Effect of early administration of fibrinogen replacement therapy in traumatic haemorrhage: a systematic review and meta-analysis of randomised controlled trials with narrative synthesis of observational studies

Abstract

Background

In severely injured trauma patients, hypofibrinoginaemia is associated with increased mortality. There is no evidence-based consensus for what constitutes optimal fibrinogen therapy, treatment dose or timing of administration. The aim of this systematic review was to evaluate the effects of early fibrinogen replacement, either cryoprecipitate or fibrinogen concentrate (FgC) on mortality, transfusion requirements and deep venous thrombosis (DVT).

Methods

A systematic search of studies was performed on MEDLINE, EMBASE and clinicaltrials.gov databases using standardised search criteria. All clinical studies which examined the use of either cryoprecipitate or FgC in patients with traumatic haemorrhage within 4 h of admission to hospital were included. Primary outcome was mortality (28-day, 30-day or in-hospital). Secondary outcomes were DVT incidence and blood component transfusions. A narrative synthesis was performed for all observational studies. Meta-analysis was completed for all included RCTs for mortality with pre-defined sub-group analysis of FgC and cryoprecipitate use. Grading of Recommendations Assessment, Development, and Evaluation was used to assess the quality of evidence.

Results

Overall, 1906 studies were screened with 12 studies included and five RCTs (all suitable for meta-analysis) totalling 1758 participants. Three RCTs reported FgC therapy, and two used cryoprecipitate. Four out of five RCTs examined empiric fibrinogen replacement for suspected traumatic haemorrhage. There was no difference in the primary outcome of mortality: early fibrinogen replacement (24%) vs control (25%), OR 1.03 (95% CI; 0.68–1.56). Subgroup analysis found no difference in outcome between the FgC and control: 18.1% vs 10.9% respectively, OR 1.99 (95% CI; 0.80–4.94). Similarly for cryoprecipitate, there was no difference in mortality between groups: cryoprecipitate (24.9%) vs control (26.1%), OR 0.71 (95% CI, 0.25–2.01). Reporting of transfusion data precluded meta-analysis. There was no difference in DVT incidence: fibrinogen replacement (3%) vs control (4%), OR 0.73 (0.43, 1.25). Overall, the quality of evidence was graded as low due to indirectness and imprecision.

Conclusions

There is no association between early fibrinogen replacement and mortality, DVT or transfusion requirements. We found no superiority between FgC or cryoprecipitate. This systematic review highlights the urgent need for further RCTs to assess the efficacy of early fibrinogen replacement, preferred strategy (goal-directed vs empiric) as well as optimal therapeutic product for both patient outcome and cost effectiveness.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13054-025-05269-y.

Background

More than four million people worldwide die from trauma every year, with haemorrhage being the primary cause of preventable death among those injured [1, 2]. In patients with traumatic haemorrhage, one of the major contributing factors to poor outcomes is trauma induced coagulopathy (TIC). This endogenous failure of haemostasis has multifactorial causes with tissue injury and shock resulting in dysfunction of the endothelial, immune and coagulation systems. Both hypofibrinogenaemia and hyperfibrinolysis are recognised as key pathophysiological characteristics and therapeutic targets [3, 4].

Fibrinogen is a principle factor within the coagulation system as it is the final precursor to fibrin. It is the first clotting factor to fall during traumatic haemorrhage [5], and in severely injured trauma patients, hypofibrinogenaemia is closely associated with greater transfusion requirements and increased mortality [6]. Observational studies have shown that fibrinogen replacement either in the form of cryoprecipitate or fibrinogen concentrate (FgC) is associated with improved survival in patients with major trauma haemorrhage [6–8]. However, this finding has not been replicated in any randomised controlled trial (RCT), with no difference in mortality observed in the largest trial to date (CRYOSTAT-2 [9]) which compared high dose empiric cryoprecipitate with standard of care for trauma haemorrhage. At present, there is a lack of consensus on the optimal method of fibrinogen replacement, the dose of fibrinogen and the timing of therapy. Given that profibrinolytic activity occurs within minutes after injury [10], and fibrinogen is the first coagulation factor to deplete in traumatic haemorrhage [5], it is hypothesised that the earlier the fibrinogen levels are restored the greater benefit for patient outcomes.

The primary aim of this systematic review was to evaluate the effect of early use (within 4 h of hospital arrival) of any fibrinogen replacement therapy (cryoprecipitate or FgC) on mortality. Further aims were to compare survival between patients treated with cryoprecipitate or FgC, as well as transfusion requirements and incidence of deep venous thrombosis (DVT).

Methods

Study design

This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline [11].

Data sources and search strategies

We conducted a systematic literature search to ascertain publications which reported the use of early fibrinogen replacement, specifically cryoprecipitate or FgC, in the management of traumatic haemorrhage. EMBASE, MEDLINE and Clinicaltrials.gov were searched using a structured search equation (Additional File). Previously published systematic reviews examining the use of early fibrinogen replacement in traumatic haemorrhage and reference lists of all retrieved articles were also screened.

