RESUMO
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.
Assuntos
Fibrinogênio , Humanos , Fibrinogênio/uso terapêutico , Fibrinogênio/efeitos adversos , Fibrinogênio/administração & dosagem , Afibrinogenemia/tratamento farmacológico , Feminino , Estudos Retrospectivos , Masculino , Hemorragia , Tromboembolia/etiologiaRESUMO
Importance: Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage. Objective: To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol. Design, Setting, and Participants: CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion. Intervention: Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury. Main Outcomes and Measures: The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. Results: Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; P = .74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%). Conclusions and Relevance: Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.
Assuntos
Hemorragia , Ferimentos Penetrantes , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Hemorragia/terapia , Hemorragia/tratamento farmacológico , Fibrinogênio/efeitos adversos , Transfusão de Sangue , Transfusão de Componentes SanguíneosRESUMO
INTRODUCTION: The aims of the study were to investigate the risk factors of tigecycline-induced hypofibrinogenemia and to evaluate the safety of tigecycline with concomitant antithrombotic drugs. METHODS: We performed a retrospective analysis of patients who received tigecycline for more than 3 days between January 2015 and June 2019. Clinical and laboratory data were collected including fibrinogen concertation, tigecycline dose, duration of treatment, disease severity, complete blood count, indicators of infection, liver and renal function. Risk factors of hypofibrinogenemia were analyzed by univariate and multivariate analysis. To evaluate the safety of tigecycline and concomitant antithrombotic drugs, bleeding events were assessed by comparing the decline in hemoglobin and the amount of red blood cell transfusion in patients with antithrombotic drugs and those without. RESULTS: This study included a total of 68 cases, 20 of which experienced hypofibrinogenemia while receiving tigecycline treatment. Duration of treatment, cefoperazone/sulbactam combination therapy, and fibrinogen levels prior to initiation of tigecycline were risk factors associated with tigecycline-induced hypofibrinogenemia. There were 26 recorded bleeding incidents, 25 of which happened before the start of tigecycline. Antithrombotic and non-antithrombotic patients did not differ in their hemoglobin decline or need for red blood cell transfusions while taking tigecycline. CONCLUSION: A longer treatment duration, cefoperazone/sulbactam combination therapy, and a lower level of fibrinogen before tigecycline were associated with an increased risk of tigecycline-induced hypofibrinogenemia. A combination of antithrombotic drugs and tigecycline did not aggravate the bleeding events during tigecycline treatment.
Assuntos
Afibrinogenemia , Antibacterianos , Humanos , Tigeciclina/efeitos adversos , Antibacterianos/efeitos adversos , Estudos Retrospectivos , Fibrinolíticos/efeitos adversos , Cefoperazona/efeitos adversos , Sulbactam/efeitos adversos , Afibrinogenemia/induzido quimicamente , Afibrinogenemia/tratamento farmacológico , Hemorragia/induzido quimicamente , Fibrinogênio/efeitos adversos , HemoglobinasRESUMO
The current study was conducted to examine the effect of l-carnitine (LC) supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase/protein kinase B pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). In addition to comparing the responses in cows with or without LC, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an LC-supplemented group (CAR; 25 g LC/cow per day; d 42 ante partum to d 126 postpartum (PP), n = 27). On d 111 PP, each cow was injected intravenously with LPS (Escherichia coli O111:B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d -11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)-17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary LC supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of LC. Dietary LC supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary LC than the outer mitochondrial membrane translocase (TOM complex).
Assuntos
Doenças dos Bovinos , Lactação , Feminino , Bovinos , Animais , Lactação/fisiologia , Lipopolissacarídeos/efeitos adversos , Carnitina/metabolismo , DNA Mