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Cost-effectiveness of Fibrinogen Concentrate vs Cryoprecipitate for Treating Acquired Hypofibrinogenemia in Bleeding Adult Cardiac Surgical Patients
Abrahamyan L, Tomlinson G, Callum J, Carcone S, Grewal D, Bartoszko J, Krahn M, Karkouti K
JAMA surgery. 2023
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Free full text
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Editor's Choice
Abstract
IMPORTANCE Excessive bleeding requiring fibrinogen replacement is a serious complication of cardiac surgery. However, the relative cost-effectiveness of the 2 available therapies-fibrinogen concentrate and cryoprecipitate-is unknown. OBJECTIVE To determine cost-effectiveness of fibrinogen concentrate vs cryoprecipitate for managing active bleeding in adult patients who underwent cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS A within-trial economic evaluation of the Fibrinogen Replenishment in Surgery (FIBERS) randomized clinical trial (February 2017 to November 2018) that took place at 4 hospitals based in Ontario, Canada, hospitals examined all in-hospital resource utilization costs and allogeneic blood product (ABP) transfusion costs incurred within 28 days of surgery. Participants included a subset of 495 adult patients from the FIBERS trial who underwent cardiac surgery and developed active bleeding and acquired hypofibrinogenemia requiring fibrinogen replacement. INTERVENTIONS Fibrinogen concentrate (4 g per dose) or cryoprecipitate (10 units per dose) randomized (1:1) up to 24 hours postcardiopulmonary bypass. MAIN OUTCOMES AND MEASURES Effectiveness outcomes included number of ABPs administered within 24 hours and 7 days of cardiopulmonary bypass. ABP transfusion (7-day) and in-hospital resource utilization (28-day) costs were evaluated and a multivariable net benefit regression model built for the full sample and predefined subgroups. RESULTS Patient level costs for 495 patients were evaluated (mean [SD] age 59.2 [15.4] years and 69.3% male.) Consistent with FIBERS, ABP transfusions and adverse events were similar in both treatment groups. Median (IQR) total 7-day ABP cost was CAD $2280 (US dollars [USD] $1697) (CAD $930 [USD $692]-CAD $4970 [USD $3701]) in the fibrinogen concentrate group and CAD $2770 (USD $1690) (IQR, CAD $1140 [USD $849]-CAD $5000 [USD $3723]) in the cryoprecipitate group. Median (interquartile range) total 28-day cost was CAD $38 180 (USD $28 431) $(IQR, CAD $26 350 [USD $19 622]-CAD $65 080 [USD $48 463]) in the fibrinogen concentrate group and CAD $38 790 (USD $28 886) (IQR, CAD $26 180 [USD $19 495]-CAD $70 380 [USD $52 409]) in the cryoprecipitate group. After exclusion of patients who were critically ill before surgery (11%) due to substantial variability in costs, the incremental net benefit of fibrinogen concentrate vs cryoprecipitate was positive (probability of being cost-effective 86% and 97% at $0 and CAD $2000 (USD $1489) willingness-to-pay, respectively). Net benefit was highly uncertain for nonelective and patients with critical illness. CONCLUSIONS AND RELEVANCE Fibrinogen concentrate is cost-effective when compared with cryoprecipitate in most bleeding adult patients who underwent cardiac surgery with acquired hypofibrinogenemia requiring fibrinogen replacement. The generalizability of these findings outside the Canadian health system needs to be verified.
PICO Summary
Population
A subset of patients enrolled in the FIBERS trial who underwent cardiac surgery and experienced bleeding resulting in acquired hyperfibrinogenemia (n= 495).
Intervention
Fibrinogen concentrate (n= 251).
Comparison
Cryoprecipitate (n= 244).
