Hannadjas et al.

Critical Care (2023) 27:422 Critical Care

https://doi.org/10.1186/s13054-023-04688-z

RESEARCH Open Access

Prothrombin complex concentrate (PCC)

for treatment of trauma‑induced coagulopathy:
systematic review and meta‑analyses
Ioannis Hannadjas1†, Arthur James1,2*†, Ross Davenport1, Charlotte Lindsay1, Karim Brohi1 and Elaine Cole1

Abstract
Background Trauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrom-
bin complex concentrate (PCC) is used as a potential treatment for the correction of TIC, but the efficacy, timing,
and evidence to support its use in injured patients with hemorrhage are unclear.
Methods A systematic search of published studies was performed on MEDLINE and EMBASE databases using stand-
ardized search equations. Ongoing studies were identified using clinicaltrials.gov. Studies investigating the use of PCC
to treat TIC (on its own or in combination with other treatments) in adult major trauma patients were included. Stud-
ies involving pediatric patients, studies of only traumatic brain injury (TBI), and studies involving only anticoagulated
patients were excluded. Primary outcomes were in-hospital mortality and venous thromboembolism (VTE). Pooled
effects of PCC use were reported using random-effects model meta-analyses. Risk of bias was assessed for each study,
and we used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality
of evidence.
Results After removing duplicates, 1745 reports were screened and nine observational studies and one randomized
controlled trial (RCT) were included, with a total of 1150 patients receiving PCC. Most studies used 4-factor-PCC
with a dose of 20–30U/Kg. Among observational studies, co-interventions included whole blood (n = 1), fibrinogen
concentrate (n = 2), or fresh frozen plasma (n = 4). Outcomes were inconsistently reported across studies with wide
variation in both measurements and time points. The eight observational studies included reported mortality
with a pooled odds ratio of 0.97 [95% CI 0.56–1.69], and five reported deep venous thrombosis (DVT) with a pooled
OR of 0.83 [95% CI 0.44–1.57]. When pooling the observational studies and the RCT, the OR for mortality and DVT
was 0.94 [95% CI 0.60–1.45] and 1.00 [95% CI 0.64–1.55] respectively.
Conclusions Among published studies of TIC, PCCs did not significantly reduce mortality, nor did they increase
the risk of VTE. However, the potential thrombotic risk remains a concern that should be addressed in future studies.
Several RCTs are currently ongoing to further explore the efficacy and safety of PCC.
Keywords Major trauma, Trauma-induced coagulopathy, Prothrombin complex concentrate, Blood coagulation
factors, Blood transfusion, Trauma hemorrhage

†
Ioannis Hannadjas and Arthur James co first authors.
*Correspondence:
Arthur James
[email protected]
Full list of author information is available at the end of the article

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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Hannadjas et al. Critical Care (2023) 27:422 Page 2 of 13