Study eligibility and selection process

All prospective and retrospective, controlled and uncontrolled clinical studies that examined the use of either cryoprecipitate or FgC in patients with traumatic haemorrhage within four hours of admission to hospital were eligible for inclusion. In addition, studies had to report either in-hospital, 28-day or 30-day mortality as a defined outcome to be included in the systematic review. Studies were excluded if they were case reports, contained patients under the age of sixteen, or exclusively analysed patients with traumatic brain injury. After completion of searches, duplicates were removed, and two reviewers independently assessed the eligibility of retrieved references. The software Rayyan^TM (rayyan.ai [12]) was used for the title and abstract screening. Full text articles were then assessed for eligibility. Reviewers were blinded during the title/abstract and full text screening.

Data extraction

Data was extracted by a single reviewer. Relevant data was extracted manually into Microsoft Excel^TM (Microsoft Corporation 2021). Within retrospective studies, where adjusted and non-adjusted results were available, only adjusted results were extracted. Extracted data included information about the study; main author, year of publication, study title, study design (observational/randomised controlled trial), number of centres, number of patients included and outcomes reported. Information about the patients; sex, injury type (penetrating or blunt or both, if both then proportion of penetrating injuries), and Injury Severity Score (ISS). Information about the intervention; form of fibrinogen administered (FgC or cryoprecipitate), dose of FgC or cryoprecipitate, any co-treatments received and the comparator or control used. Outcomes of interest were mortality, red blood cell (RBC), fresh frozen plasma (FFP), and platelet transfusions as well as the incidence of DVT.

Data synthesis and statistical analysis

The results from different study designs were expected to differ systematically increasing heterogeneity. Therefore, observational studies and RCTs were not combined in meta-analysis. Observational studies were analysed with a narrative synthesis and RCTs with meta-analysis [13]. Meta-analyses were completed for all selected RCTs and separate sub-group analyses were conducted for studies including FgC and cryoprecipitate. All analyses were completed using RevMan^TM v8.1.0 software. Assuming high heterogeneity amongst the included studies a random effects model was chosen, and the Paule-Mandel estimator was used to calculate the heterogeneity variance (τ²). Odds ratio (OR) with 95% confidence interval was used as a summary measure. Significance was determined by p-value < 0.05.

Study quality assessment

The Revised Tool for Risk of Bias in Randomised Trials (RoB2) was used to assess risk of bias in all randomised control trials. The Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) was used to assess risk of bias in all observational studies. We assessed the quality of the evidence for all included studies in meta-analysis using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Publication bias was not assessed statistically given the low number of included studies for meta-analysis.

Results

Description of the studies

The initial search strategy was completed in January 2024 and identified 3516 references (MEDLINE = 1748, EMBASE = 1647, Clinicaltrials.gov = 121). After exclusion of duplicates and examination of titles and abstracts, 43 references were retrieved for full text review. After full text evaluation, we excluded all but 12 studies. Five studies were RCTs [9, 14–17] and seven were observational studies [18–24]. Further information on the study screening process is reported in the PRISMA flow diagram (Fig. 1).

Fig. 1.

PRISMA flow diagram. PRISMA flow diagram showing breakdown of exclusion at each step

Randomised controlled trials: (Early fibrinogen replacement vs. Control/Comparator)

Included studies, participants and methods

The five RCTs [9, 14–17] included a total of 1758 participants. The median age across the groups who received fibrinogen ranged from 31 to 48 years (IQR 34.5, 45.25) and 82% of the patients were male. The median ISS across fibrinogen groups ranged from 25 to 35 (IQR 26.5, 34.5). Two were double-blinded placebo controlled randomised feasibility trials [16, 17] and the remaining three were open-label randomised trials [9, 14, 15], with one being a feasibility trial [15]. Innerhofer et al. [14] investigated the use of coagulation factor concentrates (CFC), where all patients received FgC, compared to FFP alone in traumatic haemorrhage. This study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy with CFC [14]. The main characteristics of the included RCTs are described in Table 1.

Table 1.