Outcome
Patient level costs were evaluated. Median (interquartile range (IQR)) total 7-day allogeneic blood product (ABP) cost was CAD $2,280 (US dollars [USD] $1,697) (CAD $930 [USD $692]-CAD $4,970 [USD $3,701]) in the fibrinogen concentrate group and CAD $2,770 (USD $1,690) (IQR, CAD $1,140 [USD $849]-CAD $5,000 [USD $3,723]) in the cryoprecipitate group. Median (IQR) total 28-day cost was CAD $38,180 (USD $28 431) (IQR, CAD $26,350 [USD $19,622]-CAD $65,080 [USD $48,463]) in the fibrinogen concentrate group and CAD $38,790 (USD $28,886) (IQR, CAD $26,180 [USD $19,495]-CAD $70,380 [USD $52,409]) in the cryoprecipitate group. After exclusion of patients who were critically ill before surgery (11%) due to substantial variability in costs, the incremental net benefit of fibrinogen concentrate vs. cryoprecipitate was positive (probability of being cost-effective 86% and 97% at $0 and CAD $2,000 (USD $1,489) willingness-to-pay, respectively). Net benefit was highly uncertain for nonelective and patients with critical illness.
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A Randomized Pilot Trial Assessing the Role of Human Fibrinogen Concentrate in Decreasing Cryoprecipitate Use and Blood Loss in Infants Undergoing Cardiopulmonary Bypass
Tirotta, C. F., Lagueruela, R. G., Gupta, A., Salyakina, D., Aguero, D., Ojito, J., Kubes, K., Hannan, R., Burke, R. P.
Pediatric Cardiology. 2022;43(7):1444-1454
Abstract
The objective of this study was to determine whether treatment with human fibrinogen concentrate decreases the need for component blood therapy and blood loss in neonate and infant patients undergoing cardiopulmonary bypass. Pediatric patients (N = 30) undergoing elective cardiac surgery were randomized to receive human fibrinogen concentrate or placebo following cardiopulmonary bypass termination. The primary endpoint was the amount of cryoprecipitate administered. Secondary endpoints included estimated blood loss during the 24 h post-surgery; perioperative blood product transfusion; effects of fibrinogen infusion on global hemostasis, measured by laboratory testing and rotational thromboelastometry; and adverse events. No clinically significant differences were identified in baseline characteristics between groups. A significantly lower volume of cryoprecipitate was administered to the treatment group during the perioperative period [median (interquartile range) 0.0 (0.0-0.0) cc/kg vs 12.0 (8.2-14.3) cc/kg; P < 0.0001] versus placebo. No difference was observed between treatment groups in blood loss, laboratory coagulation tests, use of other blood components, or incidence of adverse events. FIBTEM amplitude of maximum clot firmness values was significantly higher among patients treated with human fibrinogen concentrate versus placebo (P ≤ 0.0001). No significant differences were observed in post-drug HEPTEM, INTEM, and EXTEM results. Human fibrinogen concentrate (70 mg/kg) administered after the termination of cardiopulmonary bypass reduced the need for transfusion with cryoprecipitate in a neonate and infant patient population.ClinicalTrials.gov identifier: NCT02822599.
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Impact of cardiopulmonary bypass duration on efficacy of fibrinogen replacement with cryoprecipitate compared with fibrinogen concentrate: a post hoc analysis of the Fibrinogen Replenishment in Surgery (FIBRES) randomised controlled trial
Bartoszko J, Martinez-Perez S, Callum J, Karkouti K
British journal of anaesthesia. 2022
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Free full text
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Full text
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Editor's Choice
Abstract
BACKGROUND Coagulopathy in cardiac surgery is frequently associated with acquired hypofibrinogenaemia, which can be treated with either purified fibrinogen concentrate (FC) or cryoprecipitate. Because the latter is not purified and therefore contains additional coagulation factors, it is thought to be more effective for treatment of coagulopathy that occurs after prolonged cardiopulmonary bypass (CPB). We examined the impact of CPB duration on the efficacy of the two therapies in cardiac surgery. METHODS This was a post hoc analysis of the Fibrinogen Replenishment in Surgery (FIBRES) RCT comparing FC (4 g) to cryoprecipitate (10 U) in adult patients undergoing cardiac surgery and experiencing bleeding with acquired hypofibrinogenaemia (n=735). The primary outcome was allogeneic blood products transfused within 24 h after CPB. Subjects were stratified by CPB duration (≤120, 121-180, and >180 min). The interaction of treatment assignment with CPB duration was tested. RESULTS Subjects with longer CPB duration experienced more bleeding and transfusion. With CPB time ≤120 min (FC, n=134; cryoprecipitate, n=146), the ratio of least-squares means between the FC and cryoprecipitate groups for total allogeneic blood products at 24 h was 0.90 (one-sided 97.5% confidence interval [CI]: 0.00-1.12); P=0.004. For subjects with CPB time 121-180 min, it was 1.00 ([one-sided 97.5% CI: 0.00-1.22]; P=0.03], and for CPB time >180 min it was 0.91 ([one-sided 97.5% CI: 0.00-1.12]; P=0.005). Results were similar for all secondary outcomes, with no interaction between treatment and CPB duration for all outcomes. CONCLUSIONS The haemostatic efficacy of FC was non-inferior to cryoprecipitate irrespective of CPB duration in cardiac surgery. CLINICAL TRIAL REGISTRATION NCT03037424.
PICO Summary
Population
Adult patients undergoing cardiac surgery and experiencing bleeding with acquired hypofibrinogenaemia, enrolled in the FIBRES trial, across 11 centres in Canada (n= 735).
Intervention
Fibrinogen concentrate (FC), (n= 372).
Comparison
Cryoprecipitate (n= 363).
Outcome
The primary outcome was allogeneic blood products transfused within 24 hours after cardiopulmonary bypass (CPB). Patients with longer CPB duration experienced more bleeding and transfusion. With CPB time ≤120 min (FC, n= 134; cryoprecipitate, n= 146), the ratio of least-squares means between the FC and cryoprecipitate groups for total allogeneic blood products at 24 hours was 0.90 (one-sided 97.5% confidence interval (CI), [0.00, 1.12]). For patients with CPB time 121-180 min, it was 1.00 ([one-sided 97.5% CI [0.00, 1.22]), and for CPB time >180 min it was 0.91 ([one-sided 97.5% CI [0.00, 1.12]). Results were similar for all secondary outcomes, with no interaction between treatment and CPB duration for all outcomes.
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Does Intraoperative Fibrinogen Affect Blood Loss or Transfusion Practice After Aortic Arch Surgery: A Prematurely Ended Randomized Trial
Vlot EA, Hackeng CM, Aper SJA, Sonker U, Heijmen RH, van Dongen EPA, Noordzij PG
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2022;28:10760296221144042
Abstract
Cardiovascular surgery is often complicated by significant bleeding due to perioperative coagulopathy. The effectiveness of treatment with fibrinogen concentrate to reduce the perioperative blood transfusion rate after thoracic aortic replacement surgery in prior studies has shown conflicting results. Therefore, we conducted a double-blind randomized controlled trial to investigate if a single dose of intraoperative fibrinogen administration reduced blood loss and allogeneic transfusion rate after elective surgery for thoracic arch aneurysm with deep hypothermic circulatory arrest. Twenty patients were randomized to fibrinogen concentrate (N = 10) or placebo (N = 10). The recruitment of study patients was prematurely ended due to a low inclusion rate. Perioperative transfusion, 5-minute bleeding mass after study medication and postoperative blood loss were not different between the groups with fibrinogen concentrate or placebo. Due to small volumes of postoperative blood loss and premature study termination, a beneficial effect of fibrinogen concentrate on the number of blood transfusions could not be established. However, treatment with fibrinogen efficiently restored fibrinogen levels and clot strength to preoperative values with a more effective preserved postoperative thrombin generation capacity. This result might serve as a pilot for further multicenter studies to assess the prospective significance of automated and standardized thrombin generation as a routine assay for monitoring perioperative coagulopathy and its impact on short- and long-term operative results.
