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Background: Traumatic haemorrhage is common after severe injury, leading to disability and death. Cryoprecipitate, a source of fibrinogen, may improve outcomes for patients with traumatic haemorrhage., Objective: To investigate the effects of early fibrinogen supplementation in the form of 3 pools (15 units, approximately 6 g of fibrinogen) of cryoprecipitate on 28-day mortality., Design: A randomised, parallel-group, unblinded, multicentre, international trial and economic evaluation. Patients were randomised to either the intervention (early cryoprecipitate) or the comparator (standard major haemorrhage protocol) arm via opaque, sealed envelopes in the emergency department or the transfusion laboratory/blood bank. All analyses were performed on an intention-to-treat basis. A cost-effectiveness analysis was undertaken., Setting: Twenty-five major trauma centres in the UK and one level 1 trauma centre in the USA., Participants: Adults who had traumatic haemorrhage following severe injury requiring activation of the major haemorrhage protocol and had received a blood transfusion., Intervention: Early cryoprecipitate - 3 pools (equivalent to 15 single units of cryoprecipitate or 6 g of fibrinogen supplementation), infused as rapidly as possible, within 90 minutes of arrival at hospital in addition to standard major haemorrhage protocol or standard major haemorrhage protocol only., Main Outcome Measures: The primary outcome was all-cause mortality at 28 days. The secondary outcomes were all-cause mortality at 6 hours, 24 hours, 6 months and 12 months from admission; death from bleeding at 6 hours and 24 hours; transfusion requirements at 24 hours from admission; destination of participant at discharge; quality-of-life measurements (EuroQol-5 Dimensions, five-level version and Glasgow Outcome Scale) at discharge/day 28 and 6 months after injury; and hospital resource use up to discharge or day 28 (including ventilator-days, hours spent in critical care and inpatient stays)., Results: Eight hundred and five patients were randomised to receive the standard major haemorrhage protocol (control arm). Seven hundred and ninety-nine patients were randomised to receive an additional three pools of cryoprecipitate in addition to standard care (intervention arm). Baseline characteristics appeared well matched. Patients had a median age of 39 (interquartile range 26-55) years, and the majority (79%) were male. All-cause 28-day mortality ( n  = 1531 patients; intention to treat) was 25.3% in the intervention arm compared with 26.1% in the control arm (odds ratio 0.96; p  = 0.74)., Limitations: There was variability in the timing of cryoprecipitate administration, with overlap between the treatment arms, limiting the degree of intervention separation., Conclusions: There was no evidence that early empiric administration of high-dose cryoprecipitate reduced the risk of death in unselected patients with traumatic haemorrhage. There was also no difference in adverse events. The cost-effectiveness of the intervention was similar to that of standard care., Future Work: Research to evaluate if fibrinogen replacement is more beneficial for selected patients, for example those with low fibrinogen blood levels, is needed, as is further exploration of whether there is a difference in outcome according to mechanism of injury., Trial Registration: This trial is registered as ISRCTN14998314., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/57/02) and is published in full in Health Technology Assessment ; Vol. 28, No. 76. See the NIHR Funding and Awards website for further award information.

Objective: Knee osteoarthritis is the most common osteoarthritis and imposes a significant burden on patients' lives. Several treatment methods can promote cartilage repair to varying extents, but there are limited studies on the combined application of different treatments. The purpose of this study is to evaluate the clinical efficacy of microfracture combined with fibrinogen and platelet-rich plasma (PRP) under arthroscopic in treating knee osteoarthritis, so as to provide a basis for clinical treatment decisions., Method: A total of 113 patients with knee osteoarthritis who received orthopedic treatment from January 2021 to June 2022 were selected. They were divided into two groups according to whether they received fibrinogen and PRP treatment in addition to microfracture treatment. The two groups were analyzed to compare the differences in knee joint function and quality of life at different points., Results: The study compared changes in knee joint function scores and quality of life between the two groups after treatment and found that the quality of life of patients in the combined treatment group was significantly better than that of patients who received microfracture only (at 12-month follow-up, EuroQol-VAS scores were 64.32 ± 5.63 for the microfracture group (MFx) and 75.65 ± 8.57 for the fibrinogen combined with platelet-rich plasma-assisted microfracture group (FPRPA MFx); P = 0.015; at 24-month follow-up, EuroQol-VAS scores were 66.47 ± 5.18 for the MFx group and 79.40 ± 7.43 for the FPRPA MFx group, P = 0.022). There was also a strong correlation between patients' quality of life and knee joint function score index (IKDC score correlation coefficient r=-0.375, Lysholm score correlation coefficient r = 0.497, MOCART score correlation coefficient r = 0.579, VAS score correlation coefficient r = 0.242, T2 value correlation coefficient r=-0.293, P < 0.001). Age-stratified analysis of the patients in the microfracture combined with fibrinogen platelet-rich plasma treatment group showed that the effect of the combined treatment was more pronounced in elderly patients., Conclusions: The results of the study showed that compared with microfracture alone, microfracture combined with fibrinogen platelet-rich plasma therapy can further improve patients' knee joint-related function and their quality of life after treatment. The improvement was more obvious in elderly patients., (© 2024. The Author(s).)

This study analyzed the long-term effects of carrier-bound fibrin sealant (CBFS) following abdominal surgery by tracking patients for years post-application. From 2006 to 2022, patients who underwent this procedure were contacted via telephone. Those who died due to underlying diseases, natural causes, or refused the check-up were excluded from the study. After 11 years of follow-up, CBFS was observed in different forms on computed tomography scans in four patients. Our findings indicate that CBFS can persist for years after the procedure. While we cannot confirm any secondary effects, it appears that CBFS sponges are not resorbed within 12 weeks and can remain for many years post-implantation., (© 2024. Italian Society of Surgery (SIC).)

Human fibrinogen (FIB) has been clinically proven to be considerably effective for the treatment of postoperative bleeding, with reported cases of allergic reactions to human FIB being rare. Here, we report a case of an anaphylactic shock in 27-year-old patients with rheumatic heart valve disease who received a human FIB infusion during mitral valve replacement, aortic valve replacement, and tricuspid valve-shaping surgery. The patients showed generalised profuse sweating, a barely noticeable skin rash, faint pulse, systolic pressure < 50 mmHg, and a heart rate of 71 beats/min. We share insights from a case of severe allergy to human FIB infusion during cardiac surgery, through which we have gained experience in the processes of diagnosing and treating. This report aims to provide a preliminary summary of the characteristics of this case to serve as a reference for fellow clinicians., (© 2024. The Author(s).)

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., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Fibrinogen concentrate treatment is recommended for acute bleeding episodes in adult and pediatric patients with congenital and acquired fibrinogen deficiency. Previous studies have reported a low risk of thromboembolic events (TEEs) with fibrinogen concentrate use; however, the post-treatment TEE risk remains a concern. A retrospective evaluation of RiaSTAP ® /Haemocomplettan ® P (CSL Behring, Marburg, Germany) post-marketing data was performed (January 1986-June 2022), complemented by a literature review of published studies. Approximately 7.45 million grams of fibrinogen concentrate was administered during the review period. Adverse drug reactions (ADRs) were reported in 337 patients, and 81 (24.0%) of these patients experienced possible TEEs, including 14/81 (17.3%) who experienced fatal outcomes. Risk factors and the administration of other coagulation products existed in most cases, providing alternative explanations. The literature review identified 52 high-ranking studies with fibrinogen concentrate across various clinical areas, including 26 randomized controlled trials. Overall, a higher number of comparative studies showed lower rates of ADRs and/or TEEs in the fibrinogen group versus the comparison group(s) compared with those that reported higher rates or no differences between groups. Post-marketing data and clinical studies demonstrate a low rate of ADRs, including TEEs, with fibrinogen concentrate treatment. These findings suggest a favorable safety profile of fibrinogen concentrate, placing it among the first-line treatments effective for managing intraoperative hemostatic bleeding.

In this research, we introduced a novel strategy for fabricating cell sheets (CSs) prepared by simply adding a fibrinogen solution to growth medium without using any synthetic polymers or chemical agents. We confirmed that the fibrinogen-based CS could be modified for target tissue regardless of size, shape, and cell types. Also, fibrinogen-based CSs were versatile and could be used to form three-dimensional (3D) CSs such as multi-layered CSs and those mimicking native blood vessels. We also prepared fibrinogen-based spheroid sheets for the treatment of ischemic disease. The fibrinogen-based spheroid sheets had much higher in vitro tubule formation and released more angiogenic factors compared to other types of platform in this research. We transplanted fibrinogen-based spheroid sheets into a mouse hindlimb ischemia model and found that fibrinogen-based spheroid sheets showed significantly improved physiological function and blood perfusion rates compared to the other types of platform in this research., (© 2023 IOP Publishing Ltd.)