Introduction Data sources and search strategies

Enhanced trauma resuscitation with major hemor- We conducted a systematic literature search to iden-
rhage protocols, balanced transfusion, and empiric use tify publications that examined the use of PCCs in
of tranexamic acid have improved early survival for the treatment of TIC in adult trauma patients. The
injured patients with hemorrhage [1]. However, mor- search was performed in MEDLINE (via PubMed) and
tality rates associated with bleeding remain high [2], EMBASE databases using a combination of free text
particularly in cases of uncontrolled hemorrhage and and structured vocabulary (MeSH terms). We also
trauma-induced coagulopathy (TIC) [3, 4]. Patients searched ClinicalTrials.gov to identify relevant ongo-
who develop TIC require more blood transfusions, have ing or completed randomized clinical trials related to
a higher incidence of multiple organ dysfunction, and this topic. Both searches included publications released
have an increased risk of death [5, 6]. Currently, stand- between January 1, 2010, and April 22, 2023. The com-
ard component therapy for TIC involves administer- plete search strategies for MEDLINE, EMBASE, and
ing tranexamic acid [7], fresh frozen plasma (FFP), and ClinicalTrials.gov can be found in Additional file 1.
supplemental fibrinogen and calcium [8]. Prothrombin
complex concentrates (PCCs) have been proposed for Selection process
the management of major bleeding and coagulopathy After removing duplicates, two reviewers (IH, AJ) inde-
after trauma, particularity when used in conjunction pendently assessed the eligibility of retrieved refer-
with fibrinogen concentrate to treat low fibrinogen lev- ences. Any discrepancies were resolved by discussion
els [9–11]. with a third reviewer (EC) to reach consensus. Eligibil-
PCCs contain vitamin K-dependent clotting factors (II, ity criteria were interventional and observational stud-
VII, IX, and X) and are traditionally used for emergency ies of adult patients being administered PCC to treat
reversal of vitamin K antagonists in major hemorrhage trauma-induced coagulopathy (Full PICO in Additional
[12]. The products are either 3- or 4-factor-PCC (3F, file 1). We excluded studies dedicated to pediatrics as
4F-PCC) formulations depending on the concentrations well as those focusing on PCC administered to reverse
of Factor VII [13]. Compared to FFP, PCC has a long anticoagulation, for traumatic brain injury only, or for
shelf-life at room temperature and therefore can be avail- liver disease. We also excluded case series, case reports,
able rapidly for treating clinicians both in-hospital and conference abstracts, and studies not published in Eng-
prehospital settings. It contains a high, supraphysiologi- lish. The software Rayyan (rayyan.ai) was used for the
cal concentration of clotting factors and is administered title and abstract screening [18].
in small volumes. However, the effectiveness of PCCs
as a treatment for TIC remains uncertain, and there is a
Data extraction
lack of international consensus regarding the indications,
Data extraction was performed independently by two
timing of administration, adjunct therapies, and dosing
reviewers (IH, AJ), and the discrepancies were dis-
protocols. Moreover, it is unclear as to whether PCC’s
cussed with a third reviewer (EC) to reach consensus.
are a safe alternative to FFP in the early or later phases
When adjusted and non-adjusted results were avail-
of major hemorrhage management, with an increased
able, only adjusted results were extracted. From each
thrombosis risk in patients who are themselves in a pro-
included study, the following data were extracted:
coagulant phase post-injury [14–16].
The overall aim of this systematic review was to inves-
• Information about the study: Main author, year of
tigate the outcomes and safety of PCC in major trauma
publication, study title, study design (observational/
patients with TIC. The primary objective was to char-
randomized controlled trial), number of centers
acterize the use of PCC administration during trauma
(single center or multi-center), number of patients
hemorrhage. Secondly, we wished to investigate clinical
included, country of the first authors, outcomes
outcomes, specifically mortality and venous thromboem-
reported
bolism (VTE), associated with PCC administration dur-
• Information about the patients: injury type (pen-
ing trauma hemorrhage.
etrating or blunt or both, if both then proportion
of penetrating injuries), INR at admission, propor-
tion of patients receiving an anti-platelet treatment,
Methods
injury severity score (ISS)
Study design
• Information about the PCC: indication (triggering
This systematic review follows the Preferred Report-
criteria if reported), timing of PCC administration
ing Items for Systematic Reviews and Meta-analyses
(PRISMA) [17] (Additional file 1).
Hannadjas et al. Critical Care (2023) 27:422 Page 3 of 13

(in minutes after the trauma), molecule used, dose Results

(in UI/Kg) Selection of the relevant studies
• Information about the comparators: molecule Following the search strategy, 1925 publications were
used, dose (in UI/Kg) identified (MEDLINE: 942, EMBASE: 727, ClinicalTrials.
• Information about co-treatment (co-treatment was gov: 256). After removal of 180 duplicates, 1745 papers
defined as pharmaceutical interventions protocol- were screened and 1722 of these were excluded accord-
ized in at least one group of the study): molecule ing to eligibility criteria. Full-text review was applied to
used, dose (in UI/Kg) the remaining 23 studies, and of these, nine observational
• Outcomes: For each included study, all reported studies [22–30], four clinical trial protocols [31–34], and
outcomes were retrieved one by one. The primary one randomized control trial were included in the analy-
outcome of this systematic review was in-hospital sis [35]. The PRISMA flow diagram can be found in Fig. 1.
mortality. We also extracted transfusion volume
(red blood cell [RBC] units, platelets units, and
FFP units and the proportion of patients with deep Observational studies
venous thrombosis (DVT)). Characteristics of the studies and of their patients
Across all nine observational studies, a total of 823
From each clinical trial protocol data were extracted patients were included in the PCC treatment group
on the inclusion criteria, the intervention planned (ranging from 9 to 234 patients per group). Two of the
and comparator, the main outcome, and current stage studies were multi-center with the remainder being
reported on clinicaltrials.gov. single center [25, 27]. The mean a26ge of the patients
ranged from 36 to 51 years and the mean ISS from 23
to 50. Blunt mechanisms predominated and penetrating
Data synthesis and statistical analysis injuries comprised 13% to 23% of the patients receiving
Data were reported as either mean with standard PCC. Only four studies reported INR at admission, and
deviation or median with interquartile range, as pro- the mean values ranged from 1.8 to 2.3 [22–24, 26]. Three
vided by the included studies. We used odds ratio (OR) studies reported pre-injury antiplatelet use, with propor-
and 95% confidence interval as a summary measure. tions ranging from 19 to 27% [22, 25, ]. The main charac-
Assuming an important heterogeneity among included teristics of the included studies can be found in Table 1.
studies results, a random-effects model was applied,
and the Paule-Mandel procedure was used to calculate
the heterogeneity variance (τ2). Subgroup meta-anal- PCC administration
yses were conducted for propensity-matched stud- The most commonly compared type of prothrombin
ies and for those without adjustment to explore the complex concentrate was 4F-PCC. Overall, six stud-
impact of the method used on the results published. ies evaluated 4F-PCC [22, 25–29], three studies used
We considered a p-value < 0.05 as significant. All anal- 3F-PCC [22–24], one did not report the type of PCC used
yses were performed using the R v4.2.1 software. [30], and one study compared 3F-PCC and 4F-PCC [22].