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Investigating the Effect of Fibrinogen Injection on Bleeding in Coronary Artery Bypass Surgery: A Clinical Trial
Javaherforoosh Zadeh F, Janatmakan F, Soltanzadeh M, Zamankhani M
Anesthesiology and pain medicine. 2019;9(4):e92165
Abstract
Background: Prevention and optimal treatment of postoperative bleeding are of great clinical importance in various types of surgeries including coronary artery bypass graft (CABG). Reducing the amount of bleeding will reduce the complications subsequent to blood transfusion. The positive effects of coagulation factors, especially fibrinogen, after cardiovascular bypass could have beneficial effects due to reduced bleeding and less need for blood transfusion. However, different studies have reported controversial findings. Objectives: The present study aimed to evaluate the effect of prophylactic administration of fibrinogen on blood loss in patients undergoing CABG surgery to achieve more accurate clinical outcomes. Methods: This was a double-blind randomized clinical trial conducted on 36 patients hospitalized in Ahvaz Imam Khomeini Hospital for coronary artery bypass graft. Patients were randomized to receive either fibrinogen concentrate (n = 18) or placebo (n = 18). Hemoglobin, hematocrit, international normalized ratio, prothrombin time, partial thromboplastin time, and fibrinogen were checked preoperatively. The transfusion of allogeneic blood components and the volume of blood loss were recorded and compared between the groups. Results: Prophylactic fibrinogen injection reduced the need for blood transfusion, blood products, and postoperative hypotension in the fibrinogen group when compared to the control group (P ≤ 0.005). There was a significant difference between the two groups in terms of the amount of bleeding during operation (P ≤ 0.005). Conclusions: Fibrinogen plays a key role in preventing and stopping the bleeding. Accordingly, fibrinogen decreases bleeding and the need for paced cell in patients in CABG. Given the adverse outcomes of bleeding and coagulopathy in patients undergoing surgery, we conclude that the use of fibrinogen could be beneficial as a prophylactic in hemorrhagic surgery.
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Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial
Morrison GA, Koch J, Royds M, McGee D, Chalmers RTA, Anderson J, Nimmo AF
Anaesthesia. 2018
Abstract
Major vascular surgery is frequently associated with significant blood loss and coagulopathy. Existing evidence suggests hypofibrinogenaemia develops earlier than other haemostatic deficiencies during major blood loss. The purpose of this study was to assess whether the use of an infusion of fibrinogen concentrate to prevent and treat hypofibrinogenaemia during surgery resulted in satisfactory haemostasis, removing or reducing the need for blood component transfusion. Twenty patients undergoing elective extent-4 thoraco-abdominal aortic aneurysm repair were randomly allocated to receive either fresh frozen plasma or fibrinogen concentrate to treat hypofibrinogenaemia during surgery. Coagulation was assessed during and after surgery by point-of-care and laboratory testing, respectively, and treatment was guided by pre-defined transfusion triggers. Despite blood losses of up to 11,800 ml in the patients who received the fibrinogen concentrate, none required fresh frozen plasma during surgery, and only two required platelet transfusions. The median (IQR [range]) allogeneic blood component administration during surgery and in the first 24 h postoperatively was 22.5 (14-28 [2-41]) units in patients allocated to fresh frozen plasma vs. 4.5 (3-11[0-17]) in patients allocated to fibrinogen concentrate (p = 0.011). All patients in both groups were assessed by the surgeon to have satisfactory haemostasis at the end of surgery. Mean (SD) postoperative fibrinogen concentrations were similar in patients allocated to fresh frozen plasma and fibrinogen concentrate (1.6 (0.3) g.l(-1) vs. 1.6 (0.2) g.l(-1) ; p = 0.36) but the mean (SD) international normalised ratio and activated partial thromboplastin time ratio were lower in patients allocated to fresh frozen plasma (1.1 (0.1) vs. 1.8 (0.3); p < 0.0001 and 1.1 (0.2) vs. 1.7 (0.5); p = 0.032, respectively). Fibrinogen concentrate may be used as an alternative to fresh frozen plasma in the treatment of coagulopathy during thoraco-abdominal aortic aneurysm repair.