There is a lack of evidence evaluating cryoprecipitate transfusion in severe postpartum haemorrhage. We performed a pilot cluster-randomised controlled trial to evaluate the feasibility of a trial on early cryoprecipitate delivery in severe postpartum haemorrhage. Pregnant women (>24 weeks gestation), actively bleeding within 24 h of delivery and who required at least one unit of red blood cells were eligible. Women declining transfusion in advance or with inherited clotting deficiencies were not eligible. Four UK hospitals were randomly allocated to deliver either the intervention (administration of two pools of cryoprecipitate within 90 min of first red blood cell unit requested plus standard care), or the control group treatment (standard care, where cryoprecipitate is administered later or not at all). The primary outcome was the proportion of women who received early cryoprecipitate (intervention) vs. standard care (control). Secondary outcomes included consent rates, acceptability of the intervention, safety outcomes and preliminary clinical outcome data to inform a definitive trial. Between March 2019 and January 2020, 199 participants were recruited; 19 refused consent, leaving 180 for analysis (110 in the intervention and 70 in the control group). Adherence to assigned treatment was 32% (95%CI 23-41%) in the intervention group vs. 81% (95%CI 70-90%) in the control group. The proportion of women receiving cryoprecipitate at any time-point was higher in the intervention (60%) vs. control (31%) groups; the former had fewer red blood cell transfusions at 24 h (mean difference -0.6 units, 95%CI -1.2 to 0); overall surgical procedures (odds ratio 0.6, 95%CI 0.3-1.1); and intensive care admissions (odds ratio 0.4, 95%CI 0.1-1.1). There was no increase in serious adverse or thrombotic events in the intervention group. Staff interviews showed that lack of awareness and uncertainty about study responsibilities contributed to lower adherence in the intervention group. We conclude that a full-scale trial may be feasible, provided that protocol revisions are put in place to establish clear lines of communication for ordering early cryoprecipitate in order to improve adherence. Preliminary clinical outcomes associated with cryoprecipitate administration are encouraging and merit further investigation., (© 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

The continuous activation and expansion of tumor-specific T cells by various means are the main goal of cancer immunotherapy. Tumor cells overexpress fibrinogen-like protein 1 (FGL1) and programmmed death-ligand 1 (PD-L1), which respectively bind to lymphocyte-activation gene 3 (LAG-3) and programmmed death-1(PD-1) on T cells, forming important signaling pathways (FGL1/LAG-3 and PD-1/PD-L1) that negatively regulate immune responses. In order to interfere with the inhibitory function of FGL1 and PD-L1 proteins, we designed a new type of reactive oxygen species (ROS)-sensitive nanoparticles to load FGL1 siRNA (siFGL1) and PD-L1 siRNA (siPD-L1), which was formed from a stimuli-responsive polymer with a poly-l-lysine-thioketal and modified cis-aconitate to facilitate endosomal escape. Moreover, tumor-penetrating peptide iRGD and ROS-responsive nanoparticles were co-administered to further enhance the delivery efficiency of siFGL1 and siPD-L1, thereby significantly reducing the protein levels of FGL1 and PD-L1 in tumor cells. Our findings indicated that the dual delivery of FGL1/PD-L1 siRNA was a new and powerful treatment method, which was characterized by increasing the infiltration of effector CD4+ and CD8+ T cells, effectively alleviating the tumor immunosuppressive microenvironment. These findings also supported the superiority and feasibility of nanoparticle-mediated tumor immunotherapy, and may provide a different perspective for cancer treatment. STATEMENT OF SIGNIFICANCE: In addition to the idea that cancer vaccines can promote T cell immune responses, nanoparticle delivery modulators (such as small interfering RNA (siRNA) targeting immunosuppressive pathways) may provide more information for the research of nanoparticle-mediated cancer immunotherapy. In this study, we designed a new intelligent nano-delivery system for co-delivery of siFGL1 and siPD-L1, and demonstrated the ability to down-regulate the expression levels of FGL1 and PD-L1 proteins in tumor cells in vitro and in vivo. The constructed nanoparticle had a good tumor microenvironment responsiveness, and the delivery efficiency was enhanced by co-injection with tumor penetrating peptide iRGD. This project proposed a new strategy for tumor immunotherapy based on smart nano-delivery systems, and explored more possibilities for tumor therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the clinical effects of early administration of fibrinogen concentrate in patients with severe trauma and hypofibrinogenemia., Methods: We conducted an open randomized feasibility trial between December 2015 and January 2017 in patients with severe trauma admitted to the emergency department of a large trauma center. Patients presented with hypotension, tachycardia, and FIBTEM findings suggestive of hypofibrinogenemia. The intervention group received fibrinogen concentrate (50 mg/kg), and the control group did not receive early fibrinogen replacement. The primary outcome was feasibility assessed as the proportion of patients receiving the allocated treatment within 60 min after randomization. The secondary outcomes were transfusion requirements and other exploratory outcomes. Randomization was performed using sequentially numbered and sealed opaque envelopes. ClinicalTrials.gov: NCT02864875., Results: Thirty-two patients were randomized (16 in each group). All patients received the allocated treatment within 60 min after randomization (100%, 95% confidence interval, 86.7%-100%). The median length of intensive care unit stay was shorter in the intervention group (8 days, interquartile range [IQR] 5.75-10.0 vs. 11 days, IQR 8.5-16.0; p=0.02). There was no difference between the groups in other clinical outcomes. No adverse effects related to treatment were recorded in either group., Conclusion: Early fibrinogen replacement with fibrinogen concentrate was feasible. Larger trials are required to properly evaluate clinical outcomes.

Objective: To assess the benefits and safety of early human fibrinogen concentrate in postpartum haemorrhage (PPH) management., Design: Multicentre, double-blind, randomised placebo-controlled trial., Setting: 30 French hospitals., Population: Patients with persistent PPH after vaginal delivery requiring a switch from oxytocin to prostaglandins., Methods: Within 30 minutes after introduction of prostaglandins, patients received either 3 g fibrinogen concentrate or placebo., Main Outcome Measures: Failure as composite primary efficacy endpoint: at least 4 g/dl of haemoglobin decrease and/or transfusion of at least two units of packed red blood cells within 48 hours following investigational medicinal product administration. Secondary endpoints: PPH evolution, need for haemostatic procedures and maternal morbidity-mortality within 6 ± 2 weeks after delivery., Results: 437 patients were included: 224 received FC and 213 placebo. At inclusion, blood loss (877 ± 346 ml) and plasma fibrinogen (4.1 ± 0.9 g/l) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the fibrinogen and placebo groups, respectively (odds ratio [OR] = 0.99) after adjustment for centre and baseline plasma fibrinogen; (95% CI 0.66-1.47; P = 0.96). No significant differences in secondary efficacy outcomes were observed. The mean plasma FG was unchanged in the Fibrinogen group and decreased by 0.56 g/l in the placebo group. No thromboembolic or other relevant adverse effects were reported in the Fibrinogen group versus two in the placebo group., Conclusions: As previous placebo-controlled studies findings, early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs or postpartum anaemia, but did prevent plasma fibrinogen decrease without any subsequent thromboembolic events., Tweetable Abstract: Early systematic blind 3 g fibrinogen infusion in PPH did not reduce anaemia or transfusion rate, reduced hypofibrinogenaemia and was safe., (© 2021 John Wiley & Sons Ltd.)