Characteristics of included studies

First author year country	Study type	Study design	Source of fibrinogen used	Age in the Fibrinogen Group(s)	Men in Fibrinogen group	ISS in the Fibrinogen group(s)	Fibrinogen level (g/dL)	Penetrating injuries in the fibrinogen group	Fibrinogen Indication	Number of patients in the fibrinogen Group	Intervention group 1	Intervention group 2	Control group
Curry [16] UK	Double-Blind placebo-controlled randomised control trial	Multi-centre	FgC	38 (31,47)	20 (83)	34 (24,43)	1.9 (0.9,2.2)	3 (12)	Pre-emptive administration	n = 24	6g FgC + MHP	–	Placebo (0.9% NaCl)  + MHP
Nascimento [17] Canada	Double-Blind Placebo-controlled randomised control trial	Single Centre	FgC	48 (19,78)*	16 (77)	25 (19,29)	1.90 (1.6,2.3)	11 (52)	Pre-emptive administration	n = 21	6g FgC + MHP	–	Placebo (0.9% NaCl)  + MHP
Curry [15] UK	Randomised open label trial	Multi-centre	CRYO	31 (16,83)*	17 (85)	28 (22,42)	1.6 (1.4,2.1)	2 (10)	Pre-emptive administration	n = 20	MHP + 2 pools CRYO	–	MHP
Davenport [9] UK	Randomised open label trial	Multi-centre	CRYO	38 (25,55)	618 (79)	29 (17,43)	-	290 (37)	Pre-emptive administration	n = 799	MHP + 3 pools CRYO	–	MHP alone
Innerhofer [14] Austria	Randomised open label trial	Single centre	FgC	42.5 (27.3, 50.5)	38 (76)	35 (29,42)	1.96 (1.38,2.18)	–	If abnormal ROTEM. Randomised to CFC(FgC) or FFP	n = 50	CFC (FgC) 50 mg/kg body weight	–	FFP
Bocci [22] Italy	Retrospective Cohort study	Multi-centre without adjustment	FgC	49 ± 19.8	85 (72.6)	29 (19,41)	2.12 (1.08)	–	Pre-emptive administration if met one of the following on hospital arrival: 1. Blood lactate level of 5 or more 2. Arterial BE < -6 3. Hb 9 or less 4. Systolic BP 90 or less	n = 117	2-4 g FgC  + 1 g TXA  + 2–4 units RBCs	–	MHP (no TXA, no FgC or CRYO)
Endo [18] Japan	Retrospective cohort study	Multi-centre with PS matching	CRYO	35 (24,52)	3938 (79.1)	29 (21,41)	–	2039 (42.0)	No information	n = 4852	CRYO + FFP within 4 h of admission	–	MHP
Fleming [23] US	Retrospective cohort study	Single centre without adjustment	CRYO	34 (22,46)	65 (79.3)	27 (18, 34)	–	48 (58.5)	Clinician discretion	n = 82	CRYO within 4 h of admission	–	No CRYO within 4 h of admission
Gaitanidis [24] US	Retrospective cohort study	Multi-centre with PS matching	CRYO	38 ± 17.3	702 (80.1)	33.1 ± 14.8	–	381 (43.4)	No information	n = 877	CRYO within 4 h of admission	–	No CRYO within 4 h of admission
Inokuchi [20] Japan	Retrospective cohort study	Single centre without adjustment	FgC	59 (42,71)	44 (40)	21 (10,33)	2.14 (1.50, 2.54)	–	Group split into 2 indications. FgC was given when FB < 150 between April 2013 and March 2014, then included in MHP pre-emptively from April 2014 to March 2015)	n = 109	3 g FgC if Fb < 1.5 g/dL or pre-emptively with MHP	–	MHP alone
Itagaki [19] Japan	Retrospective cohort study	Single centre with PS matching	FgC	53 (32,74)	19 (61.3)	34 (25—41)	1.64 (1.38,2.19)	2 (6.5)	Clinician discretion	n = 31	Any FgC within 1 h hospital admission	–	No FgC within 1 h hospital admission
Yamamoto [21] Japan	Retrospective cohort study	Single centre without adjustment	FgC	Empirical 49 ± 23.7 Fb < 150 49 ± 24	–	Empirical 16.8 ± 11.8 Fb < 150 15.3 ± 11.5	–	–	Two intervention groups. 1. Empirical administration of FgC. 2. FgC administration if fb < 1.50 g/dL	Empirical: n = 566 Fb < 1.50: n = 560	Empirical 3 g FgC on hospital arrival	3 g FgC if Fb < 1.50	No FgC within 1 h hospital admission

Continuous variables are presented either as median (IQR) % or as mean ± SD. *These continuous variables are displayed as median and range

Number of patients or relative percentages were calculated if not reported

Data not available

All variables are presented after PS matching if available

US: United States, UK: United Kingdom, FgC: Fibrinogen Concentrate, ISS: Injury Severity Score, PS: Propensity Score, RBC: Red Blood Cells, FFP: Fresh Frozen Plasma, CRYO: Cryoprecipitate, MHP: Major Haemorrhage Protocol, FB: Fibrinogen, TXA: Tranexamic Acid

Intervention

Fibrinogen-containing blood components was defined as either FgC or cryoprecipitate. Three trials [14, 16, 17] used FgC as a source of fibrinogen and two studies [9, 15] used cryoprecipitate. In the three trials investigating FgC, two [16, 17] used a fixed dose of 6g, with the remaining study [14] using a weight-based dose of 50mg/kg. Four out of five RCTs [9, 15–17] looked at empiric fibrinogen replacement if traumatic haemorrhage was suspected. Traumatic haemorrhage definitions differed and in three trials [9, 14–16] this was broadly defined as activation of the local major haemorrhage protocol. In the remaining trial [17] this was defined as a systolic blood pressure < 100 mmHg and requiring un-crossmatched RBCs at any time from injury until thirty minutes after hospital arrival.

A single RCT [14] looked at targeted administration of fibrinogen-containing blood components. Indications for transfusion were trauma patients admitted with severe injury (ISS > 15), clinical signs or risk of substantial haemorrhage and abnormal rotational thromboelastometry (ROTEM). Abnormal ROTEM was defined as FibTEM assay (10-min value of fibrinogen polymerisation [FibA10] < 9 mm) or prolonged initiation of coagulation in the EXTEM assay (coagulation time of ExTEM assay [ExCT] > 90s). This was the only study [14] which included co-interventions. Participants were randomised to either CFC (in the form of FgC and/or four-factor prothrombin complex concentrate and/or factor XIII) or FFP. Every patient in the CFC group received FgC. Four-factor PCC and/or factor XIII concentrate was co-administered within the CFC group if the ROTEM parameter remained abnormal after initial dose of the study drug. FXIII was given to every participant who required a second dose of FgC. All trial protocols included the empiric use of tranexamic acid (TXA). Blood components (RBC/FFP) were given in a one to one ratio in all studies other than Innerhofer et al. [14], where FFP was used as a comparator.