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Preoperative supplementation with fibrinogen concentrate in cardiac surgery: a randomized controlled study
Jeppsson A, Walden K, Roman-Emanuel C, Thimour-Bergstrom L, Karlsson M
British Journal of Anaesthesia. 2016;116((2)):208-14.
Abstract
BACKGROUND Bleeding remains a severe complication in cardiac surgery. Several studies have found an association between the preoperative plasma concentration of fibrinogen and postoperative bleeding in cardiac surgery patients. This raises the question of whether preoperative supplementation with fibrinogen concentrate can reduce postoperative blood loss. METHODS An investigator-initiated, prospective, randomized double-blind placebo-controlled study, was performed in 48 low-risk, coronary artery bypass grafting patients. Subjects were randomized to infusion of 2 g fibrinogen or placebo immediately before surgery, after induction of anaesthesia. The primary endpoint was blood loss during the first 12 h postoperatively. Secondary endpoints included the proportion of transfused subjects, the number of transfused allogeneic blood products (red blood cells, plasma and platelets), and haemoglobin concentration after surgery. Student's t-test and Mann-Whitney U-test was used to compare continuous data and chi(2)-test to compare categorical data between groups. RESULTS Median postoperative bleeding was not significantly different between the fibrinogen and placebo groups [650 (25/75th percentile 500-835) ml compared with 730 (543-980) ml, P=0.29]. The proportion of transfused subjects (33 vs 29%, P=0.76), number of perioperative transfusions of allogeneic blood products (0 (0-2 vs 0 (0-3), P=0.76) and haemoglobin concentration 24 h after surgery (107 (sd 11) vs 100 (12) g L-1, P=0.07) were not significantly different between the fibrinogen and placebo group, respectively. CONCLUSION Preoperative supplementation with 2 g fibrinogen concentrate did not significantly influence postoperative bleeding, in coronary artery bypass grafting patients without documented hypofibrinogenaemia. CLINICAL TRIAL REGISTRATION NCT 00968045.Copyright © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy
Rahe-Meyer N, Levy JH, Mazer CD, Schramko A, Klein AA, Brat R, Okita Y, Ueda Y, Schmidt DS, Ranganath R, et al
British Journal of Anaesthesia. 2016;117((1)):41-51.
Abstract
BACKGROUND Single-dose human fibrinogen concentrate (FCH) might have haemostatic benefits in complex cardiovascular surgery. METHODS Patients undergoing elective aortic surgery requiring cardiopulmonary bypass were randomly assigned to receive FCH or placebo. Study medication was administered to patients with a 5 min bleeding mass of 60-250 g after separation from bypass and surgical haemostasis. A standardized algorithm for allogeneic blood product transfusion was followed if bleeding continued after study medication. RESULTS 519 patients from 34 centres were randomized, of whom 152 (29%) met inclusion criteria for study medication. Median (IQR) pretreatment 5 min bleeding mass was 107 (76-138) and 91 (71-112) g in the FCH and placebo groups, respectively (P=0.13). More allogeneic blood product units were administered during the first 24 h after FCH, 5.0 (2.0-11.0), when compared with placebo, 3.0 (0.0-7.0), P=0.026. Fewer patients avoided transfusion in the FCH group (15.4%) compared with placebo (28.4%), P=0.047. The FCH immediately increased plasma fibrinogen concentration and fibrin-based clot strength. Adverse event rates were comparable in each group. CONCLUSIONS Human fibrinogen concentrate was associated with increased allogeneic blood product transfusion, an unexpected finding contrary to previous studies. Human fibrinogen concentrate may not be effective in this setting when administered according to 5-minute bleeding mass. Low bleeding rates and normal-range plasma fibrinogen concentrations before study medication, and variability in adherence to the complex transfusion algorithm, may have contributed to these results. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier no. NCT01475669; EudraCT trial no. 2011-002685-20.