treatment were Profilnine SD® (Grifols, Los Angeles,

The specific pharmaceutical products used for 3F-PCC

Study quality assessment Calif ) in three studies [22–24] or Bebulin VH® (Baxter
We used the Risk Of Bias In Non-randomized Studies Healthcare Corporation, Deerfield, Ill) in one study [22]).

thromplex® (Baxter, Vienna, Austria) (n = 2) [28, 29] or

of Interventions (ROBINS-I) [19] and the Revised Tool The product used for 4F-PCC treatment was either Pro-

Kcentra® (CSL Behring, Germany) (n = 2) [22, 26]. Two

for Risk of Bias in Randomized Trials (RoB2) [20] to
assess the quality of included observational studies and
the randomized controlled trial, respectively. Three of studies did not specify the product used [25, 27].
the authors performed the quality assessments inde- The recommended dose of FFP in each study ranged
pendently (IH, AJ, CL), and discrepancies were dis- from 20 to 30 mL/kg, but the dose which was actually
cussed with a last reviewer (EC) to reach consensus. administered was not reported [22–24, 26, 28, 29]. The
For each intervention evaluated in the meta-analysis, mean time of PCC administration was reported in four
we rated the quality of evidence for PCC administra- studies and ranged from 26 to 68 min after admission
tion according to the Grading of Recommendation, [22–25]. Indications for PCC administration included
Assessment, Development, and Evaluation (GRADE) TIC with an INR ≥ 1.5 (n = 2) [22, 26], at the discre-
Working Group system [21]. tion of the attending physician (n = 3) [23, 24, 29], if
EXTEM was superior to 80 s after fibrinogen concentrate
Hannadjas et al. Critical Care (2023) 27:422 Page 4 of 13

Fig. 1 PRISMA flow diagram search strategy [24]

administration (n = 3) [28–30] or unknown (n = 2) [25, tranexamic acid [22, 26, 28, 30]. Patients requiring sur-
27]. None of the studies reported whether treatments gical procedures were inconsistently reported among
were administered in accordance with protocols or the studies, and none stated the proportion of patients
guidelines. who received damage control surgery.
Comparators The most frequent comparator of PCC
was FFP, either administered alone (n = 4) [23–26],
Co‑interventions associated with another treatment such as another type
PCC was used as stand-alone coagulation treatment of PCC (n = 1) [22] or with PCC and fibrinogen concen-
in two studies [23, 30], while in the others PCC was trate (n = 1) [28]. There was one comparison of whole
used in association with supplementary treatments blood with and without PCC [27], and three studies
such as FFP (n = 4) [22, 23, 25, 26], fibrinogen concen- used fibrinogen concentrate as a comparator [28–30].
trate (n = 2) [28, 29], or whole blood (n = 1) [27]. Four No coagulation therapy was used as a comparator in a
studies reported the proportion of patients receiving single study [29].
Table 1 Characteristics of included observational studies
First author Study design Age in the Sex in the ISS INR Penetrating PCC Number of Intervention Intervention Control
Year PCC group(s) PCC group(s) in the PCC in the PCC injuries Indication patients in the Group 1 Group 2 Group
Country group(s) group(s) in the PCC PCC ­group&
group(s)

Jehan Single center 57 (20.9)#& 26 (65)& 30 [21–38]%& 1.8 (2)# 7 (17) Significant n = 40 4F-PCC (25 – FFP ­alone£
Hannadjas et al. Critical Care

[26] with PS bleeding units/kg) + ­FFP£

US matching and coagu-
lopathic
(INR ≥ 1.5)
Joseph Single center 46 (22)# 49 (78) 28 [17–40]%& 2.2 (0.9)# 14 (23) At the dis- n = 63 3F-PCC (25U/ – FFP alone
[31] with PS cretion kg) + FFP (15 mL/Kg)
(2023) 27:422

