Fibrinogen concentrate in bleeding patients

Anne Wikkelsø; Jens Lunde; Mathias Johansen; Jakob Stensballe; Jørn Wetterslev; Ann Merete Møller; Arash Afshari

doi:10.1002/14651858.CD008864.pub2

. 2013 Aug 29;2013(8):CD008864. doi: 10.1002/14651858.CD008864.pub2

Fibrinogen concentrate in bleeding patients

Anne Wikkelsø ^1,^✉, Jens Lunde ², Mathias Johansen ², Jakob Stensballe ³, Jørn Wetterslev ⁴, Ann Merete Møller ⁵, Arash Afshari ^2,⁶

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6517136 PMID: 23986527

Abstract

Background

Hypofibrinogenaemia is associated with increased morbidity and mortality, but the optimal treatment level, the use of preemptive treatment and the preferred source of fibrinogen remain disputed. Fibrinogen concentrate is increasingly used and recommended for bleeding with acquired haemostatic deficiencies in several countries, but evidence is lacking regarding indications, dosing, efficacy and safety.

Objectives

We assessed the benefits and harms of fibrinogen concentrate compared with placebo or usual treatment for bleeding patients.

Search methods

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (1950 to 9 August 2013); EMBASE (1980 to 9 August 2013); International Web of Science (1964 to 9 August 2013); CINAHL (1980 to 9 August 2013); LILACS (1982 to 9 August 2013); and the Chinese Biomedical Literature Database (up to 10 November 2011), together with databases of ongoing trials. We contacted trial authors, authors of previous reviews and manufacturers in the field.

Selection criteria

We included all randomized controlled trials (RCTs), irrespective of blinding or language, that compared fibrinogen concentrate with placebo/other treatment or no treatment in bleeding patients, excluding neonates and patients with hereditary bleeding disorders.

Data collection and analysis

Three review authors independently abstracted data; we resolved any disagreements by discussion. Our primary outcome measure was all‐cause mortality. We performed subgroup and sensitivity analyses to assess the effects of fibrinogen concentrate in adults and children in terms of various clinical and physiological outcomes. We presented pooled estimates of the effects of intervention on dichotomous outcomes as risk ratios (RRs) and on continuous outcomes as mean differences, with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis.

Main results

We included six RCTs with a total of 248 participants; none of the trials were determined to have overall low risk of bias. We found 12 ongoing trials, from which we were unable to retrieve any data. Only two trials provided data on mortality, and one was a zero event study; thus the meta‐analysis showed no statistically significant effect on overall mortality (2.6% vs 9.5%, RR 0.28, 95% CI 0.03 to 2.33). Our analyses on blood transfusion data suggest a beneficial effect of fibrinogen concentrate in reducing the incidence of allogenic transfusions (RR 0.47, 95% CI 0.31 to 0.72) but show no effect on other predefined outcomes, including adverse events such as thrombotic episodes.

Authors' conclusions

In the six available RCTs of elective surgery, fibrinogen concentrate appears to reduce transfusion requirements, but the included trials are of low quality with high risk of bias and are underpowered to detect mortality, benefit or harm. Furthermore, data on mortality are lacking, heterogeneity is high and acute or severe bleeding in a non‐elective surgical setting remains unexplored. Currently, weak evidence supports the use of fibrinogen concentrate in bleeding patients, as tested here in primarily elective cardiac surgery. More research is urgently needed.

Plain language summary

Use of fibrinogen concentrate in patients with bleeding

Fibrinogen is a natural blood protein involved in the coagulation process. Bleeding decreases the blood level, and low levels of this protein may increase bleeding even further, thereby increasing morbidity and mortality. Fibrinogen concentrate is widely used instead of traditional sources of fibrinogen, such as the blood products fresh frozen plasma and cryoprecipitate (a pooled concentrated plasma product), especially in some countries, despite the lack of adequate knowledge derived from previous research to support such an approach. In the present Cochrane systematic review, we set out to assess the benefits and harms of fibrinogen concentrate in patients with bleeding. We searched the databases to August 2013, we identified six randomized trials in cardiac and elective surgical settings that compared fibrinogen concentrate (248 participants) with placebo/other sources or no treatment. Additionally, we found 12 ongoing trials, but we were unable to retrieve any data from them. We could not identify beneficial effects of fibrinogen concentrate on patient survival. In our predefined outcomes, we identified a reduced proportion of patients requiring donor blood transfusion. We could not identify reduced blood loss or any harms or adverse events caused by treatment with fibrinogen concentrate. However, all trials were of low quality and were small, so evidence in support of fibrinogen concentrate in patients with bleeding remains weak.

Summary of findings

Summary of findings for the main comparison. Fibrinogen concentrate versus any comparator for patients with bleeding.

Fibrinogen concentrate versus any comparator for patients with bleeding
Patient or population: bleeding patients or at risk of severe bleeding  Settings: in‐hospital care, operative setting, intensive care or trauma  Intervention: fibrinogen concentrate  Comparison: any comparator
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Any comparator	Fibrinogen concentrate
Mortality	Study population		RR 0.28   (0.03 to 2.33)	81  (2 studies)	⊕⊝⊝⊝  very low^1,2,3
	95 per 1000	27 per 1000  (3 to 222)
	Moderate
	63 per 1000	18 per 1000  (2 to 147)
Incidence of allogenic blood transfusion   Proportion of participants transfused with RBC, FFP, PLT and/or cryo	Study population		RR 0.47   (0.31 to 0.72)	207  (5 studies)	⊕⊝⊝⊝  very low^1,4,5,6
	764 per 1000	359 per 1000  (237 to 550)
	Moderate
	800 per 1000	376 per 1000  (248 to 576)
Thrombotic episodes (arterial and venous graft occlusion, pulmonary embolus, deep venous thrombosis)  Proportion with event	Study population		RR 1.03   (0.27 to 3.97)	124  (3 studies)	⊕⊝⊝⊝  very low^1,3,5,6
	48 per 1000	49 per 1000  (13 to 189)
	Moderate
	48 per 1000	49 per 1000  (13 to 191)
Intensive care unit (ICU) stay  Duration of stay (hours)	The mean intensive care unit (ICU) stay ranged across control groups from  25 to 173 hours	The mean intensive care unit (ICU) stay in the intervention groups was  9.87 lower  (20.67 lower to 0.93 higher)		112  (3 studies)	⊕⊝⊝⊝  very low^1,3,4,6
Re‐operation due to persistent bleeding  Events during admission	Study population		RR 0.68   (0.01 to 36.71)	124  (2 studies)	⊕⊝⊝⊝  very low^3,4,6
	108 per 1000	73 per 1000  (1 to 1000)
	Moderate
	107 per 1000	73 per 1000  (1 to 1000)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; RR: Risk ratio.
GRADE Working Group grades of evidence:  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

RCT/Quasi/CCT (delete as appropriate)	Relevant participants	Relevant interventions	Relevant outcomes
Yes/No/Unclear	Yes/No/Unclear	Yes/No/Unclear	Yes/No*/Unclear

Code each paper	Author(s)	Journal/Conference proceedings, etc	Year
A	The paper listed above
B	Further papers

Participant characteristics
	Further details
Age (mean, median, range, etc)
Sex of participants (numbers/%, etc)
Disease status/type, etc (if applicable)
Patients treated with plasma expanders (colloids) before intervention (Treatment is defined as a methodical prespecified and clinically evaluated level of haemodilution)
Clinical setting: (mark with an X)	Cardiac Non‐cardiac Emergency (surgery that should be performed within 24 hours after meeting the indication for surgery) Trauma Obstetrics Paediatrics (age younger than 18 years, neonates not included) Neonates (born preterm) Critically ill (sepsis, septic shock, DIC) Other
Other

Allocation of intervention (adequate sequence generation?)
State here method used to generate allocation and reasons for grading	Grade (circle)
	Adequate (random) (yes)
	Inadequate (e.g. alternate) (no)
	Unclear

Concealment of allocation (allocation concealment?) Process used to prevent foreknowledge of group assignment in an RCT, which should be seen as distinct from blinding
State here method used to conceal allocation and reasons for grading	Grade (circle)
	Adequate (yes)
	Inadequate (no)
	Unclear

Blinding (blinding?)
Person responsible for participants' care	Yes/No
Participant	Yes/No
Outcome assessor	Yes/No
Other (please specify)	Yes/No
Intention‐to‐treat An intention‐to‐treat analysis is one in which all participants in a trial are analysed according to the intervention to which they were allocated, whether they received it or not.
All participants entering trial
15% or fewer excluded
More than 15% excluded
Not analysed as ‘intention‐to‐treat’
Unclear

Incomplete outcome data addressed?
Completeness of outcome data, including attritions and exclusions	Grade (circle)
	Adequate (yes)
	Inadequate (no)
	Unclear
Free of selective reporting?
The possibility of selective outcome reporting	Grade (circle)
	Adequate (yes)
	Inadequate (no)
	Unclear

Free of other bias? (bias not addressed in the other domains)
State here method used to conceal allocation and reasons for grading	Grade (circle)
	Adequate (yes)
	Inadequate (no)
	Unclear

Outcomes relevant to your review Copy and paste from ‘Types of outcome measures’
	Reported in paper (circle)
Overall mortality	Yes/No
Overall 28 days' mortality (30 days M. included)	Yes/No
Incidence of allogenic transfusion (e.g. avoidance of transfusion)	Yes/No
Bleeding events	Yes/No
Quantity of blood products transfused	Yes/No
Incidence of surgical interventions	Yes/No
Incidence of re‐operation due to bleeding	Yes/No
Quality of life assessment, as defined by authors in included studies.	Yes/No
Complications during the inpatient stay not specific to the trial intervention (e.g. pneumonia, congestive cardiac failure, respiratory failure, renal failure).	Yes/No
Duration of mechanical ventilation	Yes/No
Days free from ventilator (as defined by authors)	Yes/No
Number of days in hospital	Yes/No
Mean length of stay in intensive care unit (ICU)	Yes/No
	Yes/No

For continuous data
Code of paper	Outcomes (rename)	Unit of measurement	Intervention group		Control group		Details if outcome only described in text
Code of paper	Outcomes (rename)	Unit of measurement	n	Mean (SD)	n	Mean (SD)
A etc	Bleeding events and amount of blood transfused
	Quality of life assessment
	Duration of mechanical ventilation and/or improvement in respiratory failure (ventilator‐free days)
	Days free from ventilator (as defined by authors)
	Number of days in hospital
	Mean length of stay in intensive care unit (ICU)

Did this report include any references to published reports of potentially eligible trials not already identified for this review?
First author	Journal/Conference	Year of publication

Did this report include any references to unpublished data from potentially eligible trials not already identified for this review? If yes, give list contact name and details

Trial characteristics
	Further details
Single centre/multi‐centre
Country/countries
How was participant eligibility defined?
How many people were randomly assigned?
Number of participants in each intervention group
Number of participants who received intended treatment
Number of participants who were analysed
Drug treatment(s) used
Dose/frequency of administration
Co‐interventions (including if fibrinogen concentrate was given as part of a predefined transfusion algorithm)
Duration of treatment (state weeks/months, etc, if cross‐over trial give length of time in each arm)
Median (range) length of follow‐up reported in this paper (state weeks, months or years or if not stated)
Time points when measurements were taken during the study
Time points reported in the study
Time points you are using in RevMan
Trial design (e.g. parallel/cross‐over*)
Other

Study	Population	Intervention	Control	Outcome	Follow‐up	Objective	Blood loss + amount colloid transfused in control group (mean if otherwise not stated)
Cui 2010	N = 40 (14/17; 9 excluded) Elective cardiac surgery, children	Single dose, 0.5 to 1 g fibrinogen concentrate (manufacturer not stated) administration combined with traditional transfusion therapy guided by thrombelastography Dose approx = 39 to 80 mg/kg	Traditional transfusion therapy guided by clinical experience	Closure time, transfusion at closure (FFP/PLT), transfusion requirements at ICU (FFP/PLT/RBC), chest tube drainage (1, 6, 24 hours) and total transfusion requirements	Until end of hospitalization, but blood loss was only recorded the first 24 hours postsurgery	Treatment of hypofibrinogenaemia in thrombelastography‐guided algorithm	Blood loss:  At 1 hour: 3.5 mL/kg/h At 6 hours: 1.5 mL/kg/h At 24 hours: 0.7 mL/kg/h Colloid transfused: 82.5 mL/kg
Lance 2011	N = 43 (21/22) Elective cardiac, major abdominal and spinal column surgery, adults	Hemostatic transfusion with 2 units of FFP combined with single‐dose 2 g fibrinogen concentrate (Haemocomplettan^®) Dose approx = 25 mg/kg	Hemostatic transfusion with 4 units of FFP	Arrest of bleeding and fibrin clot formation (measured by whole‐blood thromboelastometry and thrombin generation)	No follow‐up after successful haemostasis (possible adverse events were recorded postsurgery)	Replacement of FFP	Blood loss: not stated Colloid transfused: not stated
Fenger‐Eriksen 2009a	N = 21 (10/10; 1 excluded) Elective urological cancer operation, adults	Fibrinogen concentrate (Haemocomplettan^®) Dose 45 mg/kg	Placebo, isotonic saline 2.25 mL/kg	Primary: whole‐blood maximum clot firmness as determined by thromboelastometry (ROTEM) Secondary: other thromboelastometric variables; platelet function; thrombin generation; bleeding and perioperative and postoperative blood product requirements	48 hours postsurgery	Reversal of colloid dilution	Blood loss: 2933 mL (at time of intervention) Colloid transfused: 2795 mL (at time of intervention)
Karlsson 2009	N = 20 (10/10), elective cardiac surgery, adults	Preoperative infusion of 2 g fibrinogen concentrate (Haemocomplettan^®) Dose 18 to 34 mg/kg	No treatment	Primary: clinical adverse events and graft occlusion assessed by multi‐slice computed tomography 3 to 4 days after surgery Secondary: postoperative blood loss, blood transfusions, haemoglobin levels 24 hours after surgery and global haemostasis assessed with thromboelastometry 2 and 24 hours after surgery	3 to 4 days' follow‐up on clinical adverse events (blood loss was recorded only 12 hours postsurgery)	Preemptive treatment	Blood loss: 830 mL (postsurgery) Colloid transfused: 1000 mL
Rahe‐Meyer 2013	N = 61 (29/32), elective thoracic or thoracoabdominal aortic replacement surgery, adults	Fibrinogen concentrate (Haemocomplettan P^®) Individualized dose using maximum amplitude of ROTEM/FIBTEM measurements before the end of CPB. (Median dose 8 g.) Dose approx = 90 mg/kg	Placebo (saline 0.9%) same volume	Primary outcome: total allogenic transfusion requirements in the 24 hours post administration phase (Transfusion therapy guided according to algorithm) Secondary outcomes: intensive care length of stay, number of allogenic units transfused, mortality and adverse events and re‐operation due to persistent bleeding	24 hours post intervention	Treatment of hypofibrinogenaemia in thrombelastography‐guided algorithm	Blood loss: postoperative blood loss 850 mL (655 to 1565 mL) (median, IQ) Intraoperative not recorded Colloid transfused: only gelatins were used, but amount not recorded
Galas 2012	N = 63 (30/33) Children (< 15 years) receiving cardiac surgery with cardiopulmonary bypass and clinically important intraoperative bleeding, and hypofibrinogenaemia	Fibrinogen concentrate dose 60 mg/kg body weight (RiaSTAP^®)	Cryoprecipitate (10 mL/kg body weight)	Primary outcome measures: number of participants not receiving any allogeneic blood products (intraoperative until hospital discharge). Transfusional requirements were based on clinical judgement Secondary outcome measures: haemostatic tests, length of ICU stay, clinical complications (renal failure, respiratory failure, sepsis, myocardial ischaemias, stroke), transfusion requirements, mechanical ventilation‐free days, length of hospital stay, vasopressor‐free days, perioperative bleeding and re‐operation due to persistent bleeding	At least 48 hours	Treatment of hypofibrinogenaemia and replacement of cryoprecipitate	Blood loss: not stated Colloid transfused: not stated

