Analyzing and modeling massive transfusion strategies and the role of fibrinogen-How much is the patient actually receiving?

BACKGROUND: Hemorrhage is a leading cause of preventable death in trauma, cardiac surgery, liver transplant, and childbirth. While emphasis on protocolization and ratio of blood product transfusion improves ability to treat hemorrhage rapidly, tools to facilitate understanding of the overall content of a specific transfusion strategy are lacking. Medical modeling can provide insights into where deficits in treatment could arise and key areas for clinical study. By using a transfusion model to gain insight into the aggregate content of massive transfusion protocols (MTPs), clinicians can optimize protocols and create opportunities for future studies of precision transfusion medicine in hemorrhage treatment. METHODS: The transfusion model describes the individual round and aggregate content provided by four rounds of MTP, illustrating that the total content of blood elements and coagulation factor changes over time, independent of the patient's condition. The configurable model calculates the aggregate hematocrit, platelet concentration, percent volume plasma, total grams and concentration of citrate, percent volume anticoagulant and additive solution, and concentration of clotting factors: fibrinogen, factor XIII, factor VIII, and von Willebrand factor, provided by the MTP strategy. RESULTS: Transfusion strategies based on a 1:1:1 or whole blood foundation provide between 13.7 and 17.2 L of blood products over four rounds. Content of strategies varies widely across all measurements based on base strategy and addition of concentrated sources of fibrinogen and other key clotting factors. DISCUSSION: Differences observed between modeled transfusion strategies provide key insights into potential opportunities to provide patients with precision transfusion strategy.

Effects of Fibrinogen Concentrate Supplementation on Postoperative Bleeding in Infants Undergoing Complex Cardiac Surgery.

The use of allogeneic blood products to restore hemostasis during pediatric cardiac surgery is associated with major risks. Consequently, there has been a growing interest in new patient blood management strategies, such as those based on the use of fibrinogen concentrate (FC). Accumulating evidence has shown FC supplementation to be safe and effective. Nevertheless, no guidelines are available on using FC in the pediatric setting, and few objective evaluations have been provided in clinical practice. The endpoint of this monocenter retrospective study was the hemostatic effect of additional FC in infants undergoing complex cardiac surgery with cardiopulmonary bypass to manage persistent clinically relevant bleeding. After weaning from cardiopulmonary bypass and after protamine administration, patients were transfused with conventional allogeneic products such as packed red blood cells, fresh frozen plasma (FFP), and platelets. In the case of redo surgery, according to the institutional protocol, patients also received tranexamic acid. In case of clinically persistent relevant bleeding, according to the anesthesiologist's judgment and thromboelastography, patients received FC supplementation (group with FC) or further FFP transfusions without receiving FC supplementation (group without FC). The primary endpoint was the hemostatic effects of FC. Secondary endpoints were the functional hypofibrinogenemia threshold value (expressed as maximum amplitude fibrinogen, MA-Fib) and postoperative MA-Fib, fibrinogenemia, intraoperative transfusions, and adverse events (AEs). In total, 139 patients who underwent cardiac surgery with CPB and aged less than 2 years were enrolled: 70 patients received allogeneic blood products and FC supplementation (group FC); 69 patients received allogeneic products without FC supplementation (group without FC). Patients that received FC supplementation were characterized by a significantly longer time of extracorporeal circulation (p < 0.001) and aortic cross-clamping (p < 0.001), a significantly lower minimum temperature (p = 0.011), increased use of concentrated prothrombin complex (p = 0.016) and tranexamic acid (p = 0.010), and a significantly higher amount of packed red blood cells, platelets (p < 0.001) and fresh frozen plasma (p = 0.03). Postoperative bleeding and severe bleeding were not statistically different between patients treated with FC and those not treated with FC supplementation (p = 0.786 and p = 0.695, respectively); after adjustment, a trend toward reduced bleeding can be observed with FC (p = 0.064). Overall, 88% of patients with severe bleeding had MA-Fib < 10 mm; a moderate association between severe bleeding and MA-Fib (odds ratio 1.7, 95% CI 0.5-6.5, p = 0.425) was found. Increased MA-Fib and postoperative fibrinogen were higher in the FC group (p = 0.003 and p < 0.001, respectively) than in FFP. AEs in the FC group were comparable to those observed in less complicated surgeries. Our results suggest a potential role of FC in complex surgery in maintaining postoperative bleeding at a level comparable to less complicated surgical procedures and favoring the increase in postoperative MA-Fib and fibrinogen.

Safety and efficacy of fibrinogen concentrate in aortic arch surgery involving moderate hypothermic circulatory arrest.

OBJECTIVE: Bleeding is a common complication of cardiac surgery, especially aortic arch surgery involving moderate hypothermic circulatory arrest. Fibrinogen concentrate has been increasingly used to treat coagulopathic bleeding in cardiac surgery, although its effectiveness and safety are unknown. The aim of this prospective study was to investigate the safety and efficacy of fibrinogen concentrate in patients with acute type A aortic dissection. METHODS: From July 2020 to August 2021, 84 patients with acute type A aortic dissection who underwent emergency aortic arch surgery involving MHCA and whose intraoperative fibrinogen level was less than 1.5 g/L were included in this study. Fifty-four patients who were supplemented with fibrinogen concentrate were included in the FC treatment group. Thirty patients were included in the non-FC treatment group. The primary endpoints included the required volumes of individual allogeneic blood products (RBCs, FFP, and PC), volumes of cumulative drainage within 24 and 48 h, and total volumes after infusion of FC, as well as reoperation rates due to bleeding. The secondary endpoint for the study was the incidence of serious adverse events from the infusion of FC to day 45. The serious adverse events defined for the evaluation of the safety of FC were death, pulmonary embolism and other thromboembolic or ischaemic events. The clinical data, routine laboratory tests and plasma fibrinogen levels were obtained at 5 time points. RESULTS: We observed rapid increases in the plasma fibrinogen level and subsequent improvement in haemostasis after the administration of fibrinogen concentrate. The mean fibrinogen level increased from 1.36 ± 0.75 g/L to 2.91 ± 0.76 g/L in the fibrinogen concentrate treatment group. The patients in the fibrinogen concentrate treatment group demonstrated lower volumes of cumulative postoperative drainage and transfused allogeneic blood products than the nonfibrinogen concentrate treatment group. There were no serious adverse events in the fibrinogen concentrate treatment group during hospitalization. CONCLUSION: Fibrinogen concentrate was effective at increasing the plasma fibrinogen level and significantly reduced the volumes of transfused allogeneic blood products and blood loss in patients with aortic arch surgery. There were no serious adverse events in the patients who received fibrinogen concentrate treatment. PERSPECTIVE STATE: The safety and efficacy of fibrinogen concentrate were investigated in acute type A aortic dissection patients with aortic arch surgery. Fibrinogen concentrate was effective at increasing the plasma fibrinogen level and significantly reduced the volumes of transfused allogeneic blood products and blood loss; there were no serious adverse events in the patients who received fibrinogen concentrate treatment.

Rotational Thromboelastometry-Guided Use of Synthetic Blood Products in Cardiac Transplant Patients: A Retrospective Before-After Study.

