nesthesiology 2025; 142:351–63 Mora et al.

 Prothrombin Complex Concentrate in Trauma

4F-PCC group vs. 11 units [6 to 19] in the placebo group; rapid replenishment of coagulation factors, along with vol-
absolute difference, 0.2 units; 95% CI, −2.99 to 3.33; P = ume replacement and erythrocyte transfusion, is the primary
0.72). However, thromboembolic events (superficial and objective. It is crucial to consider the patient’s comorbidities,
deep venous thrombosis, pulmonary embolism, stroke, and which may increase the risk of thromboembolic events, and
extremity ischemia) were more frequent in the 4F-PCC to individualize dosing to avoid overdosage.
group, with 56 patients (35%) experiencing at least one
event compared to 37 patients (24%) in the placebo group Prothrombin Complex Concentrate in Hip Fracture
(absolute difference, 11% [95% CI, 1 to 21%]; relative risk,
PCC has been evaluated in urgent scenarios involving
1.48 [95% CI, 1.04 to 2.10]; P = 0.03).48 This study rec-
frail patients with hip fractures who are on anticoagulant
ognizes as a limitation the possible bias of having admin-
medication.96 Implementing an anticoagulant protocol
istered 4F-PCC and FFP together, which would mask a
has proven effective in decreasing time to surgery without
possible excess of procoagulant factors and their influence
increasing the risk of bleeding. Current evidence suggests
on the results of thromboembolic events. Among other
that the safe window to perform surgery is within 24 to
methodologic limitations, such as the lack of monitoring
48 h.97,98 Anticoagulant reversal with 4F-PCC in these sce-
of thrombin generation deficiency before administration of
narios appears unjustified unless there is severe bleeding,
4F-PCC and its raw comparative administration versus FFP,
and waiting times should be adjusted to optimize hemosta-
we must consider all its results as valid but without extrap-
sis, taking into account quality indicators.
olating the generalization of a risk of serious adverse effects
that would discourage their use in traumatic bleeding. We Four-factor Prothrombin Complex Concentrate in
advocate the development of new randomized clinical trials Current Trauma Guidelines
to contrast these results. Previous studies have explored the
effects of FFP-only strategies versus FFP plus 4F-PCC,94,95 Many trauma guidelines do not specifically address the use
and a single-center open-label trial has compared a combi- of 4F-PCC to treat coagulopathy, such as guidelines for
nation of fibrinogen concentrate, factor XIII, and 4F-PCC pelvic fracture bleeding,99 pediatric severe traumatic brain
versus FFP.17 All of these studies reported reductions in injury,100 and pregnant trauma patients.101 The application
blood product consumption with the administration of of 4F-PCC is closely linked to POC testing, goal-directed
4F-PCC. The ongoing Trauma and Prothrombin Complex treatment algorithms, and the availability of medications,
Concentrate trial aims to determine whether 4F-PCC resulting in regional variations in recommendations. The
can reduce mortality in patients predicted to require large European guidelines on the use of PCC in trauma are sum-
volume of blood transfusions (ClinicalTrials.gov identifier marized in table 1.47,102–108 Most of these guidelines do not
NCT05568888). This trial is expected to provide further specifically mention 4F-PCC in their general recommen-
insights into the effectiveness and safety of 4F-PCC in dation, and this generalization is reflected in table 1.
trauma settings, potentially influencing future guidelines
and clinical practice. Summary
Given the growing use of low-titer O group whole The indiscriminate use of 4F-PCC in trauma-induced
blood resuscitation in the United States, it would be ben- coagulopathy is not advisable due to potential throm-
eficial to promote comparative research in exsanguinated botic risks and limited impact on mortality. Nonetheless,
patients to determine which initial resuscitation strategies 4F-PCC is increasingly used in trauma patients with major
lead to earlier and more effective hemostasis, better control bleeding, TIC, oral anticoagulants, or traumatic brain inju-
of coagulopathic bleeding, and improved survival. However, ries. For urgent DOAC reversal, both 4F-PCC and specific
designing such studies would be challenging, because antidotes are effective. Andexanet alfa, although associated
these strategies are inherently different: 4F-PCC primarily with higher thrombotic risk, has shown superiority in cases
focuses on restoring thrombin generation, whereas whole of intracranial hemorrhage.
blood serves as a more comprehensive resuscitation product. High-quality evidence for unrestricted 4F-PCC use in
Careful consideration must be given to these differences adult trauma is limited, with studies being heterogeneous
when conducting comparative research. regarding patient populations, drug formulations, and
To summarize, based on the available evidence and multi- comparator selection. Most studies are retrospective and
disciplinary guidelines endorsed by organizations such as the observational. The diagnosis and monitoring of TIC are
European Trauma Guidelines,47 the use of 4F-PCC is indi- challenging due to the need for rapid and broad availabil-
cated for severe bleeding events in which impaired thrombin ity of diagnostic tools. PT and INR, despite being influ-
generation is confirmed by the loss and/or consumption of enced by various factors, remain the most common tests.
coagulation factors, as identified through conventional coag- Viscoelastic POC tests suggest a focus on restoring throm-
ulation analysis or viscoelastic testing. 4F-PCC is not recom- bin generation, with EXTEM CT (or R in TEG) being
mended as a first-line empirical treatment, except in cases more suitable for assessing thrombin generation and plasma
of exsanguination or very rapid massive bleeding, where coagulation status. The concurrent use of different PCC

Mora et al. A nesthesiology 2025; 142:351–63 357

 Clinical Focus Review

Table 1. Summary of Recommendations of PCC in European Guidelines

Class of
Recommendation and
Guideline Main Statement on PCC Evidence Level

European Trauma Guideline (6th We recommend the early and repeated monitoring of hemostasis, using either a traditional labo- 1C
Edition)47 ratory determination such as prothrombin time/international normalized ratio, Clauss fibrinogen
level and platelet count, and/or point-of-care prothrombin time/international normalized ratio and/
or a viscoelastic method
Provided that fibrinogen levels are normal, we suggest that PCC is administered to the bleeding 2C
patient based on evidence of delayed coagulation initiation using viscoelastic testing
In the bleeding trauma patient, we recommend the emergency reversal of vitamin K–dependent oral 1A
anticoagulants with the early use of both PCC and 5–10 mg IV phytomenadione (vitamin K1)
If andexanet alfa is not available or in patients receiving edoxaban, we suggest the administration of 2C
PCC (25–50 U/kg)
German Trauma Guidelines102 Recommend PCC in patients with life-threatening bleeding and/or in shock, in addition to fibrinogen NA
Spanish “Seville document”103 Suggests PCC for coagulopathic trauma patients NA
HEMOMAS document104 Prefers fresh frozen plasma over PCC in massive bleeding and limits PCC if risk of transfusion- NA
related acute lung injury or transfusion acute cardiac overload
European Expert Meeting105 Allows PCC use in expected coagulation factor deficiency NA
Association of Anaesthetists of Recommends PCC for vitamin K antagonist reversal in trauma victims NA
Great Britain and Ireland106
British Society of Haematology107 Does not suggest the use of PCC in trauma patients outside a clinical trial NA
European Guideline on reversal If idarucizumab not available in patients on dabigatran and severe bleeding, PCC or activated PCC is 2C
of direct oral anticoagulant in suggested
patients with life threatening PCC or andexanet alfa should be considered in patients under activated coagulation factor X inhibitor 1C
bleeding108 therapy with severe bleeding
Andexanet alfa or PCC are suggested to prevent increasing hematoma volume after apixaban and 2C
rivaroxaban-associated intracerebral bleeding
If andexanet alfa or PCC are not available, activated PCC may be considered 2C
NA, not available; PCC, prothrombin complex concentrate.

formulations in studies complicates comparisons, as 3F-, Competing Interests

4F-, and activated PCCs have distinct compositions and
Dr. Mora received honoraria for consulting from
should be considered separate drugs.
Octapharma (Lachen, Switzerland) and Grifols (Los
Current literature should be interpreted cautiously due
Angeles, California). Dr. Maegele received honoraria for
to these methodologic variances. Further prospective stud-
lectures and participation in expert/advisory board com-
ies and randomized controlled trials are urgently needed
mittees and financial support for participation in con-
to compare the efficacy and safety of 4F-PCC with other
gresses and scientific projects from Abbott (Abbott Park,
strategies, such as whole blood or FFP transfusion, and
Illinois), Astra Zeneca (Cambridge, United Kingdom),
to evaluate DOAC reversal with specific antidotes versus
Baxter (Deerfield, Illinois), Bayer (Leverkusen, Germany),
4F-PCC in trauma-related major bleeding.
Biotest (Dreieich, Germany), CSL Behring (King of
Appropriate patient selection, a thorough understanding
Prussia, Pennsylvania), IL-Werfen/TEM International
of the pathophysiology, and the highly dynamic nature of
(Munich, Germany), LFB Biomedicaments France (Les
traumatic bleeding are key to optimizing the successful use
Ulis, France), Portola (South San Francisco, California),
of 4F-PCC in clinical practice. Prioritizing the restoration
and Octapharma. Dr. Grottke has received research fund-
of documented thrombin generation deficits, as identified
ing from AstraZeneca, Alexion (Boston, Massachusetts),
through viscoelastic or conventional coagulation assays, will
Alvereon (Nijmegen, The Netherlands), Bayer AG, Biotest,
provide more precise guidance. In cases of severe thrombin
Boehringer Ingelheim (Ingelheim am Rhein, Germany),
deficiency due to rapid and massive blood loss, 4F-PCC is
CSL Behring, Octapharma, Novo Nordisk (Copenhagen,
likely to be an effective option. However, the choice of therapy
Denmark), Nycomed (Zurich, Switzerland), Portola,
should always consider factors such as availability, risk-benefit
Werfen (Barcelona, Spain), Federal Ministry of Education
analysis, resources, and the urgency of the clinical situation.
and Research (BMBF; Bonn, Germany), and German
Research Foundation (DFG; Bonn, Germany); he has
Research Support also received honoraria for lectures and consultancy sup-
Support was provided solely from institutional and/or port from AstraZeneca, Baxalta (Tokyo, Japan), Bayer AG,
departmental sources. Boehringer Ingelheim, Ferring (Saint-Prex, Switzerland),

358 A nesthesiology 2025; 142:351–63 Mora et al.

 Prothrombin Complex Concentrate in Trauma

CSL Behring, Octapharma, Pfizer (New York, New York), 13. Moore HB, Moore EE, Chapman MP, et al.: Plasma-
Takeda (Tokyo, Japan), Portola, Sanofi (Paris, France), and first resuscitation to treat haemorrhagic shock during
Werfen. Dr. Levy is on the advisory committees for Bayer, emergency ground transportation in an urban area: A
Grifols, Octapharma,Takeda, and Werfen.The other authors randomised trial. Lancet 2018; 392:283–91
declare no competing interests. 14. Cardenas JC, Rahbar E, Pommerening MJ, et al.:
Measuring thrombin generation as a tool for predict-
Correspondence ing hemostatic potential and transfusion requirements
following trauma. J Trauma Acute Care Surg 2014;
Address correspondence to Dr. Erdoes: Inselspital, Bern 77:839–45
University Hospital, University of Bern, Bern, Switzerland. 15. Müller MC, Straat M, Meijers JC, et al.: Fresh frozen
gabor.erdoes@insel.ch plasma transfusion fails to influence the hemostatic
balance in critically ill patients with a coagulopathy. J
References Thromb Haemost 2015; 13:989–97
16. Tripodi A, Chantarangkul V, Primignani M, et al.:
1. World Health Organization: Global health estimates Thrombin generation in plasma from patients
2016: Deaths by cause, age, sex, by country and by region, with cirrhosis supplemented with normal plasma:
2000–2016. Geneva, World Health Organization, 2018 Considerations on the efficacy of treatment with
2. Søreide K, Krüger AJ,Vårdal AL, Ellingsen CL, Søreide fresh-frozen plasma. Intern Emerg Med 2012; 7:139–44
E, Lossius HM: Epidemiology and contemporary pat- 17. Innerhofer P, Fries D, Mittermayr M, et al.: Reversal
terns of trauma deaths: Changing place, similar pace, of trauma-induced coagulopathy using first-line coag-
older face. World J Surg 2007; 31:2092–103 ulation factor concentrates or fresh frozen plasma
3. Holcomb JB, Tilley BC, Baraniuk S, et al.; PROPPR (RETIC): A single-centre, parallel-group, open-label,
Study Group: Transfusion of plasma, platelets, and red randomised trial. Lancet Haematol 2017; 4:e258–71
blood cells in a 1:1:1 vs. a 1:1:2 ratio and mortality in 18. Grottke O, Levy JH: Prothrombin complex con-
patients with severe trauma: The PROPPR random- centrates in trauma and perioperative bleeding.
ized clinical trial. JAMA 2015; 313:471–82 Anesthesiology 2015; 122:923–31
4. Moore EE, Moore HB, Kornblith LZ, et al.: Trauma- 19. Sadeghi N, Kahn D, Sayed D, et al.: Compositional dif-
induced coagulopathy. Nat Rev Dis Primers 2021; 7:30 ferences in commercially available prothrombin complex
5. Shaw JR, James T, Douxfils J, et al.: Thrombin gen- concentrates. Clin Appl Thromb Hemost 2014; 20:256–69
eration, bleeding and hemostasis in humans: Protocol 20. Kozar RA, Peng Z, Zhang R, et al.: Plasma restoration
for a scoping review of the literature. PLoS One 2023; of endothelial glycocalyx in a rodent model of hemor-
18:e0293632 rhagic shock. Anesth Analg 2011; 112:1289–95
6. Frith D, Goslings JC, Gaarder C, et al.: Definition and 21. Levy JH, Douketis J, Steiner T, Goldstein JN, Milling
drivers of acute traumatic coagulopathy: Clinical and TJ: Prothrombin complex concentrates for periopera-
experimental investigations. J Thromb Haemost 2010; tive vitamin K antagonist and non–vitamin K antico-
8:1919–25 agulant reversal. Anesthesiology 2018; 129:1171–84
7. Dunbar NM, Chandler WL: Thrombin generation in 22. Ostermann H, Haertel S, Knaub S, Kalina U, Jung K,
trauma patients. Transfusion 2009; 49:2652–60 Pabinger I: Pharmacokinetics of Beriplex P/N pro-
8. Duarte RCF, Ferreira CN, Rios DRA, Reis HJD, thrombin complex concentrate in healthy volunteers.
Carvalho MDG: Thrombin generation assays for global Thromb Haemost 2007; 98:790–7
evaluation of the hemostatic system: Perspectives and lim- 23. Puchstein D, Kork F, Schöchl H, Rayatdoost F, Grottke
itations. Rev Bras Hematol Hemoter 2017; 39:259–65 O: 3-Factor versus 4-factor prothrombin complex
9. Martini WZ: Coagulopathy by hypothermia and aci- concentrates for the reversal of vitamin K antago-
dosis: Mechanisms of thrombin generation and fibrin- nist–associated coagulopathy: A systematic review and
ogen availability. J Trauma 2009; 67:202–9 meta-analysis. Thromb Haemost 2023; 123:40–53
10. Rizoli SB, Scarpelini S, Callum J, et al.: Clotting factor 24. Hannadjas I, James A, Davenport R, Lindsay C, Brohi K,
deficiency in early trauma-associated coagulopathy. J Cole E: Prothrombin complex concentrate (PCC) for
Trauma 2011; 71:S427–34 treatment of trauma-induced coagulopathy: Systematic
11. Woolley T, Gwyther R, Parmar K, et al.: A prospective review and meta-analyses. Crit Care 2023; 27:422
observational study of acute traumatic coagulopathy 25. Tomaselli GF, Mahaffey KW, Cuker A, et al.: 2020 ACC
in traumatic bleeding from the battlefield. Transfusion expert consensus decision pathway on management of
2020; 60:S52–61 bleeding in patients on oral anticoagulants: A report
12. Floccard B, Rugeri L, Faure A, et al.: Early coagu- of the American College of Cardiology Solution
lopathy in trauma patients: An on-scene and hospital Set Oversight Committee. J Am Coll Cardiol 2020;
admission study. Injury 2012; 43:26–32 76:594–622

Mora et al. A nesthesiology 2025; 142:351–63 359

 Clinical Focus Review

26. Pagano MB, Foroutan F, Goel R, et al.: Vitamin K concentrate-induced disseminated intravascular coagu-
antagonist reversal strategies: Systematic review and lation can be prevented by coadministering antithrom-
network meta-analysis from the AABB. Transfusion bin in a porcine trauma model. Anesthesiology 2019;
2022; 62:1652–61 131:543–54
27. Milling TJ, Voronov A, Schmidt DS, Lindhoff-Last E: 38. Ghosh S, Krege W, Doerr B, et al.: Evaluation of the
Long-term safety of a four-factor prothrombin com- prothrombotic potential of four-factor prothrombin
plex concentrate (Kcentra®/Beriplex® P/N): An complex concentrate (4F-PCC) in animal models.
updated pharmacovigilance review. Thromb Haemost PLoS One 2021; 16:e0258192
2024 [Epub ahead of print] 39. Bates SM, Weitz JI: Coagulation assays. Circulation
28. Schöchl H, Voelckel W, Maegele M, Kirchmair L, 2005; 112:e53–60
Schlimp CJ: Endogenous thrombin potential follow- 40. Deras P, Nouri J, Martinez O, Aubry E, Capdevila X,
ing hemostatic therapy with 4-factor prothrombin Charbit J: Diagnostic performance of prothrombin
complex concentrate: A 7-day observational study of time point-of-care to detect acute traumatic coagulop-
trauma patients. Crit Care 2014; 18:R147 athy on admission: Experience of 522 cases in trauma
29. Goldhammer JE, Bakowitz MJ, Milas BL, Patel PA: center. Transfusion 2018; 58:1781–91
Intracardiac thrombosis after emergent prothrom- 41. Sorensen B, Spahn DR, Innerhofer P, Spannagl M,
bin complex concentrate administration for warfarin Rossaint R: Clinical review: Prothrombin complex
reversal. Anesthesiology 2015; 123:458 concentrates—Evaluation of safety and thrombogenic-
30. Koster A, Meyer-Jark T, Schirmer U, Sandica E: ity. Crit Care 2011; 15:201
Fulminant intraoperative right heart and pulmonary 42. Teissandier D, Moustafa F, Denaives A, et al.: Thrombin
artery thrombosis following prothrombin complex con- generation in real life bleeding patients on oral antico-
centrate infusion after complex open heart surgery with agulants reversed (or not) with (activated) prothrombin
cardiopulmonary bypass. A A Case Rep 2014; 2:89–91 complex concentrate. Thromb Res 2023; 223:184–93
31. Sarode R, Milling TJ Jr, Refaai MA, et al.: Efficacy and 43. Grottke O, Rossaint R, Henskens Y, van Oerle R, Ten
safety of a 4-factor prothrombin complex concentrate Cate H, Spronk HM: Thrombin generation capacity of
in patients on vitamin K antagonists presenting with prothrombin complex concentrate in an in vitro dilu-
major bleeding: A randomized, plasma-controlled, tional model. PLoS One 2013; 8:e64100
phase IIIb study. Circulation 2013; 128:1234–43 44. Grottke O, Callum J, Cushing MM, Haas T: The use
32. Goldstein JN, Refaai MA, Milling TJ Jr, et al.: Four- of coagulation factor concentrates for periopera-
factor prothrombin complex concentrate versus plasma tive bleeding management—A global perspective.
for rapid vitamin K antagonist reversal in patients Transfusion 2020; 60:663–6
needing urgent surgical or invasive interventions: A 45. Baksaas-Aasen K, Van Dieren S, Balvers K, et al.;
phase 3b, open-label, non-inferiority, randomised trial. TACTIC/INTRN collaborators: Data-driven develop-
Lancet 2015; 385:2077–87 ment of ROTEM and TEG algorithms for the manage-
33. Milling TJ Jr, Refaai MA, Sarode R, et al.: Safety of a ment of trauma hemorrhage:A prospective observational
four-factor prothrombin complex concentrate versus multicenter study. Ann Surg 2019; 270:1178–85
plasma for vitamin K antagonist reversal: An integrated 46. Erdoes G, Koster A, Ortmann E, et al.: A European con-
analysis of two phase IIIb clinical trials. Acad Emerg sensus statement on the use of four-factor prothrombin
Med 2016; 23:466–75 complex concentrate for cardiac and non-cardiac sur-
34. Milling TJ Jr, Refaai MA, Goldstein JN, et al.: gical patients. Anaesthesia 2021; 76:381–92
Thromboembolic events after vitamin K antagonist 47. Rossaint R, Afshari A, Bouillon B, et al.:The European
reversal with 4-factor prothrombin complex concen- guideline on management of major bleeding and coag-
trate: Exploratory analyses of two randomized, plasma- ulopathy following trauma: Sixth edition. Crit Care
controlled studies. Ann Emerg Med 2016; 67:96–105.e5 2023; 27:80
35. Go AS, Leong TK, Sung SH, et al.; REVERSAL Study: 48. Bouzat P, Charbit J, Abback PS, et al.; PROCOAG Study
Thromboembolism after treatment with 4-factor pro- Group: Efficacy and safety of early administration of 4-
thrombin complex concentrate or plasma for warfarin- factor prothrombin complex concentrate in patients with
related bleeding. J Thromb Thrombolysis 2022; 54:470–9 trauma at risk of massive transfusion: The PROCOAG
36. Grottke O, Braunschweig T, Spronk HM, et al.: randomized clinical trial. JAMA 2023; 329:1367–75
Increasing concentrations of prothrombin complex 49. Schöchl H, Nienaber U, Hofer G, et al.: Goal-
concentrate induce disseminated intravascular coagu- directed coagulation management of major trauma
lation in a pig model of coagulopathy with blunt liver patients using thromboelastometry (ROTEM)-
injury. Blood 2011; 118:1943–51 guided administration of fibrinogen concentrate and
37. Grottke O, Honickel M, Braunschweig T, Reichel prothrombin complex concentrate. Crit Care 2010;
A, Schochl H, Rossaint R: Prothrombin complex 14:R55