Study	Planned size	Population	Intervention	Control	Outcome	Funding	Objective
Fries 2011	60	Trauma patients with hemorrhagic shock	50 mg/kg fibrinogen concentrate (Clottafact/LFB)	Placebo (buffer substance)	ROTEM/FIBTEM change at 60 minutes post infusion	LFB provides medicine	Preemptive treatment
Haas 2012	60	Elective paediatric patients: scoliosis or craniofacial surgery with hypofibrinogenaemia	30 mg/kg fibrinogen concentrate (Haemocomplettan/CSL Behring) and hourly repeated administration guided by ROTEM FIBTEM MCF < 13 mm	30 mg/kg fibrinogen concentrate (Haemocomplettan/CSL Behring) and hourly repeated administration guided by ROTEM FIBTEM MCF < 8 mm	Total quantity of transfused red cells	Independent	Treatment of hypofibrinogenaemia in a thrombelastography‐guided algorithm
Innerhofer 2012	200	Severe trauma patients with clinical bleeding or at risk of bleeding and coagulopathy (measured by ROTEM)	Fibrinogen concentrate (if FIBTEM MA < 7 mm) and/or prothrombin complex concentrate and/or factor XIII concentrate	15 mL/kg fresh frozen plasma (if FIBTEM MA < 7 mm or EXTEM CT > 90 s)	Multiple organ failure within 24 hours on intensive care unit	Independent	Treatment of hypofibrinogenaemia/ coagulopathy and replacement of FFP
Jeppsson 2010	60	Elective coronary artery bypass with preoperative fibrinogen level below 3.8 g/L	2 g fibrinogen concentrate (RiaSTAP/ CSL Behring)	Placebo (saline)	2 years' follow‐up on safety and 12 hours' postoperative blood loss	Independent	Preemptive treatment
Nierich 2011	120	Complex elective cardiac surgery and microvascular bleeding	Fibrinogen concentrate (Haemocomplettan/CSL Behring) guided by plasma concentration (Clauss method)	Placebo (human albumin)	Perioperative blood loss 12 hours post intervention	Receives study medication from CSL Behring	Treatment of hypofibrinogenaemia
Nimmo 2009	20	Elective thoracoabdominal aneurysm repair	2 g fibrinogen concentrate (Haemocomplettan/CSL Behring) per hour guided by clinical picture and point‐of‐care testing	Fresh frozen plasma (dose not stated)	Intraoperative coagulation pattern	Study collaborates with CSL Behring	Treatment of hypofibrinogenaemia in a guided algorithm
Rahe‐Meyer 2011c	200	Open elective cardiac surgery and 5 min bleeding mass of 60 to 250 g	Fibrinogen concentrate (Haemocomplettan/CSL Behring) guided by body weight and ROTEM measures	Placebo (saline)	Number of allogenic blood products at 24 hours post intervention	Industry initiated, collaborates with CSL Behring	Treatment of hypofibrinogenaemia in thrombelastography‐guided algorithm
Ranucci 2011	120	Complex elective cardiac surgery with CPB > 90 minutes	Fibrinogen concentrate (Haemocomplettan/CSL Behring) and prothrombin complex concentrate guided by ROTEM measures	Placebo (saline)	Avoidance of allogenic blood products at 30 days' post surgery	Study collaborates with CSL Behring	Treatment of hypofibrinogenaemia/ coagulopathy in thrombelastography‐guided algorithm
Sabate 2012	132	Liver transplantation with pretransplant plasma fibrinogen level < 2.9 g/L	Fibrinogen concentrate (RiaSTAP/CSL Behring) until expected level of 2.9 g/L is reached	Placebo (saline)	Incidence of RBC transfusion during operation	Independent	Preemptive treatment
Tanaka 2011	60	Elective cardiac surgery with CPB and microvascular bleeding	4 g fibrinogen concentrate (RiaSTAP/CSL Behring)	A single apheresis platelet unit	Coagulation disturbances intraoperatively and up to 24 hours postoperatively	Study collaborates with CSL Behring	Treatment of hypofibrinogenaemia/ coagulopathy
Wikkelsoe 2011	245	Severe postpartum haemorrhage (post vaginal delivery and during caesarean section)	2 g fibrinogen concentrate (RiaSTAP/CSL Behring)	Placebo (saline)	Incidence of allogenic transfusions within 6 weeks postpartum	Independent	Preemptive treatment
Kwapisz 2012	40	Adult elective complex cardiac surgical procedures	Fibrinogen concentrate (Haemocomplettan/CSL Behring) guided by body weight	Placebo (saline)	Number of allogenic blood products at 48 hours post intervention	Study collaborates with CSL Behring	Treatment of hypofibrinogenaemia in a thrombelastography‐guided algorithm

For dichotomous data
Code of paper	Outcomes (rename)	Intervention group (n) n = number of participants, not number of events	Control group (n) n = number of participants, not number of events
A	Overall mortality
	Overall mortality (28 days)
	Incidence of re‐operation due to bleeding
	Incidence of surgical interventions
	Complications probably related to the intervention (e.g. thrombotic episodes (pulmonary embolism, myocardial infarction, DIC), major immunological and allergic reactions, infections and sepsis)
	Complications during the inpatient stay not specific to the trial intervention (e.g. pneumonia, congestive cardiac failure, respiratory failure, renal failure)
	Incidence of allogenic blood transfusions (e.g. avoidance of transfusion)

Analysis	Study	Participants	Statistical method	Effect estimate
Mortality, 28 days	Rahe‐Meyer 2013	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03 to 2.33]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality longest follow‐up	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2 ICU stay (hours)	3	112	Mean Difference (IV, Fixed, 95% CI)	‐9.87 [‐20.67, 0.93]
3 Duration of mechanical ventilation (hours)	2	51	Mean Difference (IV, Random, 95% CI)	‐27.29 [‐89.73, 35.16]
4 Stay in hospital (days)	3	107	Mean Difference (IV, Random, 95% CI)	‐2.28 [‐7.04, 2.48]
5 Incidence of allogenic blood transfusion (types of comparison)	5	207	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.31, 0.72]
5.1 Fibrinogen versus placebo/no treatment	2	40	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.09, 0.80]
5.2 Fibrinogen versus FFP/cryoprecipitate	1	63	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.15, 0.56]
5.3 Fibrinogen in combination with FFP versus placebo/no treatment/usual treatment	1	43	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.41, 1.49]
5.4 Fibrinogen as part of transfusion algorithm versus placebo or no treatment	1	61	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.40, 0.77]
6 Incidence of allogenic blood transfusion (cardiac vs non‐cardiac)	5	207	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.31, 0.72]
6.1 Cardiac surgery	3	144	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.24, 0.76]
6.2 Non‐cardiac surgery	2	63	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.17, 1.53]
7 Incidence of allogenic blood transfusion (pediatric vs adult)	5	207	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.31, 0.72]
7.1 Paediatric studies	1	63	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.15, 0.56]
7.2 Adult studies	4	144	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.43, 0.75]
8 Incidence of allogenic blood transfusion (high dose > 50 mg/kg vs low dose)	5	207	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.31, 0.72]
8.1 High‐dose studies (> 50 mg/kg)	2	124	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.21, 0.86]
8.2 Low‐dose studies (≤ 50 mg/kg)	3	83	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.23, 1.14]
9 Re‐operation due to persistent bleeding	2	124	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.01, 36.71]
10 Incidence of RBC transfusion longest follow‐up	2	92	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.32, 2.02]
11 Thrombotic episodes (arterial and venous graft occlusion, pulmonary embolus, deep venous thrombosis)	3	124	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.27, 3.97]
12 Complications not specific to trial intervention (pleural effusion, abdominal ischaemia and other serious adverse events)	2	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.45, 3.44]
13 Blood loss/drainage, longest follow‐up	2	51	Mean Difference (IV, Random, 95% CI)	‐89.37 [‐406.05, 227.32]
14 Blood loss/Drainage (24 hours) mL/kg/h	2	92	Mean Difference (IV, Random, 95% CI)	‐32.34 [‐176.45, 111.76]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of allogenic blood transfusion (cardiac vs non‐cardiac)	2	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.09, 0.81]
1.1 Cardiac surgery	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 2.69]
1.2 Non‐cardiac surgery	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.07, 0.90]

Methods	Two‐group parallel RCT, single centre Overall study quality: high risk of bias Sample size calculation: none reported Funding: not stated
Participants	40 participants randomly assigned, of which 31 received intervention (17 in fibrinogen group) Inclusion criteria: cyanotic paediatric patients diagnosed with transposition of the great arteries (TGA) or double‐outlet right ventricle (DORV); the operation that the patients underwent was arterial switch operation (ASO) or double roots transplantation (DRT). Hematocrit higher than 54% before operation Exclusion criteria: history of blood disease; anticoagulation treatment before surgery; medication that affects haemostasis (such as prostaglandin E1); difficult sternal closure caused by anatomical or surgical reasons
Interventions	Intervention: fibrinogen (0.5 to 1 g) administration combined with traditional transfusion guided by thrombelastography (TEG, Haemoscope Corp) The type of fibrinogen substitution is not specifically described Control: traditional transfusion guided by clinical experience
Outcomes	No primary outcome is stated Closure time, transfusion at closure (FFP/PLT), transfusion requirements at ICU (FFP/PLT/RBC), chest tube drainage (1,6,24 hours) and total transfusion requirements (FFP/PLT/RBC) RBC at closure time was not assessed because residuals of blood were present in the CPB machine
Notes	Country: China We have converted the missing standard deviation in accordance with recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 7.7.3.5 We used mean body weight for each group to calculate transfused amount, when outcome was reported in mL/kg Letter to author 2 March 2012, repeated 23 May 2012. No reply received Authors' conclusion: "The present study suggests that fibrinogen might be a better haemostatic agent for paediatric patients with severely cyanotic CCHD than FFP. This new therapy method could reduce the use of allogeneic blood products and shorten the operative recovery period. In addition, TEG is effective for blood protection"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	High risk	22.5% excluded (9/40), not accounted for
Selective reporting (reporting bias)	Unclear risk	Not stated
Other bias	High risk	Sample size not stated, funding not stated, baseline parameters are provided, but it is unclear if they include the excluded patients, and if the exclusions influence baseline balance. A small study and operative recovery data show very large differences between small trial groups, suggesting that the intervention group might have consisted of healthier individuals overall
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not described. The intervention would be difficult to blind, so we expect this to be provided without blinding of personnel. It may be blinded to participants
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not described (see above)

Methods	Two‐group parallel RCT Funding: The study was supported by an unrestricted research grant from CSL Behring, the University of Aarhus Research Foundation and the A. P. Møller and Hustru Chastine McKinney Møllers Foundation Overall study quality: high risk of bias Sample size calculation: yes, based on 10% change in maximum clot strength
Participants	21 participants randomly assigned; 20 participants received intervention (10 in fibrinogen group) Inclusion criteria: Patients older than 17 years of age suffering from localized bladder cancer and admitted for radical cystectomy. Furthermore, perioperative dilution with hydroxyethyl starch (HES) to a 30% reduction in hematocrit level Exclusion criteria: 1: Presence of coagulation disorders defined as abnormal values of platelet count, PT, APTT, fibrinogen, antithrombin or D‐dimer; 2: Treatment with oral vitamin K antagonists; 3: Intake of non‐steroid anti‐inflammatory drugs within 2 days before surgery; 4: Renal or hepatic dysfunction; 5: Ischaemic heart disease; 6: Pregnancy; 7: Known hypersensitivity to HES
Interventions	Intervention: fibrinogen concentrate, Haemocomplettan, CSL Behring (dosage 45 mg/kg) Control: placebo in equivalent volume (isotonic saline 2.25 mL/kg)
Outcomes	Primary: whole‐blood maximum clot firmness as determined by thromboelastometry (ROTEM, thromboelastometry, Pentafarm, Munich, Germany) Secondary: other thromboelastometric variables; platelet function; thrombin generation; bleeding and perioperative and postoperative blood product requirements
Notes	Letter to author sent 2 March 2012. Reply received 13 March 2012, additional data were provided
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Shuffling of cards (additional information)
Allocation concealment (selection bias)	Low risk	Randomly assigned using the closed envelope principle
Incomplete outcome data (attrition bias)   All outcomes	Low risk	According to published article, one participant was excluded after randomization because of an interrupted operation. Participant did not receive intervention. Data from this participant were not included in the analysis (no intention‐to‐treat analysis). (additional information) Exclusion was due to "Spread of cancer, so it was not possible to perform planned cystectomy hence the operation was interrupted". No available data on this participant regarding outcomes of this review
Selective reporting (reporting bias)	Low risk	Compared with the official description on clinicaltrials.gov. NCT00493272
Other bias	High risk	Unrestricted funding from CSL Behring. Very small sample size aimed to assess a surrogate outcome. Baseline imbalance described but analysis not provided
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	"The study medicine was prepared and administered by a second person; thus, the study staff was blinded to infusion of the drug vehicle and to patients participating in the study"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	"Allocation concealment was sustained until all recruitment, data collection, transfusion requirement data and laboratory analyses were complete". Statistician was not blinded (additional information)

Methods	Randomized double‐blinded parallel‐assigned single‐centre clinical trial Data from abstract. No additional information available Funding: not stated Overall study quality: high risk of bias Sample size calculation: not stated
Participants	63 participants completed the study (30 in fibrinogen group) Mean age, 3 years and 5 months; mean weight, 6.7 kg Inclusion criteria: children (< 15 years) receiving cardiac surgery with cardiopulmonary bypass, clinically important intraoperative bleeding and hypofibrinogenaemia (fibrinogen level < 1 g/L or TEG < 7 mm) Exclusion criteria: previous coagulopathy (clinical history or INR > 1.5); low platelet count (lower than 100.000); product allergy; urgent procedures; active infection
Interventions	Intervention group: fibrinogen concentrate (60 mg/kg body weight) (RiaSTAP^®/CSL Behring) Median doses were 504 mg fibrinogen concentrate Control group: cryoprecipiate (10 mL/kg body weight) Median doses were 402 mg cryoprecipitate
Outcomes	Primary outcome measures: number of patients not receiving any allogeneic blood products (intraoperative until hospital discharge). Transfusional requirements were based on clinical judgement Secondary outcome measures: haemostatic tests, length of ICU stay, clinical complications (renal failure, respiratory failure, sepsis, myocardial ischemias, stroke), transfusion requirements, mechanical ventilation free‐days, length of hospital stay, vasopressors free‐days, perioperative bleeding
Notes	Estimated enrolment: 80 participants. Finished. Data submitted for publication. Abstract available International Symposium on Intensive Care and Emergency Medicine 2012 Collaborator: CSL Behring Contacted 4 April 2012. Reply received 8 April 2012. No additional information provided Participating hospitals: (Brazil) Incor ‐ Heart Institute ‐ University of Sao Paulo
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	High risk	Inclusion criteria changed from < 18 years to < 15 years compared with trial registration (NCT01187225) "Reoperation due to bleeding" not stated as secondary outcome in trial registration (NCT01187225)
Other bias	Unclear risk	Sample size not stated, funding not stated, baseline imbalance not described
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not stated

Methods	Single‐center parallel‐group RCT, pilot study Funding: The study was supported by the Swedish Heart & Lung Foundation, CSL Behring, Marburg, Germany, and Sahlgrenska University Hospital Overall study quality: high risk of bias Sample size calculation: pilot study: sample size was determined in agreement with the Regional Research Ethics Committee and the Swedish Medical Products Agency
Participants	20 participants randomly assigned (10 in fibrinogen group) Inclusion criteria: elective CABG patients with plasma fibrinogen < 3.8 g/L Exclusion criteria: known kidney/liver disease, bleeding disorder and a surgical source of bleeding at acute re‐exploration
Interventions	Intervention: preoperative infusion of 2 g fibrinogen concentrate (Haemocomplettan, CSL Behring)  Control: no treatment
Outcomes	Primary: clinical adverse events and graft occlusion assessed by multi‐slice computed tomography 3 to 4 days after surgery Secondary: postoperative blood loss, blood transfusions, haemoglobin levels 24 hours after surgery, and global haemostasis assessed with thromboelastometry, 2 and 24 hours after surgery and clinical adverse events
Notes	Country: Sweden Letter to author 14 March 2012. Reply by phone 29 May 2012 Provided additional data on mortality (6 year follow‐up), ICU stay, mechanical ventilation and length of stay Authors' conclusion: "In summary, the results of this pilot study indicate that prophylactic treatment with fibrinogen concentrate in cardiac surgery patients is feasible and reduces postoperative bleeding.  Further prospective, randomized, placebo‐controlled studies with sufficient statistical power are necessary to ensure safety, confirm efficacy, and to determine cost‐effectiveness of fibrinogen prophylaxis in cardiac surgery"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Shuffling of cards (additional information)
Allocation concealment (selection bias)	Low risk	Random assignment was conducted using unmarked envelopes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No missing data. All 20 randomly assigned participants were described
Selective reporting (reporting bias)	Low risk	Protocol not available. Apparently free of selective reporting
Other bias	High risk	Unrestricted funding from CSL Behring. Apparently without baseline imbalance but with a very small sample size because it was a pilot study
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "Only the study coordinator was informed about group assignment, that is neither the operating surgeon, the operating room staff, anaesthesiologists nor the staff at the intensive care unit, was informed." Fibrinogen was administered after induction of anaesthesia as an infusion during 5 minutes in a central venous catheter line, meaning that anaesthetic personnel at the operation theatre were not completely blinded (additional information). Pharmacist randomly assigned and dispensed the medicine
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinding of postoperative bleeding: This was assessed by ICU nurses, who were not informed of group assignment