Outcomes: mortality

Mortality data was available for all five RCTs (Table 2). Four recorded 28-day mortality [9, 15–17] and one recorded 30-day mortality [14]. There was no statistically significant difference between the groups, with 24.1% vs 24.5% mortality in the fibrinogen replacement group vs control arms respectively (OR, 1.03 [95% CI, 0.68–1.56]; p = 0.88, Fig. 2). Subgroup analysis of studies using FgC found no significant difference in outcome between the FgC group and control arms, with mortality rates of 18.1% and 10.9% respectively (OR, 1.99 [95% CI, 0.80–4.94]; p = 0.14, Fig. 3). In addition, subgroup analysis of studies using cryoprecipitate showed no significant difference in mortality between groups, 24.9% in the cryoprecipitate group vs 26.1% in the control group (OR, 0.71 [95% CI, 0.25–2.01]; p = 0.51, Fig. 4).

Table 2.

Outcomes of included studies

Study author	In-hospital mortality	28-day mortality	30-day mortality	DVT	RBC	Plts	FFP	Other reported outcomes
Curry [16]	–	FgC; 10 Placebo; 7	–	FgC; 0 (0) Placebo; 0 (0)	At 24 h FgC; 4 (2,8) Placebo; 2 (2,5) p = 0.38	At 24 h FgC; 1 (0,1)* Placebo; 0 (0,1)* p = 0.59	At 24 h FgC; 5 (2,8) Placebo; 3 (0,6) p = 0.39	Feasibility outcomes Clinical outcomes: Mortality at 3,6 and 24 h, and 28 days. Transfusion requirements in numbers of units at 3,6 and 24 h. Duration of organ support, length of inpatient stay, length of ICU stay. Quality of life. Thrombotic events, events during hospital stay Laboratory outcomes: Fibrinogen levels at 2 h and at day 7
Nascimento [17]	–	FgC; 2 (10) Placebo; 1 (4.2) RR 2.4 ( -0.2 to 23)	–	FgC; 0 (0) Placebo; 0 (0)	At 24 h FgC; 3 (2,5) Placebo; 3 (2,4) p = 0.41	At 24 h FgC; 2.81 (2.5,3.6) Placebo; 2.32 (1.9,2.7) p = 0.53	At 24 h FgC; 2.73 (2.4,3.6) Placebo; 1.75 (1.4,2.0) p = 0.72	Feasibility outcomes Clinical outcomes: Death by exsanguination, symptomatic DVT, PE, MI, Stroke, ALI, ARDS, AKI, MOF, Infection
Innerhofer [14]	–	–	CFC; 5 (10) FFP; 2 (5) p = 0.44	CFC; 4 (8) FFP; 8 (18) p = 0.22	At 24 h CFC; 4 (2,7) FFP; 6 (4,11) p = 0.028	At 24 h CFC; 2 (1,4)* FFP; 2 (1,3)* p = 0.63	At 24 h CFC; 5 (5,5) FFP; 14 (10,14) p = 0.023	Clinical outcomes: Presence of MOF, days of MOF, Haemofiltration, days of haemofiltration, ventilator free days, sepsis, infection, peripheral PE, ICU LOS, hospital LOS, 4 Factor PCC use at 24 h, FXIII use at 24 h, Number of patients requiring RBC, FFP and platelets at 24 h, Laboratory outcomes: Measured at 24 and 48 h; INR, aPTT, Fibrinogen, Antithrombin III, FXIII, Hb, Plts, Lactate, ROTEM parameters
Davenport [9]	–	CRYO; 192 (25.3) Standard; 201 (26.1) p = 0.74	–	CRYO; 20 (2.5) Standard; 23 (2.9)	At 24 h CRYO; 5 (3,9) Standard; 5 (3,8) AD 0 (-0.6,0.6)	At 24 h CRYO; 0 (0,1)* Standard; 0 (0,1)* AD 0 (0,0)	At 24 h CRYO; 4 (2,8) Standard; 4 (2,8) AD 0 (-0.5,0.5)	All-cause mortality at 6 and 24 h, 6 and 12 months from admission. ICU and hospital stay outcomes. Quality of life measures. Symptomatic venous/arterial thromboembolic events up to day 28 or discharge
Endo [18]	CRYO; 1959 (40.4) FFP Only; 2142 (44.1) OR: 0.86 (0.79–0.93)	–	–	CRYO; 353 (7.3) FFP Only; 328 (6.8)	–	–	–	Adverse events (all listed within study)
Fleming [23]	CRYO; 33 (40.2) No CRYO; 81 (23.7) p =  < 0.01	–	–	CRYO; 3 (4.6) No CRYO;; 8 (2.7) p = 0.45	At 4 h CRYO; 18 (12,28) No CRYO; 9 (6,14) p =  < 0.01	At 4 h CRYO; 3 (2,4)* No CRYO; 1 (0,2)* p =  < 0.01	At 4 h CRYO; 10 (6,17) No CRYO; 4 (3,6) p =  < 0.01	Clinical outcomes: Hospital LOS, ICU LOS, AKI, PE, VTE incidence
Inokuchi [20]	–	FgC; 6 (6) RR 0.33 (0.13–0.84) No FgC; 17 (15) RR 0.37 (0.15—0.91)	–	-	At 7 days FgC; 10 (6,20) No FgC; 10 (4,22) p = 0.958	At 7 days FgC; 20 (20,20) No FgC; 20 (20, 37.5) p = 0.251	At 7 days FgC; 8 (6,20) No FgC; 10 (6,20) p = 0.685	Implementation of surgical interventions: TAE, External fixation, Internal fixation, Pelvic packing
Yamamoto [21]	–	–	Empirical 30 (5) No FgC 35 (7) p =  < 0.05	Data not shown	In hospital Empirical; 13.2 ± 13.9 Fb < 150; 10.5 ± 10.5 No FgC; 11.0 ± 11.1 p =  ≥ 0.05	In hospital Empirical; 24.7 ± 11.9 Fb < 150; 22.4 ± 7.9 No FgC; 24.6 ± 12.3 p =  ≥ 0.05	In hospital Empirical; 15.7 ± 15.4 Fb < 150; 12.0 ± 10.2 No FgC; 13.5 ± 11.3 p =  ≥ 0.05	Fibrinogen levels before and after fibrinogen is given. 48 h mortality. 30 day mortality
Bocci [22]	FgC + TXA + RBCs; 27 MHP alone; 23 RR 1.18 (0.68; 2.06)	–	–	–	At 24 h FgC + TXA + RBCs; 1 (0, 4) MHP; 4 (1,6) MD -1.87 (-2.4; -1.34)	At 24 h FgC + TXA + RBCs; 0 (0,0) MHP;0 (0,5) MD -1.28 (-1.64; -0.91) Platelet units	At 24 h FgC + TXA + RBCs; 0 (0,3) MHP; 0 (0,5) MD -1.69 (-2.14; -1.25)	Clinical outcomes: Day 0 mortality, Day 1–28 mortality, LOS-ICU, LOS-Hospital
Itagaki [19]	–	FgC; 6 (19.3) Control; 14 (45) p = 0.03	–	–	At 6 h FgC; 8 (2,22) Control; 2 (0,10) p = 0.016	At 6 h FgC; 0 (0,20) Control; 0 (0,0) p = 0.059	At 6 h FgC; 14 (4,23) Control; 4 (0,10) p = 0.009	Interventions to haemostasis Transfusion volumes at 6 and 24 h
Curry [15]	–	CRYO; 2 (10.0) STANDARD; 6 (28.6) p = 0.14	–	CRYO; 0 (0) STANDARD; 1 (5.6)	At 24 h CRYO; 8 (5,11) STANDARD; 7 (6,9) p = 0.83	At 24 h CRYO; 1 (0,2)* STANDARD; 1 (1,2)* p = 0.56	At 24 h CRYO; 7 (4,8) STANDARD; 6 (3,8) p = 0.36	Feasibility outcomes Clinical outcomes: Thromboembolic events (arterial and venous), transfusion volumes at 6 h and at 28 days, Transfusion reactions (acute and non-acute). Presence of MOF up to 28 days. Presence of ARDS up to 28 days Laboratory outcomes: ROTEM EXTEM/FIBTEM at 3 specified points during bleeding. Fib levels at various intervals
Gaitanidis [24]	CRYO; 433 (49) No CRYO; 481 (54) p = 0.022	–	–	CRYO; 72 (8.2) No CRYO; 52 (5.9) p = 0.062	At 24 h CRYO; 7.3 ± 5 No CRYO; 6.7 ± 4.4 p = 0.011	–	At 24 h CRYO; 4.4 ± 3.6 No CRYO; 4.1 ± 3.3 p = 0.026	Clinical outcomes: 1-day mortality, in-hospital complications, surgery within 24 h