360 A nesthesiology 2025; 142:351–63 Mora et al.

 Prothrombin Complex Concentrate in Trauma

50. Maegele M:The diagnosis and treatment of acute trau- and meta-analysis. J Thromb Thrombolysis 2021;
matic bleeding and coagulopathy. Dtsch Arztebl Int 52:1137–50
2019; 116:799–806 63. Hormese M, Littler A, Doane B, et al.: Comparison
51. Schmidt DE, Chaireti R, Bruzelius M, Holmstrom M, of high- and low-dose 4-factor prothrombin complex
Antovic J, Agren A: Correlation of thromboelastogra- concentrate for the emergent reversal of oral factor Xa
phy and thrombin generation assays in warfarin-treated inhibitors. J Thromb Thrombolysis 2021; 52:828–35
patients. Thromb Res 2019; 178:34–40 64. Nederpelt CJ, Naar L, Krijnen P, et al.: Andexanet alfa or
52. Schmidt DE, Holmstrom M, Majeed A, Naslin D, prothrombin complex concentrate for factor Xa inhibi-
Wallen H, Agren A: Detection of elevated INR by tor reversal in acute major bleeding: A systematic review
thromboelastometry and thromboelastography in war- and meta-analysis. Crit Care Med 2021; 49:e1025–36
farin treated patients and healthy controls.Thromb Res 65. Jaspers T, Shudofsky K, Huisman MV, Meijer K,
2015; 135:1007–11 Khorsand N: A meta-analysis of andexanet alfa and
53. van den Brink DP, Wirtz MR, Neto AS, et al.: prothrombin complex concentrate in the treatment of
Effectiveness of prothrombin complex concentrate factor Xa inhibitor–related major bleeding. Res Pract
for the treatment of bleeding: A systematic review and Thromb Haemost 2021; 5:e12518
meta-analysis. J Thromb Haemost 2020; 18:2457–67 66. Sutton SS, Magagnoli J, Cummings TH, et al.: Real-
54. Kao TW, Lee YC, Chang HT: Prothrombin complex world clinical outcomes among US veterans with oral
concentrate for trauma induced coagulopathy: A sys- factor Xa inhibitor-related major bleeding treated with
tematic review and meta-analysis. J Acute Med 2021; andexanet alfa or 4-factor prothrombin complex con-
11:81–9 centrate. J Thromb Thrombolysis 2023; 56:137–46
55. Antonio BC, Denardin MS, Neves HAF, Padrao EMH: 67. Lu G, Lin J, Bui K, Curnutte JT, Conley PB: Andexanet
Critical appraisal and concerns regarding a meta-analysis versus prothrombin complex concentrates: Differences
on prothrombin complex concentrate (PCC) for trauma- in reversal of factor Xa inhibitors in in vitro throm-
induced coagulopathy: Unveiling methodological bin generation. Res Pract Thromb Haemost 2020;
nuances and treatment variances. Crit Care 2023; 27:454 4:1282–94
56. Hill R, Han TS, Lubomirova I, Math N, Bentley P, 68. Phillips A, Bradley C, Cash J, Sangiovanni R,Wingerson
Sharma P: Prothrombin complex concentrates are C: Effect of low- versus high-dose 4-factor prothrom-