US matching of the attend- (15 mL/Kg)

ing trauma
surgeon
Joseph Single center 48.3 (23.2)# 20 (74) 24 (14–31)%! 2.3 (0.8)# 6 (22) At the dis- n = 27 3F-PCC (25U/kg) – FFP alone
[31 with PS cretion (15 mL/Kg)
US matching of the attend-
ing trauma
surgeon
Khurrum Multicenter 48 (21)#& 102 (61)& 30 [21–38]%& – 11 (13) Unknown n = 84 4F-PCC£ + Whole – Whole Blood
[27 with PS ­Blood£
US matching
Ponschab Single center 45 [26.3– 69 (71.9) Unknown – – EXTEM > 80 s PPC alone: n = 13 PCC ­alone£^ FC FC alone (4 g)
[30] with- 60.0]% after FC PCC + FC: n = 23 (4 g) + ­PCC£^
Austria out adjust- treatment
ment OR Obvi-
ous severe
coagulopathy
OR Physician
discretion
Schlimp Single center FC-PCC: 45 FC-PCC: 51 FC–PCC: 34 – – EXTEM > 80 s FC + PCC: n = 63 FC (2 FC alone (2 Fibrinogen
[28 with- [26–57]% (81) [26–43]% after FC treat- FC + PCC + FFP: to 6 g) + 4F-PCC to 6 g) concentrate
Austria out adjust- FC-PCC-FFP: FC-PCC-FFP: FC–PCC–FFP: ment n=9 (20 to 30 IU/kg) (2-6 g) + 4F-PCC
ment 49 [29–58]% 6 (67) 50 [42–58]% (20 to 30 IU/
kg) + ­FFP£
Schöchl Single center FC: 40 (14)# NA 35.7 (13.0)# – – EXTEM > 80 s n = 17 FC FC alone No coagulation
[29] with- FC + PCC: 36 after FC (6-8 g) + 4F-PCC (6-8 g) therapy
Austria out adjust- (13)# treatment (20 to 30 IU/kg)
ment OR Obvi-
ous severe
coagulopathy
OR Physician
discretion
Page 5 of 13
 Hannadjas et al. Critical Care
(2023) 27:422

Table 1 (continued)
First author Study design Age in the Sex in the ISS INR Penetrating PCC Number of Intervention Intervention Control
Year PCC group(s) PCC group(s) in the PCC in the PCC injuries Indication patients in the Group 1 Group 2 Group
Country group(s) group(s) in the PCC PCC ­group&
group(s)

Zeeshan Single center 4F-PCC: 51 4F-PCC: 82 4F-PCC: 23 4F-PCC: 2.0 4F-PCC: 21 Trauma- 4F-PCC: n = 125 4F-PCC (25U/ – 3F-PCC (25U/
[22] with PS (19.6)# (66) [14–32]%& (0.3)#& (17)& induced 3F-PCC: n = 125 kg) + ­FFP£ kg) + ­FFP£
US matching 3F-PCC: 50 3F-PCC: 80 3F-PCC: 3F-PCC: 1.9 3F-PCC: 18 coagulopathy
(18.3)# (64) 27[15–31]%& (0.2)#& (14)& with INR ≥ 1.5
Zeeshan Multi center 50 (21)#& 171 (70.3)& 27 [20–37]%& – 32 (13.4) Unknown n = 234 4F-PCC£ + ­FFP£ – FFP ­alone£
[25] with PS
US matching
Continuous variables are presented either as median (IQR) % or as mean (SD)#; categorical variables are presented as number and relative percentages. Number of patients or relative percentages were calculated if not
reported. Some variables are presented after PS ­matching& while other are presented before PS ­matching!. £ Protocol doses are unknown; ^Unknown type of PCC. FC Fibrinogen concentrate, ISS injury severity score, INR
international normalized ratio, PCC prothrombin complex concentrate, PS propensity score, US United States
Page 6 of 13
Hannadjas et al. Critical Care (2023) 27:422 Page 7 of 13

Table 2 Outcomes reported by included studies

Studies references In-hospital DVT RBC (unit) Platelets (unit) FFP Other outcomes
Mortality In hosp (unit) reported