Background: Fibrinogen (FIB) levels less than 150 mg/dL have been associated with increased rates of bleeding and lower survival in critically ill cirrhosis patients., Objective: We aimed to determine if treatment with cryoprecipitate (CRYO) for low FIB levels is associated with bleeding outcomes or survival., Methods: A total of 237 cirrhosis patients admitted to an intensive care unit at a tertiary care liver transplant center with initial FIB levels less than 150 mg/dL were retrospectively assessed for CRYO transfusion, bleeding events, and survival outcomes., Results: The mean MELD score was 27.2 (95% confidence interval [CI]: 26.0-28.3) and CLIF-C acute on chronic liver failure score was 53.4 (51.9-54.8). Ninety-nine (41.8%) were admitted for acute bleeding and the remainder were admitted for nonbleeding illnesses. FIB level on admission correlated strongly with disease severity. After adjusting for disease severity, FIB on admission was not an independent predictor of 30-day survival (hazard ratio [HR]: 0.99, 95% CI: 0.99-1.01, p  = 0.68). CRYO transfusion increased FIB levels but had no independent effect on mortality or bleeding complications (HR: 1.10, 95% CI: 0.72-1.70, p  = 0.65)., Conclusion: In cirrhosis patients with critical illness, low FIB levels on presentation reflect severity of illness but are not independently associated with 30-day mortality. Treatment of low FIB with CRYO also does not affect survival or bleeding complications, suggesting FIB is an additional marker of severity of illness but is not itself a direct factor in the pathophysiology of bleeding in critically ill cirrhosis patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Haemorrhage during and following surgery results in increased morbidity and mortality. Low plasma fibrinogen levels have been associated with increased blood loss and transfusion requirements. Fibrinogen supplementation has been shown to reduce bleeding in coagulopathic patients. This post hoc study evaluated fibrinogen repletion and pharmacokinetic data from the REPLACE study. One hundred and fifty-two adult patients undergoing elective aortic surgery requiring cardiopulmonary bypass (CPB) with defined bleeding of 60-250 g at first 5 min bleeding mass were included in the phase III trial. Patients were randomized to receive either fibrinogen concentrate (FCH) or placebo following CPB removal. Plasma fibrinogen levels and viscoelastic testing parameters (ROTEM-based FIBTEM and EXTEM assays) were measured before, during, and after study treatment administration. A mean dose of 6.3 g FCH was administered in the FCH group, with a median infusion duration of 2 min. Immediately following completion of FCH administration, a rapid increase in plasma fibrinogen levels to near baseline (median change from baseline -0.10 g/l) was seen in the FCH group but not in the placebo group (median change from baseline -1.29 g/l). FCH administration also caused an immediate increase in FIBTEM maximum clot firmness (MCF) to 23 mm and improvements in EXTEM coagulation time and clot formation time by the end of infusion. There was a strong correlation between the plasma fibrinogen level and FIBTEM MCF. Treatment with high doses of FCH with a rapid infusion time resulted in immediate recovery to baseline levels of plasma fibrinogen and viscoelastic testing parameters., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Ultrasound-guided thrombin injection (UGTI) is often the first-line treatment for iatrogenic post-catheterization pseudoaneurysms (psA). There are also first reports of the use of biologically derived tissue glues (TG) instead of sole thrombin especially when UGTI was unsuccessful or in case of psA recurrence. Previously, we have established that a late to early velocity index (LEVI) < 0.2 could be a predictor of an increased risk of psA recurrence after standard UGTI. In this paper, we report our first experiences when the choice of the first-line treatment method was based on LEVI assessment. From May 2017 till January 2020 we included 36 patients with psA. Of them, 10 had LEVI < 0.2 and they underwent ultrasound-guided tissue glue injection (UGTGI) with biological TG and 26 had LEVI > 0.2 and they underwent UGTI. The injection set containing human thrombin and fibrinogen was used for UGTGI. Bovine thrombin was used for UGTI. The success rate was 100% and no psA recurrence was detected during a 2-week follow-up. It was significantly better when compared to the expected recurrence rates based on our previous 14 years of experience (0% vs. 13%, p = 0.01). All complications (10% in the UGTGI group and 15% in the UGTI group) were mild and transient and included clinical symptoms of paresthesia, numbness, tingling, or pain. Their rates were comparable to the rates we previously reported. No significant differences in other characteristics were observed. The approach to choose the first-line treatment method for iatrogenic psA based on LEVI is encouraging. It may increase the success rate and avoid unnecessary repetition of the procedure, without increasing complication rate while keeping costs of the procedure reasonable., (© 2021. The Author(s).)

Cryoprecipitate has been the gold standard for treating acquired hypofibrinogenemia in cardiac surgery for nearly 50 years. More recently, fibrinogen concentrate has been used off-label in the United States and is the standard in European countries and Canada to treat the acquired hypofibrinogenemia during cardiac surgery. Fibrinogen concentrate has multiple potential advantages including rapid reconstitution, greater dose predictability, viral inactivation during processing, and reduced transfusion-related adverse events. However, because fibrinogen concentrate lacks the other components contained in the cryoprecipitate, it may not be the "ideal" product for replacing fibrinogen in all cardiac surgical patients, particularly those with longer cardiopulmonary bypass duration. In this Pro-Con commentary article, we discuss the advantages and disadvantages of using fibrinogen concentrate and cryoprecipitate to treat acquired hypofibrinogenemia in cardiac surgical patients., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Due to the low prevalence of afibrinogenemia, epidemiologic data on afibrinogenemia are limited, and no data are available on health-related quality of life (HRQoL). We conducted a cross-sectional international study to characterize the clinical features, the fibrinogen supplementation modalities, and their impact on HRQoL in patients with afibrinogenemia. A total of 204 patients (119 adults and 85 children) from 25 countries were included. The bleeding phenotype was severe: 68 (33.3%) patients having at least one bleed per month and 48 (23%) a history of cerebral bleeding. About 35% (n = 72) of patients were treated with fibrinogen concentrates or cryoprecipitates as prophylaxis, 18.1% (n = 37) received ≥1 injection per week, and 16.6% (n = 34) were on home treatment. A thrombotic event was reported in venous and/or arterial territories by 37 (18.1%) patients. Thrombosis occurred even in young patients, and recurrence was frequent (7.4%). The total HRQoL was lower in children than in adults. Discomfort linked to treatment and limitations to sports and leisure were the main concerns. Women and children were particularly affected in family relationships. In multivariate analyses, younger age, residence in Asia or Africa, and a previous thrombotic event were statistically correlated with a worse HRQoL. In summary, our study underlines the severe bleeding and thrombotic phenotype and their impact on HRQoL in afibrinogenemia. The optimal strategy for fibrinogen supplementation needs to be determined. This trial was registered at www.clinicaltrials.gov as #NCT03484065., (© 2021 by The American Society of Hematology.)

Objective: To determine the relationship between the value of fibrinogen assessed by the FIBTEM clot amplitude at 10 minutes (A10 FIBTEM) measured on admission to the intensive care unit (ICU) and the amount of drainage output at 24 hours, to investigate whether the A10 FIBTEM predicts severe bleeding (SB), and to define A10 FIBTEM thresholds to prevent (trigger) and treat (target) severe bleeding by fibrinogen supplementation., Methods: In a single centre, retrospective observational study, 166 patients underwent elective open thoraco-abdominal aortic aneurysm (TAAA) repair between March 2016 and January 2019. Exclusion criteria were emergency, congenital, or acquired coagulopathy, or administration of P 2 Y 12 inhibitor antiplatelet agents in the five days before surgery. All patients were managed intra-operatively and post-operatively according to a rotational thromboelastometry driven transfusion protocol. The principal endpoint was a composite outcome, which included bleeding, large volume transfusion, and re-operation., Results: FIBTEM clot amplitude after 10 minutes measured on ICU admission and post-operative bleeding at 24 hours showed an inverse linear relationship (R 2  = .03; p = .026). Performance of A10 FIBTEM in predicting SB evaluated by Receiving Operating Curve analysis showed an area under the curve of 0.63 (95% CI 0.56 - 0.70; p = .026) with a best cutoff of 9 mm. An A10 FIBTEM of 3 mm was the cutoff associated with a positive predictive value of 50%, while an A10 FIBTEM of 9 mm showed a negative predictive value of 92%. On multivariable analysis, an A10 FIBTEM ≤ 3 mm remained independently associated with SB., Conclusion: The present investigation shows for the first time in a population undergoing open TAAA repair that an A10 FIBTEM ≤ 3mm on ICU admission is associated with post-operative severe bleeding. Trigger and target values for fibrinogen supplementation, based on A10 FIBTEM, have been provided. The transferability and reliability of these cutoff values require further study., (Copyright © 2021 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Introduction: The occurrence of massive hemorrhages in various emergency situations increases the need for blood transfusions and the risk of mortality. Use of fibrinogen concentrate (FC) may increase plasma fibrinogen levels more rapidly than the use of fresh-frozen product or cryoprecipitate. However, thus far, the efficacy of FC in significantly improving the risk of mortality and significantly reducing transfusion requirements has not been effectively demonstrated in several systematic reviews and meta-analyses., Methods and Analysis: We will conduct a systematic review and meta-analysis of FC for hemorrhages in emergency situations. We will include controlled trials, but will exclude randomized controlled trials in elective surgeries. We will include patients with hemorrhages in emergency situations. Intervention will be emergency supplementation of FC. The control group will be administered with ordinal transfusion or placebo. The primary outcome of the study is in-hospital mortality.We will search in electronic databases such as MEDLINE (PubMed), Web of Science, and the Cochrane Central Register of Controlled Trials. Two reviewers will independently screen the title and abstract, retrieve the full text of the selected articles, and extract the essential data. We will apply uniform criteria for evaluating the risk of bias associated with individual randomized controlled trial based on the Cochrane risk of bias tool. Values of the risk ratio will be expressed as a point estimate with 95% confidence intervals (CIs). Data of continuous variables will be expressed as the mean difference along with their 95% CIs and P values. We will assess the strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach., Ethics and Dissemination: This systematic review will provide physicians with updated information on the efficacy and safety of using FC for hemorrhage in emergency settings. Approval from the ethics board and patient consent were not required in our study.This study protocol has been funded through a protocol registry. The registry number is UMIN000041598., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Congenital afibrinogenemia is a rare disorder characterized by a lack of detectable fibrinogen. The mainstay of treatment for acute bleeding episodes or perioperative management is replacement with fibrinogen concentrate or fibrinogen-containing blood products. The development of neutralizing antibodies and severe allergic reactions to fibrinogen replacement is rarely reported in afibrinogenemia patients. Here the treatment regimen is described for a 6-year-old girl with a severe allergic reaction to multiple fibrinogen-containing products who became refractory to treatment because of a presumed inhibitor to fibrinogen., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Fibrinogen is the first coagulation protein to reach critically low levels during traumatic haemorrhage. There have been no differential effects on clinical outcomes between the two main sources of fibrinogen replacement: cryoprecipitate and fibrinogen concentrate (Fg-C). However, the constituents of these sources are very different. The aim of this study was to determine whether these give rise to any differences in clot stability that may occur during trauma haemorrhage. Fibrinogen deficient plasma (FDP) was spiked with fibrinogen from cryoprecipitate or Fg-C. A panel of coagulation factors, rotational thromboelastography (ROTEM), thrombin generation (TG), clot lysis and confocal microscopy were performed to measure clot strength and stability. Increasing concentrations of fibrinogen from Fg-C or cryoprecipitate added to FDP strongly correlated with Clauss fibrinogen, demonstrating good recovery of fibrinogen (r 2 = 0.99). A marked increase in Factor VIII, XIII and α 2 -antiplasmin was observed in cryoprecipitate ( p < 0.05). Increasing concentrations of fibrinogen from both sources were strongly correlated with ROTEM parameters (r 2 = 0.78-0.98). Cryoprecipitate therapy improved TG potential, increased fibrinolytic resistance and formed more homogeneous fibrin clots, compared to Fg-C. In summary, our data indicate that cryoprecipitate may be a superior source of fibrinogen to successfully control bleeding in trauma coagulopathy. However, these different products require evaluation in a clinical setting.