Methods	Single‐centre, parallel‐group RCT Funding: The study group received unrestricted grants from CSL Behring Overall study quality: high risk of bias Sample size calculation: yes, based on 10% reduction in blood loss
Participants	52 participants randomly assigned, of which 43 received intervention (22 in fibrinogen group) Patients with massive bleeding requiring less than 4 FFP were excluded after randomization Inclusion criteria: Major surgery (cardiovascular, abdominal, and orthopaedic spine surgery) with expected duration of operation exceeding 120 minutes. Patients requiring massive transfusion (defined as "prolonged blood loss of > 150 ml/hour or > 1.5 ml/kg/20 min, or acute blood loss of > 700 ml at once") during or after surgery Exclusion criteria: age younger than 18, active HIV infection, known coagulation abnormalities, deep hypothermia with circulatory arrest or preoperative need of transfusion
Interventions	Intervention: haemostatic transfusion with 2 units FFP plus 2 g fibrinogen concentrate (Haemocomplettan^®) Control: haemostatic transfusion with 4 units FFP Haemostatic therapy to stop bleeding was started on the basis of clinical decision Comment: 25 participants (13 in fibrinogen group and 12 in control group) received heparin (150 to 300 mg/kg) as the result of extracorporal circulation
Outcomes	According to protocol, primary outcome was blood loss: "Primary endpoint is the amount of blood loss (expressed in ml per time unit) and the further use of blood products. As secondary endpoints, the levels of thrombin generation and thromboelastografische provisions compared with conventional coagulation tests" In article: bleeding arrest after intervention, fibrin clot formation (measured by whole‐blood thromboelastometry and thrombin generation), adverse events Participants were followed up to 30 days or at least until discharge
Notes	Country: the Netherlands Letter to author 6 March 2012. Reply received 3 April 2012 and 22 June Authors' conclusion: "In conclusion, this trial showed a similar effect of 2 g fibrinogen additive to 2 units FFP compared with transfusion of 4 units FFP on haemostasis. The transfused fibrinogen had an important contribution to fibrin clot formation in thromboelastometry analysis, while the transfused 4 units FFP more increased thrombin generation and fibrinogen levels remained lower. We hence postulate that transfused FFP and fibrinogen are both relevant for early haemostasis and that both should be combined in massive haemorrhage protocols. These results argue for a larger‐scale follow‐up study, where the effects are determined of supplementing fibrinogen concentrate together with a standard dose of FFP. Herein, a pro‐haemostatic effect of fibrinogen is expected on top of the effect of normalization of other coagulation factors."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Shuffling of cards (additional information)
Allocation concealment (selection bias)	Low risk	Closed envelope method
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No intention‐to‐treat analysis, 9/52 (17%) patients were excluded after randomization because an inadequate amount of FFP was transfused; no data available on these
Selective reporting (reporting bias)	High risk	In protocol, authors state blood loss and transfusions as primary outcome (with sample size calculated on reduction in blood loss). In publication, authors describe arrest of bleeding instead
Other bias	High risk	Two of authors (not primary author) hold an unrestricted grant from CSL Behring. Three persons from CSL Behring are acknowledged for "stimulating discussions". Sample size provided. Apparently without baseline imbalance but with no data on exclusions.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Inclusion was based on clinical decision, with the attending anaesthesiologist not blinded to the study intervention (additional information): "Patients and surgeons were not aware of group. Only the attending anaesthesiologist received the products and transfused them‐ so she/he was aware of the treatment group, but lab‐parameters were taken from researchers and worked up by analysts who did not know the groups. Registration of bleeding and further treatment was done by researchers"
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	See above

Methods	Single‐centre parallel‐group RCT Data from publication and additional information provided by authors Funding: CSL Behring supported the trial Overall study quality: high risk of bias Sample size calculation: not stated
Participants	61 randomly assigned, of which 29 received fibrinogen concentrate Inclusion criteria: Age > 18 years and elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass (CPB) (aortic valve operations with root/ascending aorta replacement (thoracic aortic aneurysm) with or without aortic bow replacements and thoracoabdominal replacements (thoracoabdominal aortic aneurysm)) and clinically relevant bleeding (defined as bleeding of 60 to 250 g into the surgical site within 5 minutes after CPB and completion of surgical haemostasis) Exclusion criteria: Positive pregnancy test, pregnancy or lactation Women of childbearing age not using a medically approved method of contraception during the study Previous aortic replacement at the same aortic site (re‐do surgeries) Undergoing an emergency operation Proof or suspicion of a congenital or acquired coagulation disorder (e.g. VWD, via severe liver disease) Myocardial Infarction (MI) or apoplexy in the 2 months before study surgery ASA administration in the 3 days preceding study surgery, and a pathological (< 74.5 U) ASPI Multiplate^® test immediately before surgery began Clopidogrel administration in the 5 days preceding study surgery, and a pathological (< 31.1 U) ADP/PG Multiplate^® test immediately before surgery began Tirofiban administration in the 2 days preceding study surgery, and a pathological (< 94.1 U) TRAP Multiplate^® test immediately before surgery began Phenprocoumon administration in the 5 days preceding study surgery, and an INR > 1.28 immediately before surgery began Participation in another clinical study in the 4 weeks preceding aortic replacement Sensitivity to any of the components of study medication, or to MPs with a similar chemical structure to any of the components of study medication Any indication that the restrictions or procedures of the study may not be adhered to (e.g. an uncooperative attitude) Any indication that the study restrictions, procedures, or consequences therein have not been considered or understood, such that informed consent cannot be convincingly given Multiple morbidities, with a notably constrained remaining length of life
Interventions	Intervention: Fibrinogen concentrate (Haemocomplettan P^®/CSL Behring). Individualized dose using maximum amplitude of ROTEM/FIBTEM measurements before the end of CPB. Median dose given was 8 g (range, 3 to 12 g). Control: placebo (saline 0.9%) same volume
Outcomes	Primary outcome: total allogenic transfusion requirements in the 24 hours post administration phase Transfusion therapy in both groups was guided by algorithm based on postoperative blood drainage and platelet count Secondary outcomes: Intensive care length of stay, number of allogenic units transfused, mortality and adverse events and re‐operation due to persistent bleeding
Notes	Country: Germany Letter to author: sent 8 April 2012: reply with additional data received 18 April 2012 Authors' conclusion: "Hemostatic therapy with fibrinogen concentrate  in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products. Larger multicenter studies are necessary to confirm the role of fibrinogen concentrate in the management of perioperative bleeding in patients with life‐threatening coagulopathy"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated. 1:1 with blocks of 4
Allocation concealment (selection bias)	Low risk	Closed opaque envelopes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	One participant in placebo/control group died before 24 hours and is not included in primary outcome analysis. One participant in fibrinogen group and 4 participants in control group did not have data on length of stay. Intention‐to‐treat analyses were used to assess adverse events
Selective reporting (reporting bias)	Low risk	Compared with clinical registration NCT00701142, apparently free of bias
Other bias	High risk	(Additional information provided by author): "CSL Behring funded the trial. Sponsor participated in study design but was not involved with data collection. Data analysis was performed independently by a contract research organization funded by the study sponsor. The sponsor paid for the services of biometrics service providers and medical writing support. The clinical study report was written by medical writing vendor funded by the sponsor." Apperently free of baseline imbalance
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Randomization and dispensation of trial medication were performed by the local hospital pharmacy, and medication was delivered to the operation theatre in syringes blinded to personnel
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Only pharmacists dispensing the medicine and randomly assigning participants were unblinded and had no participant contact

PERMALINK

Fibrinogen concentrate in bleeding patients

Anne Wikkelsø

Jens Lunde

Mathias Johansen

Jakob Stensballe

Jørn Wetterslev

Ann Merete Møller

Arash Afshari

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings for the main comparison. Fibrinogen concentrate versus any comparator for patients with bleeding.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

1) Random sequence generation?

2) Allocation concealment?

3) Blinding of participants and personnel?

4) Blinding of outcome assessor?

5) Incomplete outcome data?

6) Selective reporting?

7) Other bias?

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cross‐over trials

Studies with multiple intervention groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings tables

Results

Description of studies

Results of the search

Included studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Primary outcome

1.1. Analysis.

Secondary outcomes

1.5. Analysis.

Study	Reason for exclusion
Bell 2010	Case report, obstetrical setting Six cases characterized by significant (> 1500 mL) peripartum blood loss and severe acquired hypofibrinogenaemia. Patients were treated with fibrinogen concentrate (mean dose, 3.16 g) along with allogeneic blood products (PLT, FFP, RBC) Findings: rapid normalization of coagulation parameters and improved haemorrhage Reason for exclusion: non‐RCT
Danes 2008	Retrospective cohort study, non‐controlled, single centre, mixed patient population Patients given fibrinogen concentrate according to pharmacy‐dispensing records were included, receiving a median dose of 4 g The cohort consisted of 69 participants suffering from various forms of acquired severe hypofibrinogenaemia with life‐threatening consumptive thrombo‐haemorrhagic disorders (surgery, trauma and digestive haemorrhage) (43 participants), or with underlying disease states that limit fibrinogen synthesis (hepatic dysfunction, haematological malignancies) (26 participants) Findings: improved coagulation after treatment. Acute fibrinogen deficiency probably related to mortality Reason for exclusion: non‐RCT
Glover 2010	Case report, obstetrical setting One patient suffering major antenatal obstetrical haemorrhage with DIC and severe hypofibrinogenaemia. Treated with fibrinogen concentrate (4 g) in combination with RBC and FFP transfusion Findings: Emphasis on early and timely monitoring of coagulation and rapid administration and availability of fibrinogen substitution Reason for exclusion: non‐RCT
Guasch 2008	Prospective observational cohort, non‐controlled (descriptive), single centre, obstetrical setting 124 women admitted for postpartum haemorrhage. Treatment was provided with RBCs (96.8%), prothrombin complex concentrate (7.25%), recombinant factor VIIa (3.2%) and fibrinogen concentrate (49.2%) Findings: Use of fibrinogen concentrate is common and provides good results Reason for exclusion: non‐RCT
Haas 2008	Retrospective non‐controlled study, single centre, craniofacial surgery, children Nine children undergoing major craniofacial surgery with massive blood loss. Thromboelastometry‐guided assessment of coagulopathy and guided administration of fibrinogen concentrate (30 mg/kg) Findings: no need for PLT and FFP. Fibrinogen concentrate effectively improved fibrinogen polymerisation and total cloth strength Reason for exclusion: non‐RCT
Mittermayr 2007	Randomized clinical trial, placebo‐controlled, single centre, orthopaedic spine surgery Intervention: three groups receiving modified gelatin solution, hydroxyethyl starch 130/0.4 or Ringer lactate Fibrinogen concentrate (Hemocomplettan^®) was administered (30 mg/kg) to all three groups when fibrin polymerisation was critically decreased as evaluated by thromboelastometry (ROTEM) Population: 61 patients undergoing spine surgery of more than three segments with an expected duration of surgery of longer than 3 hours Outcomes: allogeneic blood products transfused; estimated intraoperative blood loss; maximum clot firmness measured by FIBTEM Findings: fibrin/fibrinogen polymerisation is disturbed because of dilution, especially in participants receiving hydroxyethyl starch 130/0.4. This effect may be reversed by fibrinogen concentrate Reason for exclusion: Fibrinogen concentrate was not given in accordance with randomization. In this trial, it served as a rescue treatment to correct dilutional coagulopathy and was given to all three groups
Morrison 2011	Case report, elective vascular surgery Three patients undergoing elective type IV thoracoabdominal aortic aneurysm treatment. Patients were treated with continuous infusion of fibrinogen concentrate (mean dose, 13.3 g) guided by FIBTEM maximum clot firmness Findings: despite blood loss of up to 11 L, no need for FFP and cryoprecipitate transfusion Reason for exclusion: non‐RCT
Rahe‐Meyer 2009	Prospective interventional cohort study non‐randomized and non‐blinded, single centre, elective aortic valve operation and ascending aorta replacement surgery Fifteen participants included: standard treatment algorithm based on ROTEM (group with five participants) compared with a group receiving fibrinogen concentrate before standard treatment targeting ROTEM/FIBTEM CF > 22 mm (group with ten participants). Increased risk of all types of bias Findings: FIBTEM‐guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 hour postoperative bleeding Reason for exclusion: non‐RCT
Rahe‐Meyer 2009a	Prospective interventional cohort study with a retrospective control group, single centre, elective thoracoabdominal aortic aneurysm surgery Retrospective control group (12 participants) with perioperative clinically relevant diffuse bleeding after weaning from cardiopulmonary bypass treated with allogeneic blood products according to predetermined algorithm Prospective intervention group (6 participants) treated with fibrinogen concentrate guided by thromboelastometry (ROTEM), in addition to the algorithm Findings: administration of 7.8 ± 2.7 g of fibrinogen concentrate established haemostasis, completely avoiding intraoperative transfusion of FFP and PLT. Lower 24 hour drainage volume in fibrinogen group Reason for exclusion: non‐RCT
Schöchl 2010a	Case report, trauma setting A severely injured patient with multiple trauma with massive blood loss. Patient receiving haemostatic therapy with coagulation factor concentrates, guided by thromboelastometry (ROTEM) Initial therapy consisted of fibrinogen concentrate Findings: suggest successful haemostatic treatment with fibrinogen concentrate and prothrombin complex concentrate, minimizing the need for allogeneic blood products Reason for exclusion: non‐RCT
Schöchl 2010b	Retrospective noncontrolled cohort study, single centre, trauma setting The cohort consists of 128 trauma patients receiving at least five units of RBC within the first 24 hours after arrival at trauma centre. Patients who died in the first hour after admission and patients who received no haemostatic therapy within the first 24 hours were excluded. Evaluation of goal‐directed coagulation management using thromboelastometry (ROTEM) with guided administration of fibrinogen concentrate and prothrombin complex concentrate Findings: Thromboelastometry was rapid and reliable for diagnosing coagulopathy and guiding transfusion of concentrates. First‐line fibrinogen concentrate and prothrombin complex concentrate seemed efficacious and quick to administer Reason for exclusion: non‐RCT
Solomon 2010	Retrospective noncontrolled study, single centre, cardiovascular surgery Aimed to assess fibrinogen recovery parameters after administration of fibrinogen concentrate. 39 patients with diffuse bleeding in relation to cardiovascular surgery and treated with fibrinogen concentrate. Patients with concomitant administration of FFP or with non‐elective or emergency intervention, age younger than 18 and terminal illness were excluded. Dosing of fibrinogen concentrate was guided by FIBTEM thromboelastometry Findings: Fibrinogen concentrate effectively increased plasma fibrinogen level. Suggests a favourable survival Reason for exclusion: non‐RCT
Thorarinsdottir 2010	Retrospective non‐controlled study, single centre, mixed patient population 37 patients receiving fibrinogen concentrate were identified using hospital database. If repeated dosage was necessary as well as recombinant factor VIIa, patients were excluded. Fibrinogen was administered when standard treatment was deemed to have failed to control the bleeding, aiming to maintain fibrinogen level above 1.5 g/L Findings: Administration of fibrinogen in the context of severe haemorrhage was associated with increased fibrinogen concentration. A significant decrease in RBC transfusions was identified after fibrinogen administration (but no control group) Reason for exclusion: non‐RCT
Weinkove 2007	Retrospective non‐controlled cohort study, single centre, mixed patient population 30 patients receiving fibrinogen concentrate in treatment of acquired hypofibrinogenaemia Findings: Fibrinogen concentrate is well suited for fibrinogen substitution Reason for exclusion: non‐RCT

Trial name or title	Fibrinogen Concentrate (FGTW) in Trauma Patients, Presumed to Bleed (FI in TIC)
Methods	Randomized double‐blind parallel‐assigned multicentre clinical trial
Participants	Inclusion criteria: adult trauma patients > 18 years, with major or occult bleeding, indicating shock and need of volume replacement therapy Exclusion criteria: penetrating trauma. Solely head injury. Hemodynamic instability (patient has to be excluded if haemodynamic stabilisation (SBP below 90 mmHg and HR more than 100 per min) is not achieved after 15 minutes of resuscitation management in spite of volume therapy and administration of catecholamines). Patient with inevitable lethal course as evaluated by emergency physician. Need for CPR on the scene. Deep hypothermia (below 30°C). Obviously pregnant women. Known recent history of thromboembolic events within the last 6 months. Patients receiving anticoagulant therapy
Interventions	Intervention group: infusion of 50 mg/kg body weight fibrinogen concentrate (FGTW/Clottafact^®－LFB)－one vial for each 30 kg body weight, estimated by the emergency physician: Body weight: < 30 kg/30 to 60 kg/60 to 90 kg/> 90 kg No. of vials: 1 vial (100 mL)/2 vials (200 mL)/3 vials (300 mL)/4 vials (400 mL) Fibrinogen (if applicable): 1.5 g/3 g/4.5 g/6 g Control group: placebo (a buffer substance consisting of mannitol/sucrose/sodium chloride/polysorbate 80) Infusion of one vial including 100 mL for each 30 kg body weight The flow rate should not exceed 100 mL within 5 minutes
Outcomes	Primary outcome measure: change in the fibrinogen polymerisation measured with FIBTEM^® MCF at average 60 min (arrival at hospital) post infusion Further measurements and investigations will be done until 7 days after the hospital admission and final at 30 days
Starting date	October 2011
Contact information	Pamela Schech, pamela.schech@i‐med.ac.at
Notes	Estimated enrolment: 60 participants, by 22 May, 6 participants included. The study is currently recruiting participants Participating hospitals: (Austria) Medical University Innsbruck, Emergency Hospital Salzburg, PMU Salzburg, Regional Hospital Vöcklabruck, Medical University Graz Contacted 3 April 2012 and again 22 May 2012; reply 22 May 2012 Funding: US Department of Defence. LFB provides medicine and placebo‐drug together with unrestricted grant

Trial name or title	Fibrinogen for Treatment of Pediatric Dilutional Coagulopathy: FibPaed Study
Methods	Randomized single‐blinded parallel‐assigned single‐centre clinical trial
Participants	Inclusion criteria: children aged 6 months to 17 years scheduled for elective scoliosis surgery or major craniofacial surgery presenting with intraoperative hypofibrinogenaemia according to definition of treatment groups Exclusion criteria: preexisting congenital or acquired coagulation disorder. Medical history of estimated increased bleeding tendency. Ongoing coagulation therapy. Clinical signs or diagnosis of acute thromboembolism. Intolerance of study drug. Pregnant or lactating women. Participation in another clinical trial
Interventions	Intervention group: fibrinogen concentrate (Haemocomplettan P, CSL Behring, 30 mg/kg body weight) over 15 min Repetition if hourly intraoperative ROTEM measurements revealed hypofibrinogenaemia according to treatment group definition (administration of fibrinogen concentrate if ROTEM FIBTEM revealed MCF < 13 mm) Control group: fibrinogen concentrate (Haemocomplettan P, CSL Behring, 30 mg/kg body weight) over 15 min Repetition if hourly intraoperative ROTEM measurements revealed hypofibrinogenaemia according to treatment group definition (administration of fibrinogen concentrate if ROTEM FIBTEM revealed MCF < 8 mm)
Outcomes	Primary outcome measures: total amount of transfused red cell concentrate at 24 hours after start of surgery Secondary outcome measures: coagulation measurements, length of stay on paediatric intensive care unit, additional transfusion/blood product requirements, occurrence of rebleeding, surgical revision, occurrence of (severe) adverse events
Starting date	January 2012
Contact information	Thorsten Haas, MD, thorsten.haas@kispi.uzh.ch
Notes	Estimated enrolments: 60 participants. The study is currently recruiting participants Collaborator/funding: independent Contacted 4 April; reply 4 April 2012 Participating hospitals: (Switzerland) University Children's Hospital, Zurich