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Fibrinogen supplementation after cardiac surgery: insights from the Zero-Plasma trial (ZEPLAST)
Ranucci M, Baryshnikova E
British Journal of Anaesthesia. 2016;116((5):):618-23
Abstract
BACKGROUND Fibrinogen supplementation has been proposed both to prevent and treat postoperative bleeding in cardiac surgery. The optimal fibrinogen concentration trigger and target values and the fibrinogen concentrate dose required remain uncertain. This subanalysis of data from the Zero-Plasma Trial (ZEPLAST) assessed target fibrinogen values and the corresponding fibrinogen concentrate dose for supplementation. METHODS We performed a post hoc analysis of 116 subjects included in the randomized, placebo-controlled ZEPLAST trail. Data considered were fibrin-based thromboelastometry (FIBTEM) maximum clot firmness (MCF) determined by whole-blood thromboelastometry (ROTEM) before and after placebo or fibrinogen concentrate, Clauss fibrinogen concentration after placebo or fibrinogen concentrate, postoperative bleeding and severe bleeding (SB). The association between FIBTEM MCF and Clauss fibrinogen concentration was tested with linear regression analyses. The predictive value for SB of FIBTEM MCF and Clauss fibrinogen concentration was tested with receiver operating characteristic analyses. RESULTS There was a good association between FIBTEM MCF and Clauss fibrinogen concentration in the baseline study population (r2 = 0.66), which worsened in fibrinogen-supplemented subjects. Both FIBTEM MCF and Clauss fibrinogen concentration yielded a good discriminative power for SB (area under the curve 0.721 and 0.767, respectively). The negative predictive value for SB was 100% for a Clauss fibrinogen concentration of 287 mg dl-1 and 98% for an FIBTEM MCF of 14 mm. Based on these newly defined target values, the dose of fibrinogen concentrate needed would be 3 g lower than the dose used in ZEPLAST. CONCLUSIONS A dose of fibrinogen concentrate rarely exceeding 2 g might be sufficient to prevent bleeding in cardiac surgery.
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Fibrinogen concentrate as first-line therapy in aortic surgery reduces transfusion requirements in patients with platelet counts over or under 100x10(9)/L
Solomon C, Rahe-Meyer N
Blood Transfusion. 2015;13((2):):248-54.
Abstract
BACKGROUND Administration of fibrinogen concentrate, targeting improved maximum clot firmness (MCF) of the thromboelastometric fibrin-based clot quality test (FIBTEM) is effective as first-line haemostatic therapy in aortic surgery. We performed a post-hoc analysis of data from a randomised, placebo-controlled trial of fibrinogen concentrate, to investigate whether fibrinogen concentrate reduced transfusion requirements for patients with platelet counts over or under 100x10(9)/L. MATERIAL AND METHODS Aortic surgery patients with coagulopathic bleeding after cardiopulmonary bypass were randomised to receive either fibrinogen concentrate (n=29) or placebo (n=32). Platelet count was measured upon removal of the aortic clamp, and coagulation and haematology parameters were measured peri-operatively. Transfusion of allogeneic blood components was recorded and compared between groups. RESULTS After cardiopulmonary bypass, haemostatic and coagulation parameters worsened in all groups; plasma fibrinogen level (determined by the Clauss method) decreased by 43-58%, platelet count by 53-64%, FIBTEM maximum clot firmness (MCF) by 38-49%, FIBTEM maximum clot elasticity (MCE) by 43-54%, extrinsically activated test (EXTEM) MCF by 11-22%, EXTEM MCE by 25-41% and the platelet component of the clot by 23-39%. Treatment with fibrinogen concentrate (mean dose 7-9 g in the 4 groups) significantly reduced post-operative allogeneic blood component transfusion requirements when compared to placebo both for patients with a platelet count >100x10(9)/L and for patients with a platelet count <100x10(9)/L. DISCUSSION FIBTEM-guided administration of fibrinogen concentrate reduced transfusion requirements when used as a first-line haemostatic therapy during aortic surgery in patients with platelet counts over or under 100x10(9)/L.