OBJECTIVES: Viscoelastic hemostatic assays, such as rotational thromboelastometry (ROTEM), are used increasingly in cardiac surgery to guide transfusion decisions. After separation from cardiopulmonary bypass (CPB), achieving hemostasis rapidly is the main goal before chest closure. The authors hypothesized that introducing a ROTEM-guided factor- concentrate transfusion algorithm would reduce the duration from CPB separation to chest closure during cardiac transplantation. DESIGN: A retrospective cohort study of 21 patients before and 28 patients after implementation of the ROTEM-guided transfusion algorithm who underwent cardiac transplantation. SETTING: This single-center study was conducted at Saint Paul's Hospital, Vancouver, British Columbia, Canada. INTERVENTIONS: Using a ROTEM-guided factor-concentrate transfusion algorithm for cardiac transplant recipients. MEASUREMENT AND MAIN RESULTS: The primary outcome was the duration from CPB separation to chest closure analyzed using Mann-Whitney U tests. The secondary outcomes included the volume of postoperative chest tube drainage, packed red blood cell (pRBC) transfusion requirements within 24 hours of surgery, the incidence of adverse events, and the length of stay before and after introducing a ROTEM-guided factor-concentrate transfusion algorithm. After adjusting for confounders using multivariate linear regression analysis, using a ROTEM-guided factor-concentrate transfusion algorithm resulted in a significant decrease in time from CPB separation to skin closure of 39.4 minutes (-73.1 to 123.5 min, p = 0.016). For the secondary outcomes, the use of ROTEM-guided transfusion showed reductions in pRBC transfusion within 24 hours of surgery (-1.3 units, -2.7 to 0.1 units; p = 0.077) and chest tube bleeding (-0.44 mL, -0.96 to +0.083 mL; p = 0.097); however, neither was statistically significant after adjustment. The median hospital length of stay in the study group was lower by 3 days (13 days v 16) days; p = 0.048). CONCLUSION: The introduction of a ROTEM-guided factor-concentrate transfusion algorithm was associated with a significant reduction in time to chest closure after separation from CPB. Although it reduced the total hospital length of stay, there were no differences in mortality, major complications, or intensive care unit length of stay.

Effectiveness of Administration of Fibrinogen Concentrate as Prevention of Hypofibrinogenemia in Patients with Traumatic Brain Injury with a Higher Risk for Severe Hyperfibrinolysis: Single Center Before-and-After Study.

BACKGROUND: Coagulopathy is often observed in severe traumatic brain injury (sTBI), and hyperfibrinolysis (HF) is associated with a poor prognosis. Although the efficacy of fibrinogen concentrate (FC) in multiple trauma has been reported, its efficacy in sTBI is unclear. Therefore, we delineated severe HF risk factors despite fresh frozen plasma transfusion. Using these risk factors, we defined high-risk patients and determined whether FC administration to this group improved fibrinogen level. METHODS: In the first part of this study, successive adults with sTBI treated at our hospital between April 2016 and March 2019 were reviewed. Patients underwent transfusion as per our conventional protocol and were divided into two groups based on whether fibrinogen levels of ≥ 150 mg/dL were maintained 3-6 h after arrival to delineate the risk factors of severe HF. In the second part of the study, we conducted a before-and-after study in patients with sTBI who were at a higher risk for severe HF (presence of at least one of the risk factors identified in the first part of the study), comparing those treated with FC between April 2019 and March 2021 (FC group) with those treated with conventional transfusion before FC between April 2016 and March 2019. The primary outcome was maintenance of fibrinogen levels, and the secondary outcome was 30-day mortality. RESULTS: In the first part of the study, 78 patients were included. Twenty-three patients did not maintain fibrinogen levels ≥ 150 mg/dL. A D-dimer level on arrival > 50 µg/mL, a fibrinogen level on arrival < 200 mg/dL, depressed skull fracture, and multiple trauma were severe HF risk factors. In the second part, compared with 46 patients who were identified as being at high risk for severe HF but were not administered FC (non-FC group), fibrinogen levels ≥ 150 mg/dL 3-6 h after arrival were maintained in 14 of 15 patients in the FC group (odds ratio: 0.07; 95% confidence interval: 0.01-0.59). Although there were significant differences in fibrinogen levels, no significant differences were observed in terms of 30-day mortality between the groups. CONCLUSIONS: Coagulation abnormalities on arrival, severe skull fracture, and multiple trauma are severe HF risk factors. FC administration may contribute to rapid correction of developing hypofibrinogenemia.

Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia.

INTRODUCTION: Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC). AIM: This post-hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a- and hypofibrinogenaemia. METHODS: The analysis used data from the FORMA-01 (Phase 2), FORMA-02 and FORMA-04 (Phase 3) multinational, prospective, open-label studies in patients with a- and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA-01) and children (<12 years; FORMA-04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA-02 and FORMA-04 using an objective 4-point scale, with success defined as excellent/good. RESULTS: Median (range) age was 23 years for FORMA-01 (12-53; n = 22), 26.5 years for FORMA-02 (12-54; n = 25), and 6 years for FORMA-04 (1-10; n = 13). Mean PK parameters were lower for children (AUC, Cmax , IVR; p = .02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41 mg/kg (32.12-273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91 mg/kg (47.45-262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis. CONCLUSION: As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable.