Objective: To analyze all the variables in women who received fibrinogen for postpartum hemorrhage (PPH) using hierarchical cluster analysis, to provide greater insight into the risk variables involved in these women., Methods: This retrospective study of women with at least 500 mL of bleeding at birth or during the postpartum period and treated with fibrinogen was conducted at the Department of Obstetrics and Gynecology, Atatürk University School of Medicine from January 2013 to January 2018. Data on the women were obtained from medical records and various risk variables were recorded and analyzed using hierarchical cluster analysis., Results: A total of 114 women with PPH were included in the study. Based on a dendrogram, three main clusters of similar quality variables were created: 1) gravida, parity, age, cervical/vaginal hematoma, laparotomy, hypogastric artery ligation, uterine artery embolization, uterine artery ligation, uterine atony, distance from outer center, lowest hemoglobin, preoperative platelets, endometritis, preoperative white blood cells; 2) lowest fibrinogen, highest fibrinogen, type of birth, placenta invasion anomaly, Bakri balloon tamponade, postpartum hysterectomy, preoperative activated partial thromboplastin time (APTT), preoperative international normalized ratio (INR), placental abruption, in-utero ex fetus; 3) postoperative APTT, postoperative INR, maternal mortality, erythrocyte transfusion, plasma transfusion, hospital stay time, disseminated intravascular coagulation/HELLP syndrome, highest hemoglobin, blood group, postoperative platelets, platelet transfusion, pre-eclampsia/eclampsia, fibrinogen extract., Conclusion: According to the cluster analysis, we should keep fibrinogen extract in the foreground especially in the treatment of hemorrhage in patients with variable conditions. As a result, we can determine whether fibrinogen extract, which has a high economic cost, should be kept at each center. We can also direct which patient will be referred in accordance with the referral steps., (© 2020 International Federation of Gynecology and Obstetrics.)

Rational: Hemocoagulase, a hemostatic, is used in patients with trauma, gastrointestinal bleeding, or pulmonary hemorrhage or those undergoing surgery. However, paradoxical bleeding after hemocoagulase administration is not considered a clinically significant adverse effect. Here, we report a case of paradoxical pulmonary hemorrhage associated with hypofibrinogenemia after administration of the hemocoagulase batroxobin in a patient with hemoptysis., Patient Concerns: An 86-year-old woman complained of hemoptysis during hospitalization with organophosphate poisoning. Hemocoagulase was administered to manage bleeding; however, bleeding signs, such as hemoptysis, massive epistaxis, and ecchymosis, recurred., Diagnoses: The patient was diagnosed with acquired hypofibrinogenemia on the basis of the reduced plasma fibrinogen level after hemocoagulase administration and lack of other causes of bleeding., Intervention: Hemocoagulase administration was discontinued, and fibrinogen-containing plasma products were administered., Outcomes: The plasma fibrinogen level normalized and bleeding signs did not recur., Lessons: It is necessary to measure plasma fibrinogen levels regularly in patients undergoing hemocoagulase administration and discontinue its administration when acquired hypofibrinogenemia is detected., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Postoperative bleeding is a major problem in children undergoing complex pediatric cardiac surgery. The primary aim of this prospective observational study was to evaluate the effect of an institutional approach consisting of early preventive fibrinogen, prothrombin complex and platelets administration on coagulation parameters and postoperative bleeding in children. The secondary aim was to study the rate of re-intervention and postoperative transfusion, the occurrence of thrombosis, length of mechanical ventilation, ICU stay and mortality., Methods: In fifty children (age 0-6 years) with one or more predefined risk factors for bleeding after cardiopulmonary bypass (CPB), thrombelastography (TEG) and standard coagulation parameters were measured at baseline (T1), after CPB and reversal of heparin (T2), at sternal closure (T3) and after 12 h in the ICU (T4). Clinical bleeding was evaluated by the surgeon at T2 and T3 using a numeric rating scale (NRS, 0-10)., Results: After CPB and early administration of fibrinogen, prothrombin complex and platelets, the clinical bleeding evaluation score decreased from a mean value of 6.2 ± 1.9 (NRS) at T2 to a mean value of 2.1 ± 0.8 at T3 (NRS; P <  0.001). Reaction time (R), kinetic time (K), maximum amplitude (MA) and maximum amplitude of fibrinogen (MA-fib) improved significantly (P <  0.001 for all), and MA-fib correlated significantly with the clinical bleeding evaluation (r = 0.70, P <  0.001). The administered total amount of fibrinogen (mg kg - 1 ) correlated significantly with weight (r = - 0.42, P = 0.002), priming volume as percentage of estimated blood volume (r = 0.30, P = 0.034), minimum CPB temperature (r = - 0.30, P = 0.033) and the change in clinical bleeding evaluation from T2 to T3 (r = 0.71, P <  0.001). The incidence of postoperative bleeding (> 10% of estimated blood volume) was 8%. No child required a surgical re-intervention, and no cases of thrombosis were observed. Hospital mortality was 0%., Conclusion: In this observational study of children with an increased risk of bleeding after CPB, an early preventive therapy with fibrinogen, prothrombin complex and platelets guided by clinical bleeding evaluation and TEG reduced bleeding and improved TEG and standard coagulation parameters significantly, with no occurrence of thrombosis or need for re-operation., Trial Registration: German Clinical Trials Register DRKS00018109 (retrospectively registered 27th August 2019).

The treatment of diabetic ulcer (DU) remains a major clinical challenge due to the complex wound-healing milieu that features chronic wounds, impaired angiogenesis, persistent pain, bacterial infection, and exacerbated inflammation. A strategy that effectively targets all these issues has proven elusive. Herein, we use a smart black phosphorus (BP)-based gel with the characteristics of rapid formation and near-infrared light (NIR) responsiveness to address these problems. The in situ sprayed BP-based gel could act as 1) a temporary, biomimetic "skin" to temporarily shield the tissue from the external environment and accelerate chronic wound healing by promoting the proliferation of endothelial cells, vascularization, and angiogenesis and 2) a drug "reservoir" to store therapeutic BP and pain-relieving lidocaine hydrochloride (Lid). Within several minutes of NIR laser irradiation, the BP-based gel generates local heat to accelerate microcirculatory blood flow, mediate the release of loaded Lid for "on-demand" pain relief, eliminate bacteria, and reduce inflammation. Therefore, our study not only introduces a concept of in situ sprayed, NIR-responsive pain relief gel targeting the challenging wound-healing milieu in diabetes but also provides a proof-of-concept application of BP-based materials in DU treatment., Competing Interests: The authors declare no competing interest.

