A case of anaphylactic shock to human fibrinogen infusion during cardiac surgery.

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.

Long-term persistence of carrier-bound fibrin sealant (TachoSil®) following abdominal surgery: a decade-long follow-up study.

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.

Fibrinógeno humano liofilizado para solución inyectable / Lyophilized human fibrinogen for solution for injection

INTRODUCCIÓN: Algunas consideraciones quirúrgicas en pacientes con enfermedades oncológicas se asocian con hemorragias graves. Aunque la causa suele ser multifactorial, la hipofibrinogenemia (nivel de fibrinógeno plasmático <150 a 200 mg/dl) es común. El fibrinógeno es el principal componente estructural en la formación de coágulos y es esencial para una hemostasia eficaz, pero el fibrinógeno es el primer factor que cae a y sangrado quirúrgico2 . Las causas de hipofibrinogenemia incluyen el consumo de factores de coagulación, exacerbado por niveles críticamente bajos en situaciones como hemorragia importante durante cirugías, así como la hemodilución y la hiperfibrinólisis3, 4 Existe una estrecha asociación entre los niveles bajos de fibrinógeno y el sangrado posoperatorio grave5 . Además, la transfusión de componentes sanguíneos después de una cirugía cardíaca se asocia fuertemente con una mayor morbilidad, mortalidad y costos hospitalarios6 . El manejo eficaz de la coagulación es esencial para ayudar a lograr resultados exitosos. La principal coagulopatía observada durante esta cirugía abdominal extensa es la rápida caída de la concentración de fibrinógeno plasmático y, en consecuencia, la disminución de la calidad del coágulo7 . Las directrices recientes de la Asociación Europea de Cirugía Cardiotorácica y la Asociación Europea de Anestesiología Cardiotorácica recomiendan el uso de crioprecipitado o concentrado de fibrinógeno (FC) para el tratamiento de la hipofibrinogenemia adquirida durante la cirugía cardíaca. ACERCA DE LA TECNOLOGÍA SANITARIA: Hay varias fuentes de fibrinógeno disponibles, siendo el crioprecipitado y el concentrado de fibrinógeno humano (HFC) las opciones preferidas en términos de concentración de fibrinógeno. Ambos tipos de productos han demostrado capacidad para aumentar los niveles de fibrinógeno plasmático en pacientes hemorrágicos10,11. El crioprecipitado tiene un contenido variable de fibrinógeno, requiere compatibilidad con el tipo de sangre, tiempo para descongelarse y conlleva riesgos de lesión pulmonar aguda relacionada con transfusiones y transmisión de patógenos, y se ha retirado en algunos países europeos12,13 . El HFC es una preparación altamente purificada que contiene una concentración definida de fibrinógeno, no requiere coincidencia del tipo de sangre y ofrece una mayor seguridad contra patógenos debido a los pasos de inactivación del virus utilizados en la producción. El crioprecipitado se precipita descongelando plasma fresco congelado de donantes, desprovisto de leucocitos, que se centrifuga y se re-suspende en plasma; mientras que FC es una preparación inactivada por virus, altamente purificada y derivada de plasma. Existe un alto grado de variabilidad en la concentración de fibrinógeno en el crioprecipitado, que según se informa contiene entre 3 y 30 g/l de unidades de fibrinógeno. Un estudio encontró que 2 unidades de crioprecipitado por cada 10 kg de peso corporal aumentaban la concentración de fibrinógeno plasmático en 1 g/l18; sin embargo, el contenido de fibrinógeno del crioprecipitado no está estandarizado. Por el contrario, el FC reconstituido contiene un contenido estandarizado de 200 mg/dL de fibrinógeno. METODOLOGÍA: Primero se realizó una revisión de los documentos que fueron enviados a la unidad y se conversó con la Unidad funcional de Banco de Sangre y Medicina Transfusional (Unidad solicitante) del Instituto Nacional de Enfermedades Neoplásicas (INEN). La segunda parte estuvo enfocada en un análisis de la revisión de la literatura para respaldar la decisión basada en evidencia científica. Se priorizaron estudios por ensayos clínicos aleatorizados (ECA) o revisiones sistemáticas (RS), en caso de haber nuevos estudios observacionales que no fueron incluidos en RS se evaluaron su inclusión. ANALISIS DE EVIDENCIA: En Astana, Kazajstán24 se realizó un estudio prospectivo y aleatorizado realizado en pacientes que se sometieron a cirugía cardíaca y desarrollaron hemorragia e hipofibrinogenemia clínicamente significativas después de la cirugía cardiaca con circulación extracorpórea; el crioprecipitado y el fibrinógeno concentrado (FC) eran el estándar de atención en la institución. El estudio incluyó a todos los pacientes adultos de ≥18 años sometidos a cirugía cardíaca con hemorragia significativa e hipofibrinogenemia, definida como un nivel plasmático de fibrinógeno <200 mg/dL confirmado por el método Clauss. Después de la inscripción se aleatorizó en dos grupos, FC calculado como: [nivel de fibrinógeno objetivo (mg/dL) ­ nivel de fibrinógeno medido (mg/dL)] / 1,8 (mg/dL por mg/kg de peso corporal); y crioprecipitado 1 unidad/5-10kg. Además, estimaron costos directos. Ochenta y ocho pacientes adultos con hipofibrinogenemia adquirida (<2,0 g/l) distribuido en crioprecipitado (N = 40) o FC (N = 48), con datos demográficos y laboratoriales similares entre los grupos. En general, se administró una media 9,33±0,94 unidades (rango, 8-10) de crioprecipitado y 1,40±0,49 g (rango 1-2) de FC. Cabe mencionar que antes de la cirugía, los niveles de fibrinógeno plasmático eran ligeramente más bajos en el grupo FC. Después de la administración de crioprecipitado o FC, los niveles medios de fibrinógeno aumentaron en ambos grupos. Desde antes de la administración hasta 24 horas después de la administración, el nivel medio de fibrinógeno plasmático aumentó en una media de 125 ± 65 mg/dL en el grupo de crioprecipitado y 96 ± 65 mg/dL en el grupo de FC (entre grupos, p = 0,4409 para varianzas iguales. 48 horas después de la administración del fármaco del estudio, los niveles de fibrinógeno habían aumentado aún más en ambos grupos y no hubo diferencias significativas en los niveles de fibrinógeno entre los pacientes de los grupos de crioprecipitado y FC. Los autores concluyen que en el estudio mostraron que tanto el FC como el crioprecipitado fueron eficaces para aumentar los niveles de fibrinógeno plasmático en pacientes que requirieron cirugía cardíaca, que sufrieron hemorragia significativa e hipofibrinogenemia. No se informaron problemas de seguridad para ninguno de los medicamentos. Se describió que el concentrado de fibrinógeno era significativamente más barato que el crioprecipitado y ventajoso debido a la velocidad y facilidad de preparación. Debido a la necesidad de cumplir con los protocolos establecidos en el centro hospitalario, las dosis no fueron equivalentes de fibrinógeno. CONCLUSIONES: INFORME N° 000098-2024-UFBSMT- DP-DISAD/INEN remitido por la Dra. Evelyn Norabuena Mautino, Coordinador de la Unidad Funcional de Banco de Sangre y Medicina Transfusional(e) del INEN al Jefe de la Unidad Funcional de Evaluación de Tecnologías Sanitarias del INEN. Existe una estrecha asociación entre los niveles bajos de fibrinógeno y el sangrado posoperatorio grave5. Además, la transfusión de componentes sanguíneos después de una cirugía cardíaca se asocia fuertemente con una mayor morbilidad, mortalidad y costos hospitalarios6. El fibrinógeno se puede complementar mediante la administración de plasma fresco congelado (PFC), crioprecipitado o concentrado de fibrinógeno. El PFC y el crioprecipitado son productos sanguíneos alogénicos que requieren pruebas cruzadas y descongelación antes de su administración y también están relacionados con un mayor riesgo de transmisión de patógenos y reacciones inmunológicas17,18. Alternativamente, el concentrado de fibrinógeno es un derivado del plasma sometido a pasteurización que minimiza el riesgo de reacciones inmunológicas y alérgicas18,19. Se realizó una estrategia de búsqueda en PubMed encontrando un total, de 102 artículos, donde finalmente se seleccionaron 4 estudios. La evidencia científica indica que el análisis de la concentración de fibrinógeno plasmático mostró que el crioprecipitado y el FC tenían una eficacia comparable. Sin embargo, el FC tiene ventajas sobre el crioprecipitado debido a su facilidad de manipulación, menor reacción cruzada y alta pureza. Se puede considerar el uso de concentrado de fibrinógeno para el tratamiento de hemorragias en pacientes con hipofibrinogenemia adquirida en cirugías. El beneficio económico del FC es incierto, teniendo evidencias contradictorias, pero un estudio indica que puede ser competitivo con la crioterapia, si el costo del FC disminuye en un 44% o demostrar que ahorra entre 025 y 066 días de UCI, mientras que otro estudio indica el beneficio neto incremental del concentrado de fibrinógeno frente al crioprecipitado fue positivo (probabilidad de ser rentable 86% y 97% a $0 y USD $1489 disposición a pagar, respectivamente. El beneficio neto fue muy incierto para los pacientes no selectivos y con enfermedades críticas del estudio FIBERS.

Long-Term Safety Analysis of a Fibrinogen Concentrate (RiaSTAP®/Haemocomplettan® P).

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.

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.

Fibrinogen-based cell and spheroid sheets manipulating and delivery for mouse hindlimb ischemia.

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 higherin vitrotubule 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.

Early cryoprecipitate transfusion versus standard care in severe postpartum haemorrhage: a pilot cluster-randomised trial.

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.

Early administration of fibrinogen concentrate in patients with polytrauma with thromboelastometry suggestive of hypofibrinogenemia: A randomized feasibility trial.

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.

Coadministration of iRGD peptide with ROS-sensitive nanoparticles co-delivering siFGL1 and siPD-L1 enhanced tumor immunotherapy.

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.

Choosing a treatment method for post-catheterization pseudoaneurysms guided by the late to early velocity index.

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.

Pro-Con Debate: Fibrinogen Concentrate or Cryoprecipitate for Treatment of Acquired Hypofibrinogenemia in Cardiac Surgical Patients.

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.

Viscoelastic testing to assess the effects of rapid fibrinogen concentrate administration after cardiopulmonary bypass: insights from the REPLACE study.

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.

Trigger and Target for Fibrinogen Supplementation Using Thromboelastometry (ROTEM) in Patients Undergoing Open Thoraco-Abdominal Aortic Aneurysm Repair.

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 P2Y12 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 (R2 = .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.

Fibrinogen Replacement Therapy for Traumatic Coagulopathy: Does the Fibrinogen Source Matter?

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 (r2 = 0.99). A marked increase in Factor VIII, XIII and α2-antiplasmin was observed in cryoprecipitate (p < 0.05). Increasing concentrations of fibrinogen from both sources were strongly correlated with ROTEM parameters (r2 = 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.

Emergency administration of fibrinogen concentrate for hemorrhage: A protocol for systematic review and meta-analysis.

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.

Early and systematic administration of fibrinogen concentrate in postpartum haemorrhage following vaginal delivery: the FIDEL randomised controlled trial.

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.

Paradoxical pulmonary hemorrhage associated with hemocoagulase batroxobin in a patient with hemoptysis: A CARE-compliant case report.

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.

Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia.

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.

Transfusion with Cryoprecipitate for Very Low Fibrinogen Levels Does Not Affect Bleeding or Survival in Critically Ill Cirrhosis Patients.

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.

Tumour spillage of the pleomorphic adenoma of the parotid gland: A proposal for intraoperative measures.

Intraoperative rupture of a pleomorphic adenoma capsule with potential tumor spillage into the surgical field is thought to occur in approximately 5% of cases and has traditionally been recognized as one of the major causes of recurrence. It seems that recurrence of a pleomorphic adenoma is a multifactorial event, being related to surgery (capsular exposure, tumor spillage) and tumor-related factors (histologic subtype, incomplete capsule, pseudopodia, satellites). The exact quantities of these ingredients in the recipe of recurrence, as well as possible interactions between them (e.g. the potentially increased fragility of myxoid pleomorphic adenomas; satellites or pseudopodia being cut off the tumor specimen during an extremely narrow extracapsular dissection) remain unclear. A thorough literature search did not reveal any proposed algorithms for the intraoperative management of a capsular tear. The aim of this short communication is to present our department's experience-based proposal for intraoperative measures in the case of macroscopic rupture and tumor spillage of a parotid gland pleomorphic adenoma.