Jehan PCC + FFP: 10 (25) PCC + FFP: 1 (2.5) Unclear Unclear Unclear Proportion of patients
[26] FFP 26 (33) FFP: 1 (1.2) PCC + FFP: 7 (3)µ PCC + FFP: 3 (3)µ PCC + FFP: 5 (2)µ with INR correction
p = 0.04* p = 0.51* FFP: 9 (5)µ FFP: 3 (3)µ FFP: 7 (3)µ and time to INR cor-
p < 0.04* p = 0.72* p = 0.03* rection from admis-
sion*
Rate of correction
of INR*
Other TE*: PE, Mesen-
teric ischemia
ICU and Hospital LOS
Joseph PCC + FFP: 15 (23) PCC + FFP: 1 (1.6) Total Total Total Proportion of patients
[31] FFP alone: 53 (28) FFP alone: 2 (1.1) PCC + FFP: 6.6 (4.1)µ PCC + FFP: 1.2 (2.1)µ PCC + FFP: 2.8 (1.8)µ with INR correction
p = 0.04 p = 0.6* FFP alone: 10 (8.3)µ FFP alone: 1.5 (2.7)µ FFP alone: 3.9 (1.3)µ and time to INR cor-
p = 0.001* p = 0.2* p = 0.01* rection from admis-
sion*
Time to treatment*
Mesenteric infarc-
tion*
ICU and Hospital LOS
Costs: therapy*, trans-
fusion*, hospital
Joseph PCC: 6 (22.3) PCC: 3 (11.1) Total Total Total Proportion of patients
[24] FFP 15 (27.8) FFP: 4 (7.4) PCC: 3.2 (1.9)µ PCC: 1.4 (2.3)µ PCC: 5.1 (3.6)µ with INR correction
p = 0.78 p = 0.68* FFP: 5.4 (4.1)µ FFP: 1.6 (2.4)µ FFP: 90.7 (4.1)µ and time to INR cor-
p = 0.009* p = 0.72* p = 0.005* rection from admis-
sion*
Time to treatment
Time to surgery
Mesenteric or myo-
cardial infarction
ICU and Hospital LOS
Costs: therapy,
transfusion, hospital,
charges
Khurrum PCC + WB: 39 (46) PCC + WB: 3 (4) At 24 h At 24 h At 24 h PCC units
[27] WB 74 (44) WB: 8 (5) PCC + WB: 8 (5–14)$ PCC + WB: 2 (1–3)$ PCC + WB: 6 (4–10)$ In ED mortality
p = 0.72* p = 0.75 WB: 10 (6–18)$ WB: 2 (1–4)$ WB: 8 (4–12)$ ED, ICU and hospital
p = 0.04* p = 0.19* p = 0.01* LOS
AKI, ARDS, PE
Ponschab – – At 24 h At 24 h At 24 h ROTEM parameter
[30] All patients: 7 All patients: 0 All patients: 0 PCC unit, FC (g)
(3–10) [7] (0–00) [7] (0–0)7 and TXA (g) adminis-
trated at 24 h
Schlimp PCC + FC: 18 (29) – At 24 h At 24 h At 24 h Transfusion (RBC, FFP,
[28] FC: 7 (8) PCC + FC: 8 (5–11)$ PCC + FC: 0 (0–0)$ PCC + FC: none platelet, FC, PCC) vol-
PCC + FC + FFP: FC: 3 (2–6)$ FC: 0 (0–0)$ FC: none ume in ED and ICU
5 (56) PCC + FC + FFP: 21 PCC + FC + FFP: 4 PCC + FC + FFP: 6 Massive transfusion
p < 0.0001 (18–26)$ (2–4)$ (6–10)$ Standard and specific
p < 0.0001 p < 0.001 p = NA coagulation tests
including ROTEM
over 7 days
Schöchl PCC + FC: 0 (0) - At 24 h At 24 h At 24 h PCC and FC unit
[29] FC: 0 (0) PCC + FC: 8 PCC + FC: 0 (0–1)$ PCC + FC: 0 (0–0)$ transfused
NCT: 0 (0) (6–10.5)$ FC: 0 (0–0)$ FC: 0 (0–0)$ Standard and specific
FC: 3 (0–5)$ NCT: 0 (0–0)$ NCT: 0 (0–0)$ coagulation tests
NCT: 0 (0–2)$ p < 0.001 p = ns including ROTEM
p < 0.001 over 7 days
Hannadjas et al. Critical Care (2023) 27:422 Page 8 of 13

Table 2 (continued)
Studies references In-hospital DVT RBC (unit) Platelets (unit) FFP Other outcomes
Mortality In hosp (unit) reported