Continuous variables are presented either as median (IQR) % or as mean ± SD. *These continuous variables are displayed as median and range

Number of patients or relative percentages were calculated if not reported

Data not available

All variables are presented after PS matching if available

Platelet doses are presented as units. Unless * then presented as pools

MD: Mean Difference, OR: Odds Ratio, PS: Propensity Score, RR: Risk Ratio, ISS: Injury Severity Score, MHP: Major Haemorrhage Protocol, FgC: Fibrinogen Concentrate, CFC: Coagulation Factor Concentrate, Plts: Platelets, RBC: Red Blood Cells, FFP: Fresh Frozen Plasma, PCC: Prothrombin Complex Concentrate, TXA: Tranexamic Acid, FB: Fibrinogen, CRYO: Cryoprecipitate, INR: International Normalised Ratio, APTT: Activated Partial Thromboplastin Time, DVT: Deep Vein Thrombosis, ARDS: Acute Respiratory Distress Syndrome, MOF: Multi-Organ Failure, AKI: Acute Kidney Injury, VAP: Ventilator Associated Pneumonia, PE: Pulmonary Embolism, VTE: Venous Thromboembolism, CAUTI: Catheter Associated Urinary Tract Infection, SSI: Surgical Site Infection, TAE: Trans-Arterial Embolisation, LOS: Length of Stay, CU: Intensive Care Unit, ALI: Acute Limb Ischaemia

Fig. 2.

Early FCP and Mortality. Mortality (In-hospital, 28-day and 30-day) forest plot. Early fibrinogen-containing product (within 4 h) versus Control

Fig. 3.