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.

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.

Effects of pathogen reduction technology and storage duration on the ability of cryoprecipitate to rescue induced coagulopathies in vitro.

BACKGROUND: Fibrinogen concentrates and cryoprecipitate are currently used for fibrinogen supplementation in bleeding patients with dysfibrinogenemia. Both products provide an abundant source of fibrinogen but take greater than 10 min to prepare for administration. Fibrinogen concentrates lack coagulation factors (i.e., factor VIII [FVIII], factor XIII [FXIII], von Willebrand factor [VWF]) important for robust hemostatic function. Cryoprecipitate products contain these factors but have short shelf lives (<6 h). Pathogen reduction (PR) of cryoprecipitate would provide a shelf-stable immediately available adjunct containing factors important for rescuing hemostatic dysfunction. STUDY DESIGN AND METHODS: Hemostatic adjunct study products were psoralen-treated PR-cryoprecipitated fibrinogen complex (PR-Cryo FC), cryoprecipitate (Cryo), and fibrinogen concentrates (FibCon). PR-Cryo FC and Cryo were stored for 10 days at 20-24°C. Adjuncts were added to coagulopathies (dilutional, 3:7 whole blood [WB]:normal saline; or lytic, WB + 75 ng/ml tissue plasminogen activator), and hemostatic function was assessed by rotational thromboelastometry and thrombin generation. RESULTS: PR of cryoprecipitate did not reduce levels of FVIII, FXIII, or VWF. PR-Cryo FC rescued dilutional coagulopathy similarly to Cryo, while generating significantly more thrombin than FibCon, which also rescued dilutional coagulopathy. Storage out to 10 days at 20-24°C did not diminish the hemostatic function of PR-Cryo FC. DISCUSSION: PR-Cryo FC provides similar and/or improved hemostatic rescue compared to FibCon in dilutional coagulopathies, and this rescue ability is stable over 10 days of storage. In hemorrhaging patients, where every minute delay is associated with a 5% increase in mortality, the immediate availability of PR-Cryo FC has the potential to improve outcomes.

Congenital Fibrinogen Deficiency in India and Role of Human Fibrinogen Concentrate.

Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels (hypofibrinogenemia), absence of fibrinogen in circulation (afibrinogenemia), abnormal functioning (dysfibrinogenemia) or both reduced levels and abnormal functioning (hypodysfibrinogenemia) of fibrinogen. The decreased fibrinogen concentration in congenital fibrinogen deficiency necessitates fibrinogen replacement therapy with fresh frozen plasma, cryoprecipitate, or human fibrinogen concentrate. However, the use of fresh frozen plasma and cryoprecipitate is limited owing to their longer transfusion time, requirement of high doses, volume overload, risk of viral transmission, and other safety concerns. The availability of human fibrinogen concentrate has made it the preferred replacement alternative due to its reduced risk of viral transmission, smaller infusion volume, and accurate dosing. The hemostatic efficacy and safety of human fibrinogen concentrate in congenital fibrinogen deficiency is well established in the literature. We review the prevalence of congenital fibrinogen deficiency in India and the current role of human fibrinogen concentrate in its management.

Administration of fibrinogen concentrate combined with prothrombin complex maintains hemostasis in children undergoing congenital heart repair (a long-term propensity score-matched study).

BACKGROUND: Bleeding is a common problem in children with congenital heart disease undergoing major cardiac surgery requiring cardiopulmonary bypass (CPB). Little is known about optimal management with blood products. OBJECTIVE: To investigate clinical outcome and hemostatic effects of fibrinogen concentrate (FC) in combination with prothrombin complex concentrate (PCC) versus standard treatment with fresh frozen plasma (FFP) in children undergoing cardiac surgery. METHODS: For this single-institution cohort study, data on 525 children were analyzed. Propensity score matching in 210 children was applied to reduce the impact of various baseline characteristics. RESULTS: Three children treated with FC/PCC developed surgical site bleeding requiring surgical revision. One child developed central venous line-related thrombosis. Blood loss through chest tube drainage was independent of FC/PCC. Coagulation abnormalities were not present in any of these children. Time to extubation and ICU stay did not differ. In the FC/PCC group, children received (median, Q1, Q3) 52 mg/kg (32, 83) FC and 28IU/kg (13, 44) PCC. Fibrinogen concentration was comparable at baseline. On admission to the ICU, fibrinogen was higher in children receiving FC/PCC, namely, 232 mg/dL (196, 280), than in children receiving FFP (186 mg/dL, 149, 224; P < .001). On discharge from the ICU, values did not differ ((FC/PCC 416 mg/dL (288, 501)), non-FC/PCC 418 mg/dL (272, 585; P = 1.000)). CONCLUSION: FC/PCC was well tolerated and permitted hemostasis to be maintained, even in the very young. We were not able to detect a signal for inferiority of this treatment. We conclude that FC/PCC can safely replace FFP.

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future.

Hereditary fibrinogen disorders (HFD) are rare coagulation disorders. Even if the spectrum of symptoms is broad depending on the sub-type, bleeding is the most common complication. Of the available sources of fibrinogen replacement, fibrinogen concentrate provides a safer and more effective option to treat and prevent bleeding. Recent clinical trials on established and new fibrinogen concentrates have increased our knowledge on the clinical pharmacology of these products, pointing out possible age and weight differences for dose adjustment. The efficacy of fibrinogen infusions has been demonstrated, especially for the management of acute bleeding with an excellent response based on investigator rating. The target fibrinogen levels in the setting of both minor and major surgeries have been better specified. The safety has been confirmed with a low number of adverse events but there still remains concern over possible thrombotic risks. Pharmacological, clinical aspects and future perspectives on the utilization of fibrinogen concentrates in the treatment and prevention of bleeding in patients with HFD are reviewed.

The prophylactic use of fibrinogen concentrate in high-risk cardiac surgery.

BACKGROUND: Perioperative blood loss is a major contributor to morbidity and mortality in cardiac surgery. Plasma fibrinogen levels play an essential role in hemostasis and deplete quickly during hemorrhage. The objective of this study was to determine whether prophylactic fibrinogen concentrate administration lowers overall blood product transfusion requirements in high-risk cardiac surgery in patients with low fibrinogen plasma levels. METHODS: The study was performed in a prospective, randomized, and double-blinded design. The investigation included 62 patients undergoing elective, high-risk cardiac surgery. After weaning from cardiopulmonary bypass and reversal of heparin patients received either fibrinogen concentrate or placebo. The primary outcome variable was overall blood product usage 24 hours after intervention. RESULTS: The fibrinogen group received numerically fewer total units of blood products than the placebo group, but the difference was not statistically or clinically significant (for groups n = 27; n = 29 and 19 vs 37 units, respectively, P = .908). The overall transfusion rate in both groups was significantly lower than the institutional average suggested (fibrinogen group 26%, placebo group 28%). The fibrinogen group showed significantly higher fibrinogen levels (2.38 vs 1.83 g/L (end of surgery), P < .001; 3.33 vs 2.68 g/L (12 hours after intervention), P = .003) and improved viscoelastic coagulation parameters (FIBTEM MCF, 27 vs 23 mm, P = .022). CONCLUSION: This randomized, controlled trial demonstrates that point-of-care guided and prophylactic treatment with fibrinogen concentrate does not reduce transfusion of blood products in a setting of unexpectedly low transfusion rate as tested in this cohort, but may improve coagulation parameters in the setting of high-risk cardiac surgery.

The role of fibrinogen and fibrinogen concentrate in cardiac surgery: an international consensus statement from the Haemostasis and Transfusion Scientific Subcommittee of the European Association of Cardiothoracic Anaesthesiology.