Trial name or title	RETIC Trial: Reversal of Trauma Induced Coagulopathy Using Coagulation Factor Concentrates or Fresh Frozen Plasma
Methods	Single‐centre parallel open‐label randomized trial
Participants	Severely traumatized patients (ISS > 15) admitted to emergency department with obvious bleeding and/or at risk for significant haemorrhage will be screened by rotational thromboelastometry (ROTEM) assays during ED treatment and subsequent surgical/radiological interventions for having coagulopathy Inclusion criteria: Male and female patients ≥ 18 years and ≤ 80 years Major trauma (ISS > 15) Clinical signs of ongoing bleeding or at risk for significant haemorrhage as assessed and judged by the ED team in charge of the patient Presence of coagulopathy defined by ROTEM assays as follows: patients with concomitant decreased fibrinogen polymerisation (ROTEM^® FIBTEM A10 < 7 mm after 10 min). Patients with concomitant decreased coagulation factor levels (ROTEM^® EXTEM CT > 90 s) Exclusion criteria: Lethal injury CPR on the scene Isolated brain injury, burn injury Avalanche injury Administration of FFP or coagulation factor concentrates before ED admission Delayed (> 6 hours after trauma) admittance to ED Known use of oral anticoagulants or platelet aggregation inhibitors within 5 days before injury Known history of severe allergic reaction to plasma products Known history of congenital haemostasis disturbance, IgA or protein C deficiency Patients with a history of thromboembolic events or heparin‐induced thrombocytopenia (HIT) type 2 within the past year Patients with body weight < 45 kg and > 150 kg Patients known to be pregnant Jehova's Witness Known participation in another clinical trial Patient with known refusal of participation in this clinical trial
Interventions	Intervention group: receives fibrinogen concentrate and/or prothrombin complex concentrate (PCC) and/or FXIII concentrate If FIBTEM A10 < 7 mm: fibrinogen concentrate (RiaSTAP^®/CLS Behring) dose at 50 mg/kg body weight intravenously as single dose or repeated, each single vial (1 g) over 5 min If EXTEM CT > 90 s and FIBTEM A10 > 7 mm: prothrombin complex concentrate dose at 20 IE/kg body weight PCC intravenously as single dose or repeated, each single dose over 10 min If FXIII decreases below 60% as detected by laboratory measurements: FXIII concentrate dose at 20 IU/kg body weight Fibrogammin^® P administered with the second dose of fibrinogen concentrate (100 mg/kg) intravenously as single dose or repeated, each single dose over 10 min Control group: fresh frozen plasma (FFP) blood type 0, A, B and AB If FIBTEM A10 < 7 mm and/or EXTEM CT > 90 s: fresh frozen plasma dose of 15 mL/kg body weight intravenously as single dose or repeated, each single U (200 mL) over 5 min Additional treatment/rescue treatment: Treatment failure will be registered if bleeding persists and ROTEM parameters do not improve after two times dosages of study drug. In these cases, haemostatic rescue therapy will be administered. CFC (fibrinogen concentrate and/or PCC, and/or FXIII concentrate) will be administered to participants randomly assigned to receive FFP, and FFP will be administered to participants in the CFC group. In cases unresponsive to comprehensive treatment or normal ROTEM combined with diffuse bleeding, other haemostatic medications can be administered (e.g. rFVIIa, DDAVP, VWF/FVIII concentrate) as judged by the anaesthetist in charge. The need for and type of any rescue therapy will be documented, and ROTEM will be performed thereafter
Outcomes	Multiple organ failure (MOF) until 24 h on ICU Difference between treatment groups in MOF as assessed by the Sequential Organ Failure Assessment score (SOFA)
Starting date	March 2012
Contact information	Petra Innerhofer, MD, petra.innerhofer@uki.at
Notes	Estimated enrolment: 200 participants. The study is currently recruiting participants Participating hospital: University Hospital Innsbruck Contacted 3 April 2012; reply 3 April 2012 Relation to the industry: independent

Trial name or title	Fibrinogen and Bleeding After Cardiac Surgery (Fibro‐3)
Methods	Randomized double‐blind placebo‐controlled parallel‐assigned single‐centre study
Participants	Inclusion criteria: adults 18 to 85 years eligible for first‐time coronary artery bypass (CABG) surgery with a preoperative fibrinogen plasma concentration less than 3.8 g/L Exclusion criteria: patients undergoing re‐do surgery. Clinical or laboratory signs of bleeding disorder, liver disease or other significant disease/condition, which in the investigators' judgment interferes with haemostasis. Any medications with agents that may interfere with haemostasis within 14 days before study start. Clopidogrel and warfarin are withdrawn at least 24 hours before surgery. Oral aspirin is allowed as co‐medication. Administration of other investigational drugs within eight weeks before the pre‐entry examination. Pregnant or lactating women
Interventions	Intervention group: fibrinogen concentrate 2 g (RiaSTAP^®, CSL Behring) in 100 mL sterile water Control group: (placebo) saline 100 mL Administration during a period of 15 minutes after induction of anaesthesia and before start of surgery. Pharmacist randomly assigns and dispenses the medicine
Outcomes	Primary outcome measures: to evaluate safety of prophylactic fibrinogen infusion in patients with fibrinogen levels in the lower normal range undergoing cardiac surgery (2 years' follow‐up) Blood loss at first 12 postoperative hours Secondary outcome measures: transfusion requirements at 7 days. Biomarkers of coagulation, fibrinolysis and platelet function and pharmacoeconomic analysis
Starting date	April 2009
Contact information	Contact: Anders Jeppsson, MD, PhD, anders.jeppsson@vgregion.se
Notes	Same group behind Karlsson 2009 Estimated enrolment: 60 participants. The study is currently recruiting participants Contacted 14 March 2012 and again 22 May 2012; reply by phone 29 May 2012 Participating hospitals: Cardiothoracic Surgery Unit, Sahlgrenska University Hospital Funding/relation to the industry: independent

Trial name or title	Prospective Double Blinded Randomized Control Study of the Use of Fibrinogen in High‐Risk Cardiac Surgery
Methods	Randomized double‐blind placebo‐controlled parallel‐assigned single‐centre study
Participants	Inclusion criteria: adults, elective complex cardiac surgical procedures (double procedures re‐do sternotomies, thoraco‐abdominal aortic aneurysm, aortic root) Participants will be randomly assigned after protamine administration. Surgeon and anaesthetist have to agree on diffuse, non‐surgical bleeding Exclusion criteria: any known congenital or preexisting bleeding disorder, preexisting abnormal fibrinogen level (normal: 1.8 to 4.7 g/L), severe liver disease (alanine aminotransferase or aspartate aminotransferase > 150 U/L), inability to provide informed consent, emergency surgery, pregnancy or nursing, younger than 18 years, intake of anti‐platelet drugs within three days preoperatively (low‐dose ASA is allowed), allergy to concentrated fibrinogen or other components in the product, anaemia (Hgb < 110), diagnosed deep vein thrombosis (DVT), pulmonary embolism, acute stroke
Interventions	Intervention group: fibrinogen concentrate (Haemocomplettan P^®/CSL Behring) infused according to a haemostatic algorithm based on FIBTEM (MCF, maximum clot firmness) Control group: intravenous saline All syringes and tubing will be covered. A study nurse who is not involved in treatment of the participant will prepare the syringes
Outcomes	Primary outcome measure: the number of used blood products, including packed red cells, fresh frozen plasma, platelets and cryoprecipitate within 48 hours after surgery Secondary outcome measures: (one‐year follow‐up) fibrinogen levels, TEG (R‐value, K‐value, angle), CVICU stay, hospital stay, in‐hospital mortality, haemoglobin, adverse events (anaphylaxis, stroke, myocardial infarction, pulmonary embolism, and deep vein thromboembolism) and usage of factor VII concentrate and prothrombin complex concentrate
Starting date	Not yet recruiting
Contact information	Myron M Kwapisz, MD, myron.kwapisz@gmail.com, Heather E Mingo, RN, PhDc, heather.mingo@cdha.nshealth.ca
Notes	Information is based on clinical trials registration and contact with authors Estimated enrolment: 40 participants. Currently awaiting IRB approval Participating hospital: Halifax, Nova Scotia, Canada, B3H3A7 Funding/relation to the industry: collaborates with CSL Behring Contacted 20 March 2013; reply 22 March 2013