Early Fibrinogen Concentrate and Mortality. Mortality forest plot. Early fibrinogen concentrate (within 4 h) versus Control

Fig. 4.

Early Cryoprecipitate and Mortality. Mortality forest plot. Early Cryoprecipitate (within 4 h) versus Control

Data on RBC, FFP and platelet transfusion at 24 h was available for all five studies [9, 14–17]. Four of these reported no significant difference in RBC, FFP and platelet requirement at 24 h between the fibrinogen replacement group and the control/comparator group [9, 15–17]. Innerhofer et al. reported decreased RBC transfusion in the FgC group compared to FFP only group at 24 h (p = 0.028) [14]. Curry et al. [16], reported transfusion volume at 3, 6 and 24 h with no significant difference in RBC, FFP and platelet requirement reported at any of these timepoints [16]. Curry et al. [15] analysed transfusion requirement at 6 h and 28 days with again no difference in transfusion requirements between groups [15].

All five studies [9, 14–17] reported data on incidence of DVT, but two studies [16, 17] were excluded from meta-analysis as no DVTs were reported in the fibrinogen replacement group or control group. In the remaining studies there was no significant association between administration of fibrinogen-containing blood components and mortality (OR, 0.73 [95% CI, 0.43–1.25]; p = 0.25, Fig. 5).

Fig. 5.

Early FCP and DVT incidence. DVT incidence forest plot. Early fibrinogen-containing product (within 4 h) versus Control

Observational studies: (Fibrinogen replacement vs. Control/Comparator)

Included studies, participants and methods

Of the seven observational studies [18–24], three [18, 22, 24] were multi-centre and the remainder were single centre [19–21, 23]. Where reported, the median age across the fibrinogen groups ranged from 34 to 59 years (IQR 35, 53) [18–20, 22–24], and the median ISS ranged from 21 to 34 (IQR 25, 31.5) [18–20, 22, 23]. The clinical characteristics of patients included in the observational studies are reported in Table 1.

Definition of traumatic haemorrhage differed across all seven studies [18–24]. Three studies [18, 23, 24] included patients if they received a specified amount of RBCs within a given time frame. Endo et al. [18] used 5 units of RBCs within four hours, Fleming et al. [23] used 6 units of RBCs within 4 h and Gaitanidis et al. [24] used 10 units of RBCs within 24 h. Bocci et al. [22] included patients using specific physiological and biochemical criteria that indicated bleeding. Inokuchi et al. [20] included patients who required activation of MHP. Two studies included patients based upon ISS. Itagaki et al. [19] included patients if ISS ≥ 16. Yamamoto et al. [21] included patients with an ISS of 26 with a comparative group of patients with ISS of 44 or more.

Intervention

In three studies [18, 23, 24] fibrinogen replacement was by cryoprecipitate and in four studies [19–22] it was FgC. In the studies that examined cryoprecipitate, two studies [23, 24] reported cryoprecipitate administration as a binary function; received cryoprecipitate versus did not receive cryoprecipitate, with no dose reported. In the remaining study [18] that examined cryoprecipitate the median volume administered was 183 (100–300)ml. In those that examined FgC a 3g dose was given in two studies [20, 21]. Itagaki et al. [19] used a dose that was determined by the overseeing physician at the time. Bocci et al. [22] used a 2g dose. Time of administration varied between observational studies. In three studies [18, 23, 24] patients were included if fibrinogen replacement was given less than four hours from admission. Two studies [20, 21] included patients who received fibrinogen-containing blood components on arrival to hospital. Itagaki et al. [19] included patients if fibrinogen replacement was administrated within 1 h of ED admission. Bocci et al. [22] investigated the use of an early coagulation support protocol. This protocol included FgC being given within 30 min of hospital arrival alongside TXA and 2 units of RBC. The protocol was compared to standard MHP and TXA was not protocolised in the MHP group.

Outcomes: mortality

The clinical outcomes of the included observational studies are reported in Table 2. Mortality definition varied with four studies [18, 22–24] reporting in-hospital mortality, two studies [19, 20] reported 28-day mortality and one study [21] reported 30-day mortality. A significant reduction in mortality in the fibrinogen replacement group was noted in five studies [18–21, 24] and one study [23] showed a significant increase in mortality in the fibrinogen containing blood component group.

Endo et al. [18] used a propensity score matched design to compare the outcomes of patients treated with cryoprecipitate and FFP to those treated with FFP only. Patients were included if they received greater than or equal to 5 units of RBC and at least 1 unit of FFP within the first 4 h of arrival to hospital. Significantly lower in-hospital mortality was seen in the cryoprecipitate group (OR, 0.86; 95% [CI, 0.79–0.93]). Gaitanidis et al. [24] used a similar propensity matched design. Patients were included if they were transfused more than 10 units of RBCs within 24 h. In-hospital mortality was lower among patients who received cryoprecipitate (49.4% v. 54.9%, p = 0.02) [24]. Subgroup analyses showed that mortality was lower with cryoprecipitate in patients with penetrating (37.5% v. 48%, p = 0.01), but not blunt trauma (58.5% v. 59.8%, adjusted p = 1.00) [24].

Itagaki et al. [19] used a propensity-matched cohort design comparing patients who received FgC within 1 h of ED arrival and those who received FgC 1 to 24 h after admission. Matched groups received a similar amount of FgC within the first 24 h (p = 0.96) however the group which received FgC within 60 min of ED arrival showed a lower rate of in-hospital mortality (19.3 v. 45%, p = 0.03) [19]. Yamamoto et al. [21] used a before/after cohort design graded by ISS (≥ 26 and > 44) to compare standard care to 3g of FgC pre-emptively on hospital arrival and reported a mortality reduction in both subgroups.

Inokuchi et al. [20] used a before/after matched cohort design and compared 3g of FgC on hospital arrival with FFP versus FFP alone in patients with pelvic fractures after trauma and showed a mortality difference of 6.0% compared to 15.0% (p < 0.05) [20]. Fleming et al. [23] found that mortality was greater among patients who received cryoprecipitate (40.2 vs 23.7%, p < 0.01) on univariate analysis, but found no association between early cryoprecipitate administration and mortality after propensity score analysis [23]. Bocci et al. [22] reported a non-significant increase in mortality in an unmatched population with the introduction of the early coagulation support protocol where 2g FgC was administered empirically on patient admission, 23.1% versus 19.5% (RR 1.18 [0.68; 2.06]) [22].

Six out of seven studies [19–24] reported data on transfusion requirement. No significant difference was noted in the use of RBC, FFP and platelets between the fibrinogen replacement group and the comparator in four out of the seven studies [19, 22–24]. Bocci et al. [22] reported a significant decrease in the average consumption of RBC (− 1.87 units, [− 2.40; − 1.34]), platelets (− 1.28 units; [− 1.64; − 0.91]), and FFP (− 1.69; [− 2.14; − 1.25]) in the first twenty-four hours. Gaitanidis et al. [24] reported an increased use of RBC and FFP in the cryoprecipitate group at twenty-four hours, this corresponded with data reported with Itagaki et al. [19] at six hours. Fleming et al. [23] reported increased administration of RBC, platelets and FFP in the cryoprecipitate group at four hours.

Three out of the seven observational studies [18, 23, 24] reported data on DVT incidence and there were no significant differences between the early fibrinogen replacement group and comparator.

Quality assessment and GRADE

In the RCTs the overall risk of bias was ‘some concerns’ in four studies [9, 15–17] and ‘low’ in one study [14] (Fig. 6). In the observation studies risk of bias was deemed serious in six studies [18, 20–24] and moderate in one study [19] (Fig. 7). The summary of the quality of evidence according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) is reported in Table 3.

Fig. 6.

Risk of Bias Summary RCTs. Risk of Bias Summary. RCTs only, using RoB2 tool

Fig. 7.

Risk of Bias Summary Observational Studies. Risk of Bias Summary. Observational studies only using ROBINS-I tool

Table 3.

Summary of findings table including GRADE Assessment

Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with Control/Comparator	Risk with FCP
Mortality	25 per 100	25 per 100 (18 to 34)	OR 1.03 (0.68 to 1.56)	1758 (5 RCTs)	⨁⨁◯◯ Lowa,b,c,d,e	The evidence suggests that early FCP results in little to no difference in mortality
DVT	4 per 100	3 per 100 (2 to 5)	OR 0.74 (0.43 to 1.25)	1739 (3 RCTs)	⨁⨁◯◯ Lowa,b,e,f	The evidence suggests that early FCP results in little to no difference in DVT incidence

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)

CI: confidence interval; OR: odds ratio

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect

Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

^aDifferences in patient baseline characteristics due to small sample size

^bPatients lost to follow up resulting in missing outcome data

^cNot all patients received allocated intervention

^dThree out of the five studies were feasibility studies. Mortality not primary outcome

^eWide confidence interval spanning, slight benefit, no effect and slight harm. Cannot be put down to heterogeneity

^fStudies not powered to DVT, powered to either feasibility to mortality

Discussion

In this systematic review we evaluated the effects of early fibrinogen replacement in trauma haemorrhage and found that after combined analysis of seven observational studies and five RCTs the use of cryoprecipitate or FgC was not associated with improved clinical outcomes. This is consistent with previous systematic reviews and meta-analyses, prior to inclusion of the CRYOSTAT-2 results, which investigated fibrinogen-containing blood components in traumatic haemorrhage and found no mortality benefit [25, 26]. Subgroup analysis showed no differential association on mortality between early FgC or cryoprecipitate although importantly there are to date no RCTs specifically powered to look at FgC use and mortality. This contrasts with cryoprecipitate, where the CRYOSTAT2 trial [9], a large multi-centre international RCT powered for 28-day mortality, made up a large proportion of the participants within the sub-group meta-analysis for cryoprecipitate. One observational study reported that patients treated with FgC compared to cryoprecipitate required less units of RBC, FFP and platelets, but there was no mortality benefit [27]. Meta-analysis was not completed for transfusion requirements given the heterogeneity of data measurement and presentation. Finally, when examining venous thrombotic events, meta-analysis did not show any association between early fibrinogen replacement and DVT incidence.

There may be some logistical benefits to using FgC over cryoprecipitate to improve care processes in major haemorrhage. FgC contains the highest concentration of fibrinogen per volume; ABO matching is not required; it can be stored at ambient temperatures; and it can be reconstituted and rapidly administered. Conversely to these presumed advantages of FgC, ex-vivo studies have shown cryoprecipitate compared to FgC restores key fibrinolytic regulators and limits plasmin generation to enable stronger clot formation. However, there is a lack of adequately powered RCTs for mortality to determine FgC efficacy in trauma haemorrhage. Studies included were either powered to feasibility or the trial protocol included co-interventions that would not routinely be used in trauma haemorrhage management. Further evidence to determine the utility of FgC will be available upon completion of the FIESTY II [28] RCT which will evaluate the efficacy and cost-effectiveness of FgC vs cryoprecipitate in trauma patients with major haemorrhage and hypofibrinogenaemia diagnosed by viscoelastic assays [28].

Individually within the RCTs included in this systematic review there was no association between fibrinogen therapy and transfusion requirement. Gaitanidis et al. [24], Itagaki et al. [19] and Fleming et al. [23] noted an increased use of blood components at varying time points in the early fibrinogen replacement group. In all three studies the fibrinogen-containing blood component group were either more severely injured, more haemodynamically unstable or had greater biochemical derangement. This is likely to have resulted in more liberal blood component transfusions in the initial resuscitation. Gaitanidis et al. [24] and Fleming et al. [23], did not include admission fibrinogen values in their propensity score matching. Studies have shown that low admission fibrinogen levels are associated with increased blood component transfusion, and this may explain the increased transfusion requirements reported [29, 30].

It is important to consider the limitations to this systematic review. Firstly, within the observational studies there was a serious risk of bias in six out of the seven studies with a high level of heterogeneity. This is likely to be explained by the high level of heterogeneity within the trauma patient population at baseline. This is based upon co-morbidities, variation in pre-hospital care and mechanism of injury. Methods to limit confounders can reduce this risk of bias but are unable to eliminate this completely. Within the RCTs, all studies showed some concerns, this was predominantly due to the lack of blinding between groups as well as a large proportion of patients who were randomised not receiving the allocated intervention. This is likely due to the inherit nature of conducting a RCT in trauma populations. Interventions are time critical, injuries are multifactorial and focus is likely to be on other time critical factors, rather than study enrolment, randomisation and allocation.

Second, the chosen primary outcomes for this systematic review were in-hospital mortality, 28-day mortality and 30-day mortality. This represents the variety in which mortality is measured within trauma research. These mortality cut-offs later in the patient journey can obscure the treatment effect of an initial intervention considering death by other causes other than haemorrhage predominate. Alternative outcomes could be explored further such as correction of coagulopathy, cessation of bleeding, or earlier mortality outcomes.

Third, timing of early fibrinogen therapy varied across studies. Death from exsanguination typically occurs within 3 h from admission [31, 32]. There are documented challenges of achieving the intervention within this timeframe especially with cryoprecipitate use. In the CRYOSTAT2 study [9], within the cryoprecipitate group 68% of patients received their first dose of cryoprecipitate within the study goal of 90 min after admission [9]. Equally, there are also challenges with administering FgC [16], however feasibility studies have demonstrated that it is possible to administer FgC as part of an RCT within 1 h of admission [17, 33].

Conclusion

This systematic review has highlighted the paucity of evidence to determine the effect of early fibrinogen replacement on mortality for trauma patients with severe bleeding. This is especially evident in the early use of FgC in major haemorrhage. After consideration of all the studies reviewed; early fibrinogen therapy was not associated with reduced mortality, transfusion requirements or DVT incidence.

Abbreviations

AKI

Acute kidney injury

ALI

Acute Limb Ischaemia

APTT

Activated partial thromboplastin time

ARDS

Acute respiratory distress syndrome

BE

Base excess

BP

Blood pressure

CAUTI

Catheter associated urinary tract infection

CFC

Coagulation factor concentrate

CI

Confidence interval

CRYO

Cryoprecipitate

DVT

Deep venous thrombosis

ECS

Early Coagulation Support Protocol

ED

Emergency department

Fb

Fibrinogen

FgC/FC

Fibrinogen concentrate

FCP

Fibrinogen-containing product

FFP

Fresh frozen plasma

Hb

Haemoglobin

ICU

Intensive care unit

INR

International normalised ratio

ISS

Injury severity score

LOS

Length of stay

MD

Mean difference

MHP

Major haemorrhage protocol

MOF

Multi-organ failure

OR

Odds ratio

PCC

Prothrombin complex concentrate

PE

Pulmonary embolism

Plts

Platelets

PS

Propensity score

RBC

Red blood cells

RCT

Randomised control trial

RR

Relative risk

SSI

Surgical site infection

TAE

Trans-arterial embolisation

TIC

Traumatic induced coagulopathy

TXA

Tranexamic acid

VAP

Ventilator associated pneumonia

VTE

Venous thromboembolism

Author contributions

TB contributed to conceptualisation, formal analysis, validation, investigation, writing original draft and editing. AG contributed to formal analysis, investigation and editing. EC contributed to methodology and editing. RD contributed to conceptualisation, methodology and editing. All authors read and approved the final manuscript.

Funding

No funding received.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

RD was a Principal Investigator for the CRYOSTAT-2 trial. RD reports receiving grants from Barts Charity and UK National Institute for Health and Care Research: Health Technology Assessment during the conduct of the CRYOSTAT-2 trial. Personal fees from Octapharma, personal fees and nonfinancial support from Werfen, and grants from HemoSonics.