Background: Acute fatty liver of pregnancy (AFLP) is a potentially lethal condition of pregnant women with a high mortality rate. Potential predictors related to postpartum recovery time and prognostic factors of AFLP are still unclear. This study aimed to evaluate potential predictors for prognosis and postpartum recovery time of AFLP., Methods: We retrospectively analyzed the clinical data of 76 AFLP patients in our hospital from 2002 to 2017 and investigated potential predictors using univariate analysis and multivariate logistic regression analysis., Results: Hepatic encephalopathy (HE) was found to be associated with prognosis in AFLP patients (P = 0.005, OR = 26.844). The postpartum recovery time analysis showed that AFLP patients with a age < 25 had the shortest recovery time, but no significant difference (P = 0.134, OR = 5.952). The postpartum recovery time of patients with liver failure (LF) was significantly prolonged compared to those without LF (P = 0.036, OR = 10.052). Cryoprecipitate, and plasma infusion showed no significant effect on prognosis or recovery time. Artificial liver support therapy (ALST) had no effect on prognosis, but it might affect postpartum recovery time with no statistical significance (P = 0.128, OR = 5.470)., Conclusion: HE is a potential predictor for prognosis of AFLP. LF is a potential predictor for postpartum recovery time.

Global alterations in the metabolic network provide substances and energy to support tumor progression. To fuel these metabolic processes, extracellular matrix (ECM) plays a dominant role in supporting the mass transport and providing essential nutrients. Here, we report a fibrinogen and thrombin based coagulation system to construct an artificial ECM (aECM) for selectively cutting-off the tumor metabolic flux. Once a micro-wound is induced, a cascaded gelation of aECM can be triggered to besiege the tumor. Studies on cell behaviors and metabolomics reveal that aECM cuts off the mass transport and leads to a tumor specific starvation to inhibit tumor growth. In orthotopic and spontaneous murine tumor models, this physical barrier also hinders cancer cells from distant metastasis. The in vivo gelation provides an efficient approach to selectively alter the tumor mass transport. This strategy results in a 77% suppression of tumor growth. Most importantly, the gelation of aECM can be induced by clinical operations such as ultrasonic treatment, surgery or radiotherapy, implying this strategy is potential to be translated into a clinical combination regimen.

A 26-year-old woman was found to have congenital dysfibrinogenaemia after presenting to our hospital with premature rupture of the membranes and vaginal bleeding. Given the absence of clear guidelines for the management of pregnancy complicated by dysfibrinogenaemia, we followed expert consensus that exists among published works, with some modifications. This case was managed by a multidisciplinary team of obstetrics-gynaecology, haematology and paediatric haematology. Here we review how the patient presented, the investigations that led to the diagnosis and the treatment options., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Thromboelastography (TEG®) functional fibrinogen (FF) test is a point-of-care test for fibrinogen measurement and is preferred for its rapid turnaround time. This study was designed to compare TEG® functional fibrinogen level (FLEV) with classic Clauss fibrinogen in patients undergoing scoliosis surgery and to evaluate the concordance between the two methods., Methods: Patients in this study were part of a larger study evaluating the effect of fibrinogen concentrate (FC) supplementation on perioperative blood loss in scoliosis surgery. Paired samples for TEG® FF and Clauss fibrinogen assays were taken from 40 patients at three different timepoints perioperatively. The agreement between FLEV and Clauss was assessed, and the possibility of using FLEV measurements to predict Clauss fibrinogen was explored., Results: One hundred and seventeen paired samples from 39 patients were finally analyzed. Pearson correlation test confirmed positive linear correlations between FLEV and Clauss at all three timepoints (r = .70, .67, and .66 at baseline, before FC administration, and after FC administration, respectively; P < .001 for all) and together for all measures (r = .76, P < .001), while Bland-Altman plots showed FLEV significantly overestimated Clauss constantly. Optimum diagnostic values of FLEV at 4.27 and 3.77 g/L were generated to predict normal fibrinogen as Clauss ≥ 3.0 g/L (AUROC 0.941, 95% CI: 0.891-0.991) and critical intraoperative hypofibrinogenemia as Clauss ≤ 2.0g/L (AUROC 0.894, 95% CI: 0.838-0.950), respectively., Conclusions: In adolescents undergoing scoliosis surgery, FLEV correlated linearly with Clauss fibrinogen. Though FLEV overestimates Clauss constantly, FLEV values are able to predict hypofibrinogenemia and normal fibrinogen with both AUROC > 0.85., (© 2020 John Wiley & Sons Ltd.)

Background: This study compared the resuscitation effects of platelets and fibrinogen concentrate (FC) on coagulation and hemodynamics in pigs with traumatic hemorrhage and reduced platelet counts., Methods: Thirty pigs (40 ± 3 kg) were anesthetized and catheterized with an apheresis catheter to remove platelets using the Haemonetics 9000 (Haemonetics, Braintree, MA). Afterward, a femur fracture was induced, followed by hemorrhage of 35% the estimated blood volume. Pigs were then randomized to be resuscitated with 5% human albumin (12.5 mL/kg), FC (250 mg/kg, 12.5 mL/kg), or platelets collected from apheresis (11.0 ± 0.5 mL/kg). Animals were monitored for 2 hours or until death. Blood samples were collected before (baseline [BL]) and after apheresis, after hemorrhage, and after resuscitation to assess changes in hemodynamics and coagulation using Rotem., Results: No change in mean arterial pressure (MAP) or heart rate (HR) was observed by platelet apheresis. Hemorrhage reduced MAP to 57% ± 5% and elevated HR to 212% ± 20% of BL (both p < 0.05). Resuscitation with albumin, FC, or platelets did not revert MAP or HR to BL. Platelet counts were reduced by apheresis from BL 383 ± 20 × 10/μL to 141 ± 14 × 10/μL and were reduced further after resuscitation with albumin (88 ± 18 × 10/μL) or FC (97 ± 13 × 10/μL, all p < 0.05), but improved with platelet resuscitation (307 ± 24 × 10/μL). Fibrinogen concentration was reduced by apheresis from BL 225 ± 9 mg/dL to 194 ± 8 mg/dL, fell after albumin infusion (134 ± 11 mg/dL), increased to 269 ± 10 mg/dL after FC resuscitation (all p < 0.05), and was not affected by platelet resuscitation. Rotem α-angle decreased from 79 ± 2 degrees to 69 ± 1 degrees by apheresis and hemorrhage (p < 0.05), and recovered similarly by resuscitation with FC (87 ± 1 degrees) or platelets (78 ± 2 degrees), but not by albumin (63 ± 3 degrees). Similar responses were observed in Rotem maximum clot firmness., Conclusion: In this traumatic hemorrhage swine model, low-volume resuscitation with FC or platelets was similarly effective in restoring coagulation.

Patients undergoing treatment of acute lymphoblastic leukemia (ALL) are at risk for thrombosis, caused in part by the use of l-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent venous thromboembolism (VTE) and thus may increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatrics-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia- ALL were included. The incidence rate of VTE was 16%, with 69% of cases occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or who developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE. Administration of fibrinogen concentrates was associated with an increased risk of VTE, whereas transfusion of fresh frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE. Prophylactic measures were not associated with an increased risk of grade 3 to 4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1 of 34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. VTE developed despite extensive AT supplementation, which suggests the need for additional prophylactic measures. Although this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. This trial was registered at www.clinicaltrials.gov as #NCT00327678., (© 2020 by The American Society of Hematology.)

Introduction: . Massive hemorrhage continues to be a treatable cause of death. Its management varies from prefixed ratio-driven administration of blood components to goal-directed therapy based on point-of-care testing and administration of coagulation factor concentrates., Areas Covered: . We review the current role of fibrinogen concentrate (FC) for the management of massive hemorrhage, either administered without coagulation testing in life-threatening hemorrhage, or within an algorithm based on viscoelastic hemostatic assays and plasma fibrinogen level. We identified relevant guidelines, meta-analyzes, randomized controlled trials, and observational studies that included indications, dosage, and adverse effects of FC, especially thromboembolic events., Expert Opinion: . Moderate- to high-grade evidence supports the use of FC for the treatment of severe hemorrhage in trauma and cardiac surgery; a lower grade of evidence is available for its use in postpartum hemorrhage and end-stage liver disease. Pre-emptive FC administration in non-bleeding patients is not recommended. FC should be administered early, in a goal-directed manner, guided by early amplitude of clot firmness parameters (A5- or A10-FIBTEM) or hypofibrinogenemia. Further investigation is required into the early use of FC, as well as its potential advantages over cryoprecipitate, and whether or not its administration at high doses leads to a greater risk of adverse events.

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., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Fibrinogen concentrate is widely used in traumatic hemorrhagic shock despite weak evidence in the literature. The aim of the study was to evaluate the effect of fibrinogen concentrate administration within the first 6 hours on 24-hour all-cause mortality in traumatic hemorrhagic shock using a causal inference approach., Methods: Observational study from a French multicenter prospective trauma registry was performed. Hemorrhagic shock was defined as transfusion of four or more red blood cell units within the first 6 hours after admission. The confounding variables for the outcome (24-hour all-cause mortality) and treatment allocation (fibrinogen concentrate administration within the first 6 hours) were chosen by a Delphi method. The propensity score was specified with a data-adaptive algorithm and a doubly-robust approach with inverse proportionality of treatment weighting allowed to compute the average treatment effect. Sensitivity analyses were performed., Results: Of 14,336 patients in the registry during the study period, 1,027 in hemorrhagic shock were analyzed (758 receiving fibrinogen concentrate within 6 hours and 269 not receiving fibrinogen concentrate). The average treatment effect, expressed as a risk difference, was -0.031 (95% confidence interval, -0.084 to 0.021). All sensitivity analysis confirmed the results., Conclusions: Fibrinogen concentrate administration within the first 6 hours of a traumatic hemorrhagic shock did not decrease 24-hour all-cause mortality., Level of Evidence: Prognostic, level III.

Background: Radical lymph nodes dissection (RLND) is the standard procedure for regional control of disease in patients with metastatic melanoma (stage III). Because of its aggressiveness, lymphorrhoea is a constant problem in postoperative., Methods: In this prospective nonrandomized study with a retrospective analysis of data, patients undergoing surgical treatment of axillary or iliac-inguinal RLND received standard treatment plus a collagen-fibrin sealant patch (TachoSil) (N.=50) or standard treatment alone (N.=50). The first endpoint was the comparison between the treated population and the control group, in terms of persistence of drainage and average daily volume of lymphorrhoea. The second aim was to relate patients' BMI, volume of lymphorrhoea and time of drainage in the two groups., Results: In the comparison between the two groups receiving or not the treatment with collagen-fibrin patch, we found an average difference both in the volume of daily lymphorrhoea (42.91±6.61 cc) and in the persistence of drainage (9.292±1.644 days) with P value <0.0001. Besides, the collagen-fibrin patch was actually effective in reducing lymphorrhoea and time of drainage, regardless of patients' BMI., Conclusions: The results of this study confirm and support the starting thesis: TachoSil is an effective tissue sealant able to reduce lymphorrhoea and drainage removal times following a radical lymphadenectomy, independently from the BMI.

Background:  We investigated whether fibrinogen concentrate administration to bleeding patients is associated with an increased risk of thromboembolic complications and death., Methods:  All consecutive patients who underwent first-time cardiac surgery at Sahlgrenska University Hospital from 2009 to 2014 were included. Patients, who had received fibrinogen concentrate, were compared with those who had not received fibrinogen concentrate. The primary endpoint was a composite of thromboembolic complications and death within 1 year after surgery. Secondary endpoints included the composite and mortality within 30 days and mortality within 1 year after surgery. Multivariable logistic regression and Cox regression models were used to compare the groups. Propensity score (PS)-matched models were used for sensitivity analyses., Results:  A total of 5,408 patients were included in the present study, of which 564 (10.4%) received fibrinogen concentrate. The composite endpoint occurred in 3.5% of patients at 30 days and 10.5% at 1 year. There was no significant difference between the groups in the composite endpoint at 1 year (adjusted hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.84-1.46, p  = 0.45) or in the secondary endpoints, that is, mortality at 1 year (adjusted HR: 1.38, 95% CI: 0.93-2.04, p  = 0.11), composite at 30 days (adjusted odds ratio [OR]: 1.07, 95% CI: 0.64-1.81, p  = 0.79) and mortality at 30 days (adjusted OR: 1.00, 95% CI: 0.51-1.96, p  = 0.50). The results of the sensitivity analyses were consistent with those of main analyses., Conclusion:  Perioperative administration of fibrinogen concentrate to bleeding cardiac surgery patients is not associated with an increased risk of thromboembolic complications or death., Competing Interests: K.W. and S.N. have no conflicts of interest. A.J. has received an honorarium for consultancy and lectures from CSL Behring, LFB and Octapharma. M.K. has received a speaker's honorarium from CSL Behring., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Infants undergoing cardiac surgery are at risk for bleeding and massive transfusion due to an immature coagulation system, complex surgeries, and cardiopulmonary bypass (CPB) effects. Hemodilution from CPB promotes an acquired hypofibrinogenemia that results in impaired fibrin formation, inadequate clot formation, and increased bleeding. In North America, the current standard of care to supplement fibrinogen is cryoprecipitate. An alternative option is the off-label use of fibrinogen concentrate (FC; RiaSTAP; CSL Behring, Marburg, Germany), a purified fibrinogen. Because perioperative allogenic transfusions are associated with increased morbidity and mortality, we sought to determine whether FC would be an acceptable alternative to cryoprecipitate in a post-CPB transfusion algorithm in infants undergoing open-heart surgery., Methods: We randomized 60 infants (<12 months) undergoing nonemergent cardiac surgery with CPB at 2 tertiary care children's hospitals to receive either cryoprecipitate or FC in a post-CPB transfusion algorithm. Infants underwent a stratified randomization based on institution and surgical complexity. The primary outcome was the difference in number of intraoperative allogenic blood product transfusions. Secondary outcomes included 24-hour chest tube output (CTO), mechanical ventilation time, adverse events (AEs), intensive care unit (ICU) length of stay (LOS), hospital LOS, postoperative thrombosis, and death within 30 days of surgery. The primary analysis followed the intent-to-treat (ITT) principle and was performed using linear regression adjusted for institution and complexity of surgery. A per-protocol (PP) analysis was also performed., Results: Between June 2016 and January 2018, we enrolled 60 patients with complete data available for 25 patients who received cryoprecipitate and 29 patients who received FC. Patients in the cryoprecipitate group (median age: 4 months [2-6 months]) received 5.5 (4.0-7.0) allogeneic blood units in the ITT analysis and 6.0 units (5.0-7.0 units) in the PP analysis. Patients in the FC group (median age: 4 months [2-5]) received 4 units (3.0-5.0 units) in the ITT analysis and 4.0 units (3.0-5.0 units) in the PP analysis. In the adjusted ITT analysis, the FC group received 1.79 units (95% confidence interval [CI], 0.64-2.93; P = .003) less than the cryoprecipitate group. In the adjusted PP analysis, the FC group received 2.67 units (95% CI, 1.75-3.59; P < .001) less than the cryoprecipitate group. There were no significant differences in secondary outcomes or AEs., Conclusions: Our findings suggest that FC may be considered as an alternative to cryoprecipitate for the treatment of hypofibrinogenemia in infants with bleeding after CPB. Although we found no significant differences between secondary outcomes or AEs, further studies are needed to assess safety.

Background: Fibrinogen plays an important role in haemostasis during the early phase of trauma, and low fibrinogen levels after severe trauma are associated with haemostatic impairment, massive bleeding, and poor outcomes. Aggressive fibrinogen supplementation may improve haemostatic function, as fibrinogen levels deteriorate before other routine coagulation parameters in this setting. Therefore, we evaluated whether early administration of fibrinogen concentrate (FC) was associated with improved survival in severe trauma patients., Methods: This single-centre retrospective study evaluated patients with severe trauma (injury severity score ≥ 16) who were admitted to our emergency department between January 2010 and July 2018. The exclusion criteria included age < 18 years, cardiac arrest before emergency department arrival, cervical spinal cord injury not caused by a high-energy accident, and severe burn injuries. The FC and control groups included trauma patients who received and did not receive FC within 1 h after emergency department arrival, respectively. Propensity scores were used to balance the two groups based on the trauma and injury severity score (TRISS), heart rate at emergency department admission, and age. The primary outcome was the in-hospital survival rate., Results: The propensity scoring model had a c -statistic of 0.734, the Hosmer-Lemeshow chi-squared value was 7.036 (degrees of freedom = 8), and the non-significant p value of 0.533 indicated a good model fit. The propensity score matching created 31 matched pairs of patients, who had appropriately balanced characteristics. The FC group had a significantly higher in-hospital survival rate than the control group (log-rank p = 0.013). The FC group also used significantly higher amounts of red blood cells and fresh frozen plasma within 6 h after emergency department admission. However, the two groups had similar transfusion amounts between 6 and 24 h after emergency department admission., Conclusions: The present study revealed that early FC administration was associated with a favourable survival rate among severe trauma patients. Therefore, FC may be useful for the early management of trauma-induced coagulopathy and may improve outcomes in this setting., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2020.)