superior to fresh frozen plasma for emergency reversal bin complex concentrate in factor Xa inhibitor-
of vitamin K antagonists: A meta-analysis in 2606 sub- associated bleeding: A qualitative systematic review. Am
jects. Drugs 2019; 79:1557–65 J Health Syst Pharm 2024; 81:e274–82
57. Hood C, Goldstein JN, Milling TJ, et al.: INR and vita- 69. Rayatdoost F, Deventer K, Rossaint R, Schöchl H,
min K–dependent factor levels after vitamin K antago- Grottke O: Comparative analysis of andexanet alfa and
nist reversal with 4F-PCC or plasma. Blood Adv 2023; prothrombin complex concentrate in reversing antico-
7:2206–13 agulation by rivaroxaban ex vivo. Br J Anaesth 2024;
58. Abdoellakhan RA, Khorsand N, Ter Avest E, et al.: 132:251–9
Fixed versus variable dosing of prothrombin complex 70. Honickel M, Braunschweig T, Rossaint R, Schöchl
concentrate for bleeding complications of vitamin K H, Grottke O: Evaluation of combined idarucizumab
antagonists—The PROPER3 randomized clinical and prothrombin complex concentrate treatment for
trial. Ann Emerg Med 2022; 79:20–30 bleeding related to dabigatran in a lethal porcine model
59. Mohammadi K, Yaribash S, Sani MA, Talasaz AH: of double trauma. Transfusion 2019; 59:1376–87
Efficacy and safety of the fixed-dose versus variable- 71. Sheikh-Taha M, Clark HL, Crawley RM: Efficacy and
dose of 4-PCC for vitamin K antagonist reversal: A safety of activated prothrombin complex concentrate
comprehensive systematic review and meta-analysis. for reversal of the anticoagulant effect of apixaban and
Cardiovasc Drugs Ther 2022; 36:533–46 rivaroxaban in patients with major bleeding. Clin Drug
60. Stoecker Z, Van Amber B, Woster C, et al.: Evaluation Investig 2023; 43:883–8
of fixed versus variable dosing of 4-factor prothrombin 72. Costa OS, Connolly SJ, Sharma M, et al.:Andexanet alfa
complex concentrate for emergent warfarin reversal. versus four-factor prothrombin complex concentrate
Am J Emerg Med 2021; 48:282–7 for the reversal of apixaban- or rivaroxaban-associated
61. Schulman S, Bhagirath V, Chan N, et al.: Prothrombin intracranial hemorrhage: A propensity score-overlap
complex concentrate for emergency surgery in weighted analysis. Crit Care 2022; 26:180
patients on oral Xa-inhibitors. J Thromb Haemost 73. Cooksey GE, Hamilton LA, McMillen JC, Griffard
2024; 22:2761–6 JH, Rowe AS: Impact of factor Xa inhibitor reversal
62. Milioglou I, Farmakis I, Neudeker M, et al.: with prothrombin complex concentrate in patients
Prothrombin complex concentrate in major bleeding with traumatic brain injuries. Neurocrit Care 2022;
associated with DOACs: An updated systematic review 37:471–8