Zeeshan 4F-PCC: 32 (26) 4F-PCC: 2 (1.4) Total Total Total Proportion of patients
[25] 3F-PCC: 35 (28) 3F-PCC: 3 (2.1) 4F-PCC: 7 (2)µ 4F-PCC: 3 (3)µ 4F-PCC: 6 (2)µ with INR correction
p = 0.78* p = 0.81* 3F-PCC: 10 (3)µ 3F-PCC: 3 (3)µ 3F-PCC: 8 (2)µ and time to INR cor-
p = 0.04* p = 0.23* p = 0.03* rection from admis-
sion*
ICU and Hospital LOS
Other TE*: Mesenteric
infarction, PE
Costs: therapy, trans-
fusion, total hospital
Zeeshan 2018 4-PCC + FFP: 41 PCC + FFP: 8 (3.4) At 24 h At 24 h At 24 h ED mortality*
[26] (17.5) FFP: 13 (5.5) PCC + FFP: 6 (4)µ PCC + FFP: 3 (2)µ PCC + FFP: 3 (2)µ Transfusion at 4 h*
FFP: 65 (27.7) p = 0.11 FFP: 10 (4)µ FFP: 3 (3)µ FFP: 6 (3)µ ICU and Hospital LOS
p = 0.01* p = 0.02* p = 0.72* p = 0.01* Skilled nursing facility
or rehab. disposition
Complications: AKI,
ARDS, PE
* Continuous variables are presented either as median (IQR) % or as mean (SD)#; categorical variables are presented as number and relative percentages. Number of
patients or relative percentages were calculated if not reported. * Reported as primary outcome(s). Some variables are presented after PS m­ atching& while others
are presented before PS ­matching!. £ Protocol doses are unknown; ^Unknown type of PCC. AKI Acute Kidney Injury, ARDS acute respiratory distress syndrome,
ED emergency department, FC fibrinogen concentrate, ICU intensive care unit, ISS injury severity score, INR international normalized ratio, LOS length of stay, PE
pulmonary embolism, PCC prothrombin complex concentrate, PS propensity score, TXA tranexamic acid, US United States

Outcomes in DVT incidence when comparing 4F-PCC + FFP with

In-hospital mortality was an outcome in eight studies and 3F-PCC + FFP groups (2.1% vs 1.4%; p = 0.81) [22]. The
emergency department (ED) mortality in two (Table 2). pooled odds ratio of DVT was 0.83 [95% CI 0.44–1.57]
Among six propensity-matched studies, four compared with no heterogeneity (­I2 = 0%) (Additional file 1). PCC
PCC to FPP alone [23–26], and three of these reported a administration was also not associated with pulmonary
significantly lower mortality with PCC [23, 25, 26]. Con- embolism in three studies [25–27], and when comparing
versely, Joseph et al. [24] did not find any mortality dif- the 3F-PCC + FFP group and the 4F-PCC + FFP group,
ference using the same comparison (6% vs 15%, p = 0.78). no change in the incidence of PE was reported [25].
When PCC was added to whole blood, Khurrum et al. All studies reported transfusion volume (RBC, FFP,
reported no effect on either ED mortality (6% vs 4%; and platelets) either at hospital discharge or at 24 h.
p = 0.42) or in-hospital mortality (44% vs 46%; p = 0.72) Seven compared a group with PCC to a group without
[27]. Similarly, there were no significant reductions PCC irrespective of the co-treatment involved [23, 24,
in mortality when 3F-PCC was compared to 4F-PCC, 26–29]. Five of these seven studies used propensity score
both with FFP (32%, vs 35%; p = 0.78) [22]. Schlimp (PS) adjustment and reported a significant reduction in
et al. reported, for those only receiving fibrinogen con- RBC and FFP use [23–27], but platelet transfusions were
centrate and in a non-adjusted comparison, the lowest not reduced by PCC. At 24 h, Zeeshan et al. reported a
mortality followed by combinations of fibrinogen con- reduction from 10 to 6 units of RBC when comparing
centrate + PCC, and fibrinogen concentrate + PCC + FFP PCC alone to FPP alone (p = 0.02) [25]. Similarly, Khur-
(respectively, 8%, 29%, and 56%; p < 0.001) [28]. rum et al. reported a reduction from 10 to 8 units of RBC
The overall pooled odds ratio (OR) of in-hospital when comparing PCC with whole blood to whole blood
mortality across all observational studies was 0.97 [95% alone (p = 0.04) [27] (Table 2).
CI 0.56–1.69] with a high proportion of heterogene- Two studies did not adjusted comparisons and
ity ­(I2 = 70%) (Additional file 1). In propensity-matched observed that patients treated with PCC received sig-
studies the pooled OR was 0.75 [95% CI 0.54–1.04] with nificantly more RBC and platelets, but not FFP [28, 29].
low heterogeneity ­(I2 = 0%), while one non-adjusted study When comparing 3F-PCC + FFP to 4F-PCC + FFP, the
reported events with an OR of 4.46 [95% CI 1.73–11.49] 4F-PCC + FFP intervention group had a reduced average
(Additional file 1). number of RBC requirements (10 RBC units vs 7 RBC
Five studies reported DVT incidence which ranged units; p = 0.04) and the FFP requirements (8 FFP units
from 1.6 to 11.1% in groups treated by PCC + FFP and vs 6 FFP units; p = 0.03), while platelet requirements
PCC alone [23–27] (Table 2). There was no difference were not altered (3 vs 3 units; p = 0.23) (Table 2) (1). The
Hannadjas et al. Critical Care (2023) 27:422 Page 9 of 13