Trial name or title	Haemocomplettan^® P During Elective Complex Cardiac Surgery
Methods	Randomized double‐blind parallel‐assigned single‐centre clinical trial
Participants	Inclusion criteria: adults (> 18 years) undergoing elective complex cardiac surgery with clinically relevant non‐surgical microvascular bleeding after removal of cardiopulmonary bypass. Exclusion criteria: positive pregnancy test, pregnancy or lactation. Proof or suspicion of a congenital or acquired coagulation disorder. Emergency operation. Clopidogrel use in the 5 days preceding surgery. INR > 1.4 if on Coumadin
Interventions	Intervention group: fibrinogen concentrate (Haemocomplettan P^®/CSL Behring) Dose: study medication will be individually determined on the basis of plasma fibrinogen concentrations (measured with Clauss method during the reperfusion period on CPB) and body weight. Intravenous infusion within 10 minutes Control group: human albumin with concentration 200 g/L Study bottles of 50 mL will be diluted with saline and will contain 2 g in total. This concentration resembles the total protein load in the bottles with Haemocomplettan^® P
Outcomes	Primary outcome measure: perioperative blood loss within 12 hours (measured as blood loss in mL between infusion of study medication and closure of chest) Secondary outcome measures: postoperative blood loss (measured as blood loss at the ICU between closure of chest and 1st hour and 6th hour and after 24 hours). Postoperative transfusion requirements within 24 hours after closure of chest. Major clinical events: mortality at 30 days post‐surgery, MACE (major adverse cardiac event), cerebrovascular accident/ transient ischaemic attack, renal insufficiency or failure, venous thromboembolism/pulmonary embolism, allergic or other systemic reaction to study medication
Starting date	February 2011
Contact information	Marga Hoogendoorn, MSc, m.e.hoogendoorn@isala.nl
Notes	Estimated enrolment: 120 participants. The study is currently recruiting participants Participating hospitals: (Netherlands) Isala Klinieken, Zwolle, Overijssel Funding/relation to the industry: investigator initiated but receives study medication from industry Contacted 4 April 2012 and again 22 May 2012; reply 22 May 2012

Trial name or title	Fibrinogen as an Alternative to Fresh Frozen Plasma in Aortic Surgery
Methods	Randomized single‐blinded parallel‐assigned single‐centre clinical trial
Participants	Inclusion criteria: patients > 18 years undergoing elective thoracoabdominal aneurysm repair Exclusion criteria: previous aortic surgery (re‐do surgery). Emergency surgery. Pregnancy. Females of child‐bearing age (younger than 45 years) not using medically approved method of contraception. Congenital or acquired coagulopathy. Known allergy to study drug
Interventions	Intervention group: fibrinogen concentrate (Haemocomplettan P^®/CSL Behring) administered initially at 2 g per hour by continuous infusion. This rate will be adjusted in response to the clinical picture and results of point‐of‐care coagulation tests. The infusion will be used intraoperatively Control group: fresh frozen plasma (dose not described)
Outcomes	Primary outcome measures: pattern of coagulation disturbance intraoperatively and up to 24 hours postoperatively Secondary outcome measures: proportion of participants in the fibrinogen group requiring FFP during operation. Number of FFP units transfused－during surgery and up to 24 hours after surgery. Numbers of platelet and red blood cell units transfused－during surgery and up to 24 hours after surgery
Starting date	October 2009
Contact information	Alastair Nimmo, MBChB, a.nimmo@ed.ac.uk, University of Edinburgh
Notes	Estimated enrolment: 20 participants. Apparently not yet recruiting but registered in 2009 Collaborators: NHS Lothian and CSL Behring Participating hospitals: (United Kingdom) The Royal Infirmary of Edinburgh Funding/relation to the industry: yes, collaborates with CSL Behring Contacted 4 April 2012 and again 22 May 2012; no reply received

Trial name or title	The ZEro PLASma Trial (ZEPLAST): Avoidance of Fresh Frozen Plasma in Cardiac Surgery
Methods	Prospective randomized double‐blind comparative parallel‐assigned single‐centre clinical trial
Participants	Inclusion criteria: Combined cardiac operation with expected cardiopulmonary bypass(CPB) duration > 90 minutes At least one additional risk factor within the following: age > 65 years; non‐elective surgery; serum creatinine > 1.36 mg/dL; re‐do operation Exclusion criteria: Age < 18 years Patients receiving thienopyridines Known coagulopathy Known autoimmune disorders Participation in another RCT Pregnancy Emergency operation Baseline HCT < 35% Baseline antithrombin < 80% BSA < 1.7 m² Withdrawal/additional exclusion criterion (exclusion following randomization): Lowest HCT on CPB < 23% Transfusions during CPB Participants randomly assigned and not withdrawn will be given the investigational/place drugs in accordance with allocation All participants randomly assigned and not withdrawn will be tested 20 minutes before removal of aortic cross‐clamping with a thromboelastometric fibrinogen test ROTEM^®/FIBTEM
Interventions	Intervention group: fibrinogen concentrate (Haempcpmplettan P^®/CSL Behring) and prothrombin complex concentrate (PCC) (Confidex^®/CSL Behring) Dose fibrinogen: According to the formula based on ROTEM^®/FIBTEM test: (22 [mm] − MCF [mm]) * body weight [kg]/140 [m] = whole g fibrinogen Co‐intervention: After 15 min from study drug administration and in the presence of ongoing microvascular bleeding: ROTEM^®/EXTEM ‐ prolonged CT time (> 80 seconds): PCC at a weight‐based dose of 7 U/kg body weight Control group: (placebo) saline Study drugs or placebo has to be administered after protamine
Outcomes	Primary outcome measures: avoidance of allogeneic blood product transfusion within 30 days (packed red cells, FFP, platelet concentrates, cryoprecipitates)    Secondary outcome measures: reduction in allogeneic blood product transfusions within 30 days
Starting date	November 2011
Contact information	Marco Ranucci, MD, cardioanestesia@virgilio.it,
Notes	Estimated enrolment: 120 participants. 16 included by 4 April 2012 Participating hospitals: (Italy) IRCCS Policlinico San Donato Funding/relation to the industry: collaborates with CSL Behring Contacted 4 April 2012; reply 4 April 2012

Trial name or title	The Efficacy of the Administration of Fibrinogen in Liver Transplantation (FibstudLT)
Methods	Randomized placebo‐controlled double‐blind parallel‐assigned multi‐centre clinical trial
Participants	Inclusion criteria: patients who are candidates for liver transplantation with a value of pretransplant plasma fibrinogen less than 2.9 g/L Exclusion criteria: Patients with a value of fibrinogen in the 24 hours before the intervention greater than 2.9 g/L, known history of thromboembolic events in 30 days, known or suspected pregnancy, previous randomization in this trial, known or suspected allergy to trial products or related products, known presence of congenital bleeding disorder, patients treated with aspirin or warfarin. The following indications for transplantation: familial polyneuropathy, acute liver failure, biliary cirrhosis and sclerosing cholangitis, Budd‐Chiari syndrome. Heart beating donors and living donors
Interventions	Intervention group: fibrinogen concentrate (RiaSTAP^®/CSL Behring) will be administered until an expected plasmatic value of 2.9 g/L is achieved: The dose calculated as 1 g of fibrinogen to obtain an increase in plasma fibrinogen value of 0.29 g/L to reach a final value of 2.9 g/L Control group: (placebo) saline in same volume Administration before surgery starts, intravenous infusion for 10 minutes
Outcomes	Primary outcome measures: percentage of participants requiring transfusion of packed red blood cells during the procedure    Secondary outcome measures: Percentage of participants requiring intraoperative blood products other than red cell concentrates, number of units of fresh frozen plasma transfused during surgery, number of platelet units transfused during surgery, grams of fibrinogen administered during surgery, operative outcome until 4 weeks' follow‐up, operative mortality, liver graft survival. Thrombotic complications of all types and causes. Liver transplantation outcome at follow‐up 1 year
Starting date	March 2012
Contact information	Antoni Sabate, MD, asabatep@bellvitgehospital.cat
Notes	Estimated enrolment: 132 participants. The study is currently recruiting participants Participating hospitals: (Spain) Hospital de Cruces, Bilbao, Vizcaya, Hospital Universitari de Bellvitge, Barcelona, Hospital Clinic, Barcelona, Hospital Virgen de la Arrixaca, Murcia, Hospital Virgen del Rocio, Sevilla Funding/relation to the industry: independent of industry with institutional and governmental support Contacted 4 April 2012; reply 20 April 2012