Mora et al. A nesthesiology 2025; 142:351–63 361

 Clinical Focus Review

74. Heath M, Hall B, De Leon J, et al.: Comparative hemo- trauma-associated haemorrhage and massive transfu-
static efficacy of 4F-PCC in patients with intracranial sion. Injury 2011; 42:697–701
hemorrhage on factor Xa inhibitors versus warfarin. 87. Joseph B, Khalil M, Harrison C, et al.: Assessing the
Am J Emerg Med 2022; 57:149–52 efficacy of prothrombin complex concentrate in mul-
75. Chaudhary R, Singh A, Chaudhary R, et al.: Evaluation tiply injured patients with high-energy pelvic and
of direct oral anticoagulant reversal agents in intra- extremity fractures. J Orthop Trauma 2016; 30:653–8
cranial hemorrhage: A systematic review and meta- 88. Hofmann N, Zipperle J, Brettner F, et al.: Effect of
analysis. JAMA Netw Open 2022; 5:e2240145 coagulation factor concentrates on markers of endo-
76. Pham H, Medford WG, Horst S, et al.: Andexanet thelial cell damage in experimental hemorrhagic
alfa versus four-factor prothrombin complex con- shock. Shock 2019; 52:497–505
centrate for the reversal of apixaban- or rivaroxaban- 89. da Luz LT, Callum J, Beckett A, et al.: Protocol for a
associated intracranial hemorrhages. Am J Emerg Med multicentre, randomised, parallel-control, superiority
2022; 55:38–44 trial comparing administration of clotting factor con-
77. Lipski M, Pasciolla S,Wojcik K, Jankowitz B, Igneri LA: centrates with a standard massive haemorrhage proto-
Comparison of 4-factor prothrombin complex con- col in severely bleeding trauma patients: The FiiRST 2
centrate and andexanet alfa for reversal of apixaban and trial (a 2020 EAST multicentre trial). BMJ Open 2021;
rivaroxaban in the setting of intracranial hemorrhage. J 11:e051003
Thromb Thrombolysis 2023; 55:519–26 90. Tripodi A, Chantarangkul V, Mannucci PM: Acquired
78. Pon G, Pelsue B, Reddy ST, et al.: Hemostatic efficacy coagulation disorders: Revisited using global coagulation/
of four factor prothrombin complex concentrate in anticoagulation testing. Br J Haematol 2009; 147:77–82
intracerebral hemorrhage patients receiving warfarin 91. David JS, Levrat A, Inaba K, et al.: Utility of a point-
vs. factor Xa inhibitors. Thromb Res 2023; 229:46–52 of-care device for rapid determination of prothrombin
79. Faulkner H, Chakankar S, Mammi M, et al.: Safety time in trauma patients: A preliminary study. J Trauma
and efficacy of prothrombin complex concentrate Acute Care Surg 2012; 72:703–7
(PCC) for anticoagulation reversal in patients under- 92. Balendran CA, Lövgren A, Hansson KM, et al.:
going urgent neurosurgical procedures: A system- Prothrombin time is predictive of low plasma pro-
atic review and metaanalysis. Neurosurg Rev 2021; thrombin concentration and clinical outcome in
44:1921–31 patients with trauma hemorrhage: Analyses of pro-
80. Connolly SJ, Sharma M, Cohen AT, et al.; ANNEXA-I spective observational cohort studies. Scand J Trauma
Investigators: Andexanet for factor Xa inhibitor–asso- Resusc Emerg Med 2017; 25:30
ciated acute intracerebral hemorrhage. N Engl J Med 93. Larsen JB, Hvas AM: Predictive value of whole blood
2024; 390:1745–55 and plasma coagulation tests for intra- and postopera-
81. Tanaka KA, Shettar S,Vandyck K, Shea SM,Abuelkasem tive bleeding risk: A systematic review. Semin Thromb
E: Roles of four-factor prothrombin complex concen- Hemost 2017; 43:772–805
trate in the management of critical bleeding. Transfus 94. Jehan F, Aziz H, OʼKeeffe T, et al.: The role of four-
Med Rev 2021; 35:96–103 factor prothrombin complex concentrate in coag-
82. Uttaro E, Young MR, Falvey J, Corvelli JM, Acquisto ulopathy of trauma: A propensity matched analysis. J
NM: Use of four-factor prothrombin complex con- Trauma Acute Care Surg 2018; 85:18–24
centrate (4F-PCC) for management of bleeding not 95. Zeeshan M, Hamidi M, Feinstein AJ, et al.: Four-factor
associated with therapeutic anticoagulant use. Transfus prothrombin complex concentrate is associated with
Apher Sci 2023; 62:103759 improved survival in trauma-related hemorrhage: A
83. Tanaka KA, Mazzeffi M, Durila M: Role of prothrom- nationwide propensity-matched analysis. J Trauma
bin complex concentrate in perioperative coagulation Acute Care Surg 2019; 87:274–81
therapy. J Intensive Care 2014; 2:60 96. You D, Xu Y, Krzyzaniak H, Korley R, Carrier M,
84. Kuckelman J, Barron M, Moe D, et al.: Plasma coad- Schneider P: Safety of expedited-surgery protocols
ministration improves resuscitation with tranexamic in anticoagulant-treated patients with hip fracture: A
acid or prothrombin complex in a porcine hemor- systematic review and meta-analysis. Can J Surg 2023;
rhagic shock model. J Trauma Acute Care Surg 2018; 66:E170–80
85:91–100 97. Maegele M: Management of patients with proximal
85. Stein P, Kaserer A, Sprengel K, et al.: Change of transfu- femur fractures under DOACs. Eur J Trauma Emerg
sion and treatment paradigm in major trauma patients. Surg 2024; 50:359–66
Anaesthesia 2017; 72:1317–26 98. Levack AE, Moore HG, Stephan S, et al.: Delayed sur-
86. Nienaber U, Innerhofer P, Westermann I, et al.: The gery does not reduce transfusion rates in low-energy
impact of fresh frozen plasma vs. coagulation fac- hip fractures on direct oral anticoagulants. J Orthop
tor concentrates on morbidity and mortality in Trauma 2022; 36:172–8