variation in reporting time points of the transfusion vol- trial, 327 patients at risk of massive transfusion were
umes (either 24 h, overall, or unclear) prevented meta- recruited in 12 French trauma centers to empirically
analysis for these outcomes. receive 4F-PCC (25 U/Kg) in addition to a ratio-based
massive transfusion protocol including fibrinogen con-
Quality assessment centrate [35]. There was no significant between-group
The overall risk of bias was serious in eight stud- difference for the primary outcome with a median 24-h
ies [23–30] and moderate in one study [22] (Fig. 2, and total number of blood products of 12 [5–19] in the
Additional file 1). Bias due to “deviations from intended 4F-PCC group versus 11 [6–19] in the placebo group
interventions” and to “missing data” could not be prop- (p = 0.72). The trial nevertheless highlighted that 56
erly assessed due to the lack of information available in patients (35%) presented with at least one thromboem-
the majority of the manuscripts. bolic event in the 4F-PCC group compared to 37 (24%)
in the placebo group (p = 0.03). PCC administration had
Published randomized clinical trial no effect on the 28-day mortality, with 17% (n = 26) dying
PROCOAG was the only RCT identified. In this double- in the PCC group and 21% (n = 30) in the placebo group
blind, placebo-controlled (saline solution) superiority (p = 0.48).

Fig. 2 Risk of bias summary plot [25]

Fig. 3 In-hospital or 28-day mortality forest plot

Hannadjas et al. Critical Care (2023) 27:422 Page 10 of 13

When the results from observational studies were Discussion

pooled with the findings from this RCT, the OR of This meta-analyses evaluated the effects of PCC admin-
0.94 [95% CI 0.60–1.45] confirmed that PCC given to istration in trauma patients with TIC and demonstrated
treat TIC had no effect on mortality (Fig. 3, Additional that amongst eight observational studies and one RCT,
file 1). The pooled odds ratio (OR) for DVT, combining PCCs were not associated with a mortality reduction.
results from both randomized controlled trials (RCTs) Pooled data in observational studies did not reveal an
and observational studies, was 1.00 (95% CI 0.64–1.55). increased VTE risk. However, the only RCT found
(Fig. 4). However, it was not possible to meta-analyze the reported increased rate of thromboembolic events in
risk of having at least one thromboembolic event as this patients allocated to the PCC group. In addition, the
outcome was not reported in the observational studies. qualitative analysis demonstrated the low level of evi-
The risk of bias, evaluated using the ROB2 tool, was low dence on which the use of PCCs to treat TIC currently
in this trial (Additional file 1). relies. Most included studies are non-randomized, have
serious risk of bias with inconsistent or no adjustment
Ongoing clinical trials methods, and small numbers of patients from single
We identified four ongoing RCTs involving the use of centers.
PCC in adult trauma patients (Additional file 1). The We found no overall beneficial effect of PCC use on
“REPLACE” (Randomized Trial Evaluating the Use of in-hospital mortality although four studies included
Prothrombin complex concentrate to Improve Survival in reported statistically significant reductions [23, 25, 26,
Patients With Traumatic Coagulopathy, NCT03981484) 28]. Three of these studies involved the use of FFP as
[31], the “FiiRST-2” (Factor In the Initial Resuscitation co-treatments of PCC, which may have contributed
of Severe Trauma 2, NCT04534751) trial [32], “Pre- to the observed treatment effect on mortality [23, 25,
hospital Use of 4F-PCC for Hemorrhagic Shock trial” 26]. Of note, four of the six propensity-matched studies
(NCT04019015) [33], and the “Evaluation of the Efficacy were published by the same research team, using simi-
of Early Bunching of a FF-PCC in Patients With Severe lar datasets [23–26], and three of these four studies were
Traumatic Hemorrhage” trial (NCT05738642) [34]. None included in the meta-analysis by Kao et al. [36]. These
of these trials reported results yet. findings may suggest a potential publication bias, which
has, at the end, influenced the European guideline on
Quality of evidence according to the Grading management of major bleeding [10].
of Recommendation Assessment, Development, Incidence of VTE was 35% in the PCC treatment arm
and Evaluation (GRADE) compared to placebo (24%) in the RCT. Other studies
The summary of the quality of evidence according to the have found rates of VTE from 3 to 15% following routine
Grading of Recommendation Assessment, Development, screening. [12]. TIC is comprised of several intercon-
and Evaluation (GRADE) is reported in Table 3. nected phenotypes attributed to differing mechanistic