To date, data regarding the efficacy and safety of administering fibrinogen concentrate in cardiac surgery are limited. Studies are limited by their low sample size and large heterogeneity with regard to the patient population, by the timing of fibrinogen concentrate administration, and by the definition of transfusion trigger and target levels. Assessment of fibrinogen activity using viscoelastic point-of-care testing shortly before or after weaning from cardiopulmonary bypass in patients and procedures with a high risk of bleeding appears to be a rational strategy. In contrast, the use of Clauss fibrinogen test for determination of plasma fibrinogen level can no longer be recommended without restrictions due to its long turnaround time, high inter-assay variability and interference with high heparin levels and fibrin degradation products. Administration of fibrinogen concentrate for maintaining physiological fibrinogen activity in the case of microvascular post-cardiopulmonary bypass bleeding appears to be indicated. The available evidence does not suggest aiming for supranormal levels, however. Use of cryoprecipitate as an alternative to fibrinogen concentrate might be considered to increase plasma fibrinogen levels. Although conclusive evidence is lacking, fibrinogen concentrate does not seem to increase adverse outcomes (i.e., thromboembolic events). Large prospective multi-centre studies are needed to better define the optimal perioperative monitoring tool, transfusion trigger and target levels for fibrinogen replacement in cardiac surgery.

Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial.

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.

Safety of Fibrinogen Concentrate and Cryoprecipitate in Cardiovascular Surgery: Multicenter Database Study.

OBJECTIVES: To investigate whether administering fibrinogen concentrate or cryoprecipitate is associated with increased postoperative thromboembolic events and improved mortality in patients undergoing thoracic aortic surgery. DESIGN: Multicenter retrospective cohort study using propensity-score analyses and multivariate logistic regression analysis to control for confounders. SETTING: Four hospitals (1 national cardiovascular center and 3 university hospitals). PARTICIPANTS: Patients undergoing thoracic aortic surgery with cardiopulmonary bypass between January 2010 and October 2012 (n = 1,047). INTERVENTIONS: Outcomes in patients treated with fibrinogen concentrate or cryoprecipitate (fibrinogen group) were compared with those who did not receive these products (no fibrinogen group) based on propensity-score matching. Multivariate logistic regression analysis then was performed to confirm the results. MEASUREMENTS AND MAIN RESULTS: Among 1,047 patients enrolled in this study, 247 patients received fibrinogen concentrate or cryoprecipitate. The median amount of administered fibrinogen was 3 g (interquartile range 2-4 g). Eighty-seven patients were excluded from the propensity-score matching because of missing data. Propensity-score-matched analysis showed no significant difference in the incidence of thromboembolic events or 30-day mortality rate between the groups. Multivariate analysis revealed that the fibrinogen group showed no significant difference in thromboembolic events (odds ratio 1.22; 95% confidence interval 0.76-1.95; p = 0.408) or mortality rate (odds ratio 0.44; 95% confidence interval 0.18-1.12; p = 0.081) compared with those in the no fibrinogen group. CONCLUSIONS: Administering fibrinogen concentrate or cryoprecipitate was associated with neither thromboembolic events nor 30-day mortality in patients undergoing thoracic aortic surgery. Administering fibrinogen concentrate or cryoprecipitate is safe and does not appear to increase thromboembolic events and mortality in thoracic aortic surgery patients.

Fibrinogen for the management of critical obstetric hemorrhage.

AIM: In cases of critical obstetric hemorrhage leading to extreme hypofibrinogenemia, fibrinogen is the marker that indicates the critical severity, and early fibrinogen supplementation centering on hemostatic resuscitation is a vital treatment to stabilize a catastrophic condition. In this review, we investigated the effect of fibrinogen level on hemostasis and what we can do to treat hypofibrinogenemia efficiently and improve patients' outcome. METHODS: We reviewed numerous articles related to hypofibrinogenemia in critical obstetric hemorrhage. Especially, we performed a systematic review on target value of fibrinogen for hemostasis and effectiveness of fibrinogen concentrate. We also reviewed the articles about the methods for early normalization of fibrinogen level such as tranexamic acid, massive transfusion protocol, and point-of-care testing. RESULTS: The target value of fibrinogen calculated by needs for massive transfusion was 200 mg/dL or 10 mm of A5FIBTEM . Although fibrinogen concentrate worked poorly on fibrinogen levels within the normal range, it improved the blood fibrinogen levels rapidly when it was administered to critical obstetric hemorrhage patients with serious hypofibrinogenemia. Hence, the volume of FFP transfused could be reduced along with a reduction in the frequency of pulmonary edema due to volume overload. CONCLUSION: The patient group for which fibrinogen concentrate works most effectively is cases with severe hypofibrinogenemia. Further research is required in the light of evidence. The essence of the transfusion algorithm in critical obstetric hemorrhage is to approach the target value for obtaining hemostasis, ensure an accurate and prompt grasp of the severity using point-of-care testing, introduce a massive transfusion protocol and use tranexamic acid.

Postauthorization safety study of Clottafact® , a triply secured fibrinogen concentrate in acquired fibrinogen deficiency: a prospective observational study.

BACKGROUND AND OBJECTIVES: A postauthorization safety study was performed between 2009 and 2012 to describe the use of Clottafact® in acquired fibrinogen deficiency in real-life medical practice in France. MATERIALS AND METHODS: One hundred and fifty patients were planned for 28 days of prospective follow-up after infusion. The analysis of this observational study was descriptive and performed according to the type of treatment (curative or preventive) and the origin of the bleed. RESULTS: One hundred and fifty-six patients (16-87 years) were included in 13 centres and treated in five different medical bleeding situations: postpartum (59), other gynaecological/obstetrical (6), trauma (34), liver (13), cardiovascular (23) and other various bleeding situations (21). The mean follow-up time was 18·9 ± 12·3 days. Two patients presented adverse drug reactions: one a pulmonary embolism and the other a four-site venous thromboembolic episode. All were serious with a dubious causal relationship with the study treatment. Efficacy data were collected as a secondary objective. In 150 patients receiving curative treatment, 117 of 159 infusions (73·6%) were considered as successful by the investigators, 35 as moderate (22%) and seven as no response (4·4%). CONCLUSION: The Clottafact® safety profile observed during the study matched the known profile of fibrinogen during use.

Utility of prothrombin complex concentrate as first-line treatment modality of coagulopathy in patients undergoing liver transplantation: A propensity score-matched study.

BACKGROUND: Transfusion management during liver transplantation (LT) is aimed at reducing blood loss and allogeneic transfusion requirements. Although prothrombin complex concentrate (PCC) has been used satisfactorily in various bleeding disorders, studies on its safety, and efficacy during LT are limited. METHODS: A retrospective chart review of adult patients who underwent living donor LT at a single institute between October 2016 and January 2018 was carried out. The safety and efficacy of PCC in reducing transfusion requirements intraoperatively in patients who received PCC were compared with patients who did not receive PCC. A propensity score-matching technique was used, at a 1:1 ratio, to remove selection bias. RESULTS: After completing the 1:1 propensity score-matched analysis, 60 pairs of patients were identified. The use of PCC was associated with significantly decreased red blood cell transfusion requirements (6.2 ± 4.1 vs 8.23 ± 5.18, P < 0.001) and fresh frozen plasma transfusion requirements (2.6 ± 2 vs 6.18 ± 4.1, P < 0.001). The number of patients developing postoperative hemorrhagic complications was higher in the non-PCC group. CONCLUSIONS: During LT, the use of PCC led to decreased transfusion requirements. No thromboembolic complications related to PCC were noted in this series.

Biochemical characterization, stability, and pathogen safety of a new fibrinogen concentrate (fibryga®).

Fibryga® is a new lyophilized fibrinogen concentrate for intravenous use for the treatment of congenital fibrinogen deficiency. fibryga® is produced from pooled human plasma and the final product is characterized by high purity, integrity, and pathogen safety. Functional activity of fibrinogen was demonstrated by cross-linking studies and thromboelastometry; integrity of the fibrinogen molecule was demonstrated by size exclusion chromatography and the detection of only trace amounts of activation markers in the final product. Pathogen safety of fibryga® was proved by downscaling studies for the two dedicated pathogen inactivation/removal steps, i.e. solvent detergent treatment and nanofiltration. Fibryga® is stable for at least three years when stored at room temperature. In conclusion, the performed studies demonstrated that fibryga® meets the requirements for a state-of-the-art fibrinogen concentrate, such as a satisfactory activity profile combined with a favorable pathogen safety profile and stability.