Backgorund: Multifactorial haemostasis disorders are typical of patients with end-stage renal disease (ESRD) on chronic haemodialysis (HD). Thromboelastometry and impedance aggregometry allow for a comprehensive assessment of clot formation, lysis, and platelet (PLT) function. This study aims to determine the haemostatic profile in a group of patients with ESRD on chronic, interrupted dialysis, especially in terms of PLT function and the impact of in vitro fibrinogen concentrate supplementation on clot properties., Methods: A total of 22 patients on chronic HD and 22 healthy controls (HC) were enrolled in the prospective study with a control group. Global haemostasis assays (GHA) were used to describe the haemostasis profile and to assess the effect of fibrinogen concentrate supplementation on improving clot quality., Results: Despite the lack of considerable differences in the number of PLTs, there was a significantly lower potential of PLT aggregation in the HD group (922 ±163 AU*min). A higher concentration of fibrinogen was also observed in this group which presented considerably higher maximum clot firmness (MCF) FIBTEM (22 ±5.3 mm). Clotting time (CT) EXTEM was also prolonged (72 ±23 s). No hyperfibrinolysis was reported. In vitro fibrinogen concentrate supplementation resulted in significant improvement in MCF FIBTEM (30 mm vs. 22 mm; P < 0.001). However, it also led to a deterioration in PLT aggregation as assessed by TRAPtest., Conclusions: The haemostasis profile of ESRD patients demonstrates a limited potential of PLT aggregation, with no improvement after fibrinogen addition.

Objectives: Fibrin glue is used to reinforce anastomosis in aortic surgery. There has not yet been a consensus on how it should be applied optimally. This study aimed to define the optimal condition of applying fibrin glue., Methods: In experiment 1, we determined the optimal condition for spraying fibrin glue using an expanded polytetrafluoroethylene graft within a needle hole. The length and area of the fibrin cap within the hole were measured. In experiment 2, methods for applying fibrinogen were assessed by comparing brushing and spraying. In experiment 3, swine aorta segments sutured with a Dacron graft were divided into the following three groups: nothing was applied; fibrinogen was sprayed and rubbed using brush. The aorta was clamped and blood was infused from an occlusion catheter inserted into the graft. The pressure at the first appearance of blood leak was recorded., Results: In experiment 1, among the four groups divided by the pressure and distance of spraying, the fibrin cap area in the group with 0.075 MPa and 2-cm spray distance was significantly larger than that in the group with 0.15 MPa and 2 cm (P < 0.01). In experiment 2, the fibrin cap area in the brushing group was significantly larger than that in the spraying group (P < 0.05). In experiment 3, the capacity to resist endoluminal pressure was higher in the brushing and combined spraying group compared with that in the sequential combined spraying group (P < 0.01)., Conclusions: The brush and spray methods showed excellent hemostatic outcomes.

Background: Fibrin sealants and topical glue have been studied to reduce the incidence of postoperative pancreatic fistulas (POPF) after pancreatico-enteric anastomosis, but a definitive innovation is still needed. We aim to evaluate the effectiveness of fibrin sealant patch applied to pancreatico-enteric anastomosis to reduce postoperative complications, including POPF., Methods: This study was a single-center, prospective, randomized, phase IV trial involving three pancreaticobiliary surgeons. The primary outcome was POPF; secondary outcomes included complications, drain removal days, hospital stay, readmission rate, and cost. Risk factors for POPF were identified by logistic regression analysis., Results: A total of 124 patients were enrolled. Biochemical leakage (BL) or POPF occurred in 16 patients (25.8%) in the intervention group and 23 patients (37.1%) in the control group (no statistical significance). Clinically relevant POPF occurred in 4 patients (6.5%) in both the intervention and control groups (p = 1.000). Hospital stay (11.6 days vs. 12.1 days, p = 0.585) and drain removal days (5.7 days vs. 5.3 days, p = 0.281) were not statistically different between two groups. Complication rates were not different between the two groups (p = 0.506); nor were readmission rates (12.9% vs. 11.3%, p = 1.000) or cost ($13,549 vs. $15,038, p = 0.103). In multivariable analysis, age and soft pancreas texture were independent risk factors for BL or POPF in this study. Applying fibrin sealant patch is not a negative risk factor, but the p value may indicate a likelihood of reducing the incidence of BL (p = 0.084)., Conclusions: Fibrin sealant patches after pancreaticojejunostomy did not reduce the incidence of POPF or other postoperative complications. This study was registered at clinicaltrials.gov (NCT03269955).

Objective: We hypothesised that the association of tranexamic acid (TXA) administration and thromboelastometry-guided haemostatic therapy (TGHT) with implementation of Damage Control Resuscitation (DCR) reduced blood products (BP) use and massive transfusion (MT)., Methods: Retrospective comparison of 2 cohorts of trauma patients admitted in a university hospital, before (Period 1) and after implementation of DCR, TXA (first 3-hours) and TGHT (Period 2). Patients were included if they received at least 1 BP (RBC, FFP or platelet) or coagulation factor concentrates (fibrinogen or prothrombin complex) during the first 24-hours following the admission., Results: 380 patients were included. Patients in Period 2 (n = 182) received less frequently a MT (8% vs. 33%, P < 0.01), significantly less BP (RBC: 2 units [1-5] vs. 6 [3-11]; FFP: 0 units [0-2] vs. 4 [2-8]) but more fibrinogen concentrates (3.0 g [1.5-4.5] vs. 0.0 g [0.0-3.0], P < 0.01). Multivariate logistic regression analysis identified Period 1 as being associated with an increased risk of receiving MT (OR: 26.1, 95% CI: 9.7-70.2) and decreased survival at 28 days (OR: 2.0, 95% CI: 1.0-3.9). After propensity matching, the same results were observed but there was no difference for survival and a significant decrease for the cost of BP (2370 ± 2126 vs. 3284 ± 3812 €, P: 0.036)., Conclusion: Following the implementation of a bundle of care including DCR, TGHT and administration of TXA, we observed a decrease to the use of blood products, need for MT and an improvement of survival., (Copyright © 2019 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To investigate if supplementation with fibrinogen concentrate to blood samples collected after tranexamic acid administration improve clot formation more than what can be achieved with fibrinogen in the absence of tranexamic acid., Background: It is not known if the combination of fibrinogen and tranexamic acid has additional effects than what can be achieved individually., Methods: Four blood samples were collected from 15 coronary artery bypass patients. Two samples were collected before surgery, before and after 2 g tranexamic acid was administered. The preoperative samples were diluted to haematocrit 21%. Two samples were collected after surgery, before and after a second dose of 2 g tranexamic acid. Fibrinogen concentrate corresponding to a dose of 3 g in a 70-kg patient was added to the samples. Platelet-independent clotting time and maximum clot firmness assessed by thromboelastometry (ROTEM-FIBTEM®) were compared between the samples., Results: Administration of tranexamic acid shortened clotting time marginally (-6%) before surgery, P = 0·029) but did not influence clot firmness. Fibrinogen concentrate shortened clotting time (-14% before and -12% after surgery, both P = 0·003) and increased clot firmness (+51 and +39%, both P < 0·001). The effects of fibrinogen did not differ before and after tranexamic acid administration. Fibrinolysis was not detected in any sample., Conclusions: The results of this in vitro study suggest that the enhancing effects of fibrinogen on clot firmness in blood samples from cardiac surgery patients are not further increased in the presence of tranexamic acid. Further studies on patients with ongoing bleeding and/or hyperfibrinolysis are necessary to validate the results., (© 2019 British Blood Transfusion Society.)