Fig. 4 In-hospital deep venous thrombosis forest plot

Hannadjas et al. Critical Care (2023) 27:422 Page 11 of 13

Table 3 Summary of the quality of evidence according to the Grading of Recommendation Assessment, Development, and
Evaluation (GRADE)
Patient or population: Adult patients with expected trauma-induced coagulopathy
Settings: In-hospital care
Intervention: Patients treated with PCC
Comparison: Patients treated without PCC
Outcomes Odds ratio Anticipated absolute effects Certainty of the Comments
No of participants evidence (GRADE)
(studies) Without PCC With PCC Difference

Mortality 0.94 27.2% 22.4% − 4.8% ⊕  ⊝  ⊝  ⊝ May decrease in-

(8 studies, [0.60, 1.45] Very ­lowa,b hospital mortality
n = 1685)
DVT 1.00 5.3% 7.0% + 1.3% ⊕  ⊝  ⊝  ⊝ May increase DVT
(6 studies, [0.64; 1.55] Very ­Lowa,c,d
n = 1497)
a
Downgraded because the overall risk of bias for observational studies was serious
b
Downgraded because PCC administration was not associated with mortality reduction in the only RCT published
c
Downgraded because of the large confidence intervals
d
Downgraded because the only RCT did not reported a significant increase of the DVT (but an increase of a composite outcome regrouping the occurrence of at least
one thromboembolic event)
DVT deep venous thrombosis, PCC prothrombin complex concentrate

responses occurring at varying time points post-injury requiring a broad range of interventions. Therefore, iden-
[37]. Procoagulant treatments may be administered dur- tifying the precise treatment effect and/or side effects of a
ing the hypocoagulant phase of TIC which may pro- given intervention, such as using PCC, poses a challenge,
duce effects that influence or strengthen subsequent as evidenced by the multiple inconclusive RCTs pub-
hypercoagulability leading to increased VTE. The recent lished in trauma research [35, 39–42]. Furthermore, as a
PROCOAG RCT emphasized this possibility, where it result of this underlying complexity, studies included in
is likely that patients without thrombin generation defi- this systematic review reported on different populations,
cit received PCC, exposing them to a thrombotic risk, indications, ways to administrate PCCs, co-treatments,
while they were unlikely to benefit from the intervention and comparators.
[38]. This highlights the need in current practice for tar- Second, the lack of standardization in reporting of out-
geted procoagulant treatments where VTE risk screening comes was a concern. For instance, mortality and trans-
and side effect assessment are provided alongside PCC fusion volumes were reported at various time points,
administration. This also provides the impetus for future including the emergency department, 24 h, intensive care
research to determine whether there are patient phe- units, hospital discharge, or at 30 days. Similarly, only six
notypes for which the administration of PCC can both observational studies reported on the occurrence of DVT
improve survival while avoiding an excessive risk of VTE. which may under-represent the incidence.
All four ongoing RCTs will empirically administer PCC, Third, we used mortality at discharge as a primary out-
based on clinical observations, such as blood pressure or come, which is known to be a challenging outcome to
evidence of active bleeding, or on physicians’ expecta- be measure in studies enrolling coagulopathic trauma
tions, such as predicted red blood cell transfusion. More- patients. For these reasons, it might have been worth-
over, only one of them will include VTE as an outcome while to consider other outcomes, such as the correction
[32]. Consequently, these RCTs will not be able to direct of coagulopathy, the volume of allogeneic blood products
treatment administration based on the presence of a phe- transfused, or earlier mortality. As an example, the PRO-
notype most likely to benefit from PCC with the lowest COAG study recently employed the median 24-h total
risk of harm. This may reduce these studies capacity to number of blood products as a primary outcome.
delineate the risk–benefit balance of PCC administration Finally, among the included studies, PCC was adminis-
and may warrant further investigations. trated either at the discretion of the attending physician,
based on the clinical severity of the patient, or guided
Limitations by laboratory results. It is not certain that both of these
This systematic review has several limitations. Firstly, methods are sufficient to accurately identify patients who
trauma patients with hemorrhage are complex, frequently are truly likely to benefit from PCC treatment. Clinically
Hannadjas et al. Critical Care (2023) 27:422 Page 12 of 13

determining hemorrhage at an early stage is challeng- Author details

1
Centre for Trauma Sciences, Blizard Institute, Queen Mary University of Lon-
ing, while scoring systems exist for bleeding and coagu- don, London, England. 2 GRC 29, AP‑HP, DMU DREAM, Department of Anaes-
lopathy, they lack sensitivity [43]. Treatment efficacy is thesiology and Critical Care, Pitié‑Salpêtrière Hospital, Sorbonne University,
indeed constantly modulated by a range of variables such 47‑83 Boulevard de l’Hôpital, 75013 Paris, France.
as the patients baseline characteristics or the effects of Received: 8 August 2023 Accepted: 14 October 2023
co-interventions and the assessment of traumatic hem-
orrhage has relied on a combination of factors including
clinical, physiological, and imaging parameters [10].
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