362 A nesthesiology 2025; 142:351–63 Mora et al.

 Prothrombin Complex Concentrate in Trauma

99. Cullinane DC, Schiller HJ, Zielinski MD, et al.: Eastern update of the “Seville Document.” Blood Transfus
Association for the Surgery of Trauma practice man- 2013; 11:585–610
agement guidelines for hemorrhage in pelvic frac- 104. Llau JV, Aldecoa C, Guasch E, et al.: Multidisciplinary
ture—Update and systematic review. J Trauma 2011; consensus document on the management of massive hae-
71:1850–68 morrhage: First update 2023 (document HEMOMAS-
100. Kochanek PM, Tasker RC, Carney N, et al.: II). Med Intensiva (Engl Ed) 2023; 47:454–67
Guidelines for the management of pediatric severe 105. Černý V, Maegele M, Agostini V, et al.: Variations and
traumatic brain injury, third edition: Update of the obstacles in the use of coagulation factor concentrates
Brain Trauma Foundation Guidelines, executive sum- for major trauma bleeding across Europe: Outcomes
mary. Neurosurgery 2019; 84:1169–78 from a European expert meeting. Eur J Trauma Emerg
101. Jain V, Chari R, Maslovitz S, et al.; Maternal Fetal Surg 2022; 48:763–74
Medicine Committee: Guidelines for the manage- 106. Thomas D, Wee M, Clyburn P, et al.; Association of
ment of a pregnant trauma patient. J Obstet Gynaecol Anaesthetists of Great Britain and Ireland: Blood
Can 2015; 37:553–74 transfusion and the anaesthetist: Management of mas-
102. Deutsche Gesellschaft für Unfallchirurgie e.V.: sive haemorrhage. Anaesthesia 2010; 65:1153–61
S3-Leitlinie Polytrauma/Schwerverletzten- 107. Hunt BJ, Allard S, Keeling D, Norfolk D, Stanworth
Behandlung (AWMF Registernummer 187-023), SJ, Pendry K; British Committee for Standards in
version 4.0 (31.12.2022). Available at: https://www. Haematology: A practical guideline for the haema-
awmf.org/leitlinien/detail/ll/187-023.html. Accessed tological management of major haemorrhage. Br J
September 8, 2024. Haematol 2015; 170:788–803
103. Leal-Noval SR, Muñoz M, Asuero M, et al.; Spanish 108. Grottke O, Afshari A, Ahmed A, et al.: Clinical guide-
Expert Panel on Alternatives to Allogeneic Blood line on reversal of direct oral anticoagulants in patients
Transfusion: Spanish Consensus Statement on alter- with life threatening bleeding. Eur J Anaesthesiol
natives to allogeneic blood transfusion: The 2013 2024; 41:327–50

Mora et al. A nesthesiology 2025; 142:351–63 363