Background: The objective of this study was to assess the efficacy of intra-articular injections of hyaluronic acid (HA) and a novel, on-site conjugate of HA with autologous fibrinogen in platelet-rich plasma (HA-PRP) in a canine model of osteoarthritis (OA) METHODS: Twelve beagle dogs underwent a unilateral resection of the cranial cruciate ligament (CrCL) of the stifle joint. Clinical and radiographic signs of OA were confirmed in all dogs 8 weeks following CrCL resection and prior to treatment. The dogs were randomized into three groups: saline (n = 4), HA (n = 4), and HA-PRP (n = 4). Each dog received intra-articular injections of the respective substance into the affected joint at pre-determined time points. The dogs were assessed for adverse effects for 3 days after each injection and for lameness, pain, range of motion, kinetics, and radiographic OA severity prior to treatment and 3 months after injection. OA severity as determined by radiographic examination was not significantly different among the groups at any time point. The dogs were then humanely euthanatized and the stifle joint assessed by gross and histological examinations., Results: Dogs treated with four weekly injections of HA or two biweekly injections of HA-PRP were significantly (p < 0.05) better than dogs treated with four weekly injections of saline at 2-, 4-, and 12-week time points based on a comfortable range of motion (CROM) and clinical lameness score. Gait analysis measuring symmetry and weight distribution on pressure sensor walkway showed significantly (p < 0.05) improved limb function for dogs treated with HA and HA-PRP compared with dogs treated with saline yet with better clinical outcome for the HA-PRP-treated group at 12 and 20 weeks follow-up. Gross and histological analysis of synovium and articular cartilage demonstrated significant (p < 0.05) improvement by both treatments groups compared to controls. There was however significantly (p < 0.05) less damage to the cartilage in the HA-PRP group compared to the HA-treated group., Conclusions: These data suggest that while injection of HA and HA-PRP may be sufficient for short-term amelioration of the symptoms associated with OA, treatment with HA-PRP conjugates may be superior, providing significantly better long-term cartilage preservation.

Objective: Fibrinogen is one of the first coagulation factors to be depleted during traumatic haemorrhage, and evidence suggests hypofibrinogenaemia leads to poor outcomes. A number of fibrinogen replacement products are currently available, with no clear consensus on the ideal product to use in severe traumatic haemorrhage. We hypothesised that it will be possible to rapidly administer fibrinogen concentrate (FC) guided by rotational thromboelastometry (ROTEM) FIBTEM A5 in patients presenting with trauma haemorrhage., Methods: We examined 36 consecutive patients with trauma admitted to a level 1 trauma centre in Australia who received FC as part of their initial resuscitation. ROTEM analysis was conducted at various time points from emergency department (ED) admission to 48 hours after admission. The primary outcome was time to administration of FC after identification of hypofibrinogenaemia using ROTEM FIBTEM A5. Data were collected on quantity and timing of product transfusion, demographics, Injury Severity Score and laboratory values of coagulation. Spearman rank order correlation was used to determine the correlation between FIBTEM A5 and Clauss fibrinogen (FibC)., Results: Thirty-six patients received FC as their initial form of fibrinogen replacement during the study. Patients were hypofibrinogenaemic by both FIBTEM A5 (6 mm) and FibC (1.7 g/L) on presentation to the ED. It took a median of 22 minutes (IQR, 17-30 minutes) from time of a FIBTEM A5 analysis to FC administration. Both parameters increased significantly ( P < 0.05) by 24 hours after admission., Conclusion: This study suggests that administration of FC represents a rapid and feasible method to replace fibrinogen in severe traumatic haemorrhage. However, the optimal method for replacing fibrinogen in traumatic haemorrhage is controversial and large multicentre randomised controlled trials are needed to provide further evidence. This study provided baseline data to inform the design of further clinical trials investigating fibrinogen replacement in traumatic haemorrhage.

Background: Most centres use fresh frozen plasma (FFP) based protocols to prevent or treat haemostatic disturbances during liver transplantation. In the present study, we used a rotational thrombelastometry (ROTEM™, TEM, Munich, Germany) guided haemostasis management with fibrinogen concentrates, prothrombin complex concentrates (PCC), platelet concentrates and tranexamic acid without FFP usage and determined the effect on 30 day mortality., Methods: Retrospective data analysis with 372 consecutive adult liver transplant patients performed between 2007 and 2011., Results: Thrombelastometry guided coagulation management resulted in a transfusion rate for fibrinogen concentrates in 50.2%, PCC in 18.8%, platelet concentrates in 21.2%, tranexamic acid in 4.5%, and red blood cell concentrates in 59.4%. 30 day mortality for the whole cohort was 14.2%. The univariate analyses indicated that nonsurvivors received significantly more fibrinogen concentrates, PCC, red blood cell concentrates, platelet concentrates, and infusion volume, and had a higher MELD score. However, association with mortality was weak as evidenced by receiver operating characteristic curve analyses. Further univariate analyses demonstrated, that up to 8 g of fibrinogen did not increase mortality compared to patients not receiving the coagulation factor. Multivariate analysis demonstrated that platelet concentrates (p = 0.0002, OR 1.87 per unit), infused volume (p = 0.0004, OR = 1.13 per litre), and MELD score (p = 0.024; OR 1.039) are independent predictors for mortality. Fibrinogen concentrates, PCC, and red blood cell concentrates were ruled out as independent risk factors., Conclusions: ROTEM™ guided substitution with fibrinogen concentrates and PCC does not negatively affect mortality after liver transplantation, while the well-known deleterious effect associated with platelet concentrates was confirmed.

The present study aimed to determine the impact of different sealant materials on histopathological changes to the liver surface after liver resection. Thirty-six landrace pigs underwent left anatomical hemihepatectomy and were assigned to a histopathological control group (HPC, n = 9) with no bleeding control, a clinically simulated control group (CSC, n = 9) with no sealant but bipolar cauterization and oversewing of the liver surface, and two treatment groups (n = 9 each) with a collagen-based sealant (CBS) or a fibrinogen-based sealant (FBS) on resection surface. After postoperative day 6, tissue samples were histologically examined. There were no significant differences in preoperative parameters between the groups. Fibrin production was higher in sealant groups compared with the HPC and CSC groups (both p < 0.001). Hepatocellular regeneration in sealant groups was higher than in both control groups. A significantly higher regeneration was seen in the FBS group. Use of sealants increased the degree of fibrin exudation at the resection plane. Increased hepatocellular necrosis was seen in the CBS group compared with the FBS group. The posthepatectomy hepatocellular regeneration rate was higher in the FBS group compared with the CBS group. Randomized studies are needed to assess the impact of sealants on posthepatectomy liver regeneration in the clinical setting.

Objective: To investigate the impact of cryopoor plasma (CPP) continuous rate infusion (CRI) on albumin concentration and colloid osmotic pressure (COP) in critically ill dogs with hypoalbuminemia., Design: Retrospective study between 2013 and 2015 with a 90-day follow-up on survivors., Setting: University teaching hospital., Animals: Ten hypoalbuminemic dogs receiving a CPP CRI for albumin replacement or oncotic support. All patients with documented hypoalbuminemia or low COP receiving CPP administration for albumin or oncotic support during the study period were included., Interventions: CRI of CPP., Measurements and Main Results: Mean age was 7.4 ± 4.5 years. Mean survival prediction index score was 0.66 ± 0.13. Seven dogs were septic, with 2 of 7 in septic shock and 5 of 7 having septic peritonitis. The mean pre- and postinfusion albumin was 15 ± 4 g/L and 21 ± 2 g/L, respectively. The median pre- and postinfusion COP was 8.6 mm Hg (4.9-9.7 mm Hg) and 10.2 mm Hg (8.1-13.3 mm Hg), respectively. The median duration of CRI was 16 hours (11-121 h). The mean CPP rate was 1.8 ± 0.6 mL/kg/h, the mean crystalloid rate administered concurrently was 0.8 ± 0.9 mL/kg/h, and the mean hydroxyethyl starch rate administered concurrently was 1.2 ± 0.9 mL/kg/h. The difference in pre- and postinfusion albumin was significantly correlated with CPP rate (P = 0.0004), whereas the difference in pre- and postinfusion COP was correlated with hydroxyethyl starch rate (P = 0.0128). Mean duration of hospitalization was 8.6 ± 3.9 days. Mann-Whitney U and Fisher's exact tests were used to compare survivors and nonsurvivors. Survivors were significantly younger than nonsurvivors (3.5 vs 11.5 y, P = 0.033). No side effects were reported. Survival to discharge was 40% with identical 90-day survival. Of the nonsurvivors, 50% died naturally., Conclusions: There was an association between the rate of CPP and the change in albumin after CPP CRI in critically ill dogs, suggesting that CPP may be a viable option for treatment of hypoalbuminemia., (© Veterinary Emergency and Critical Care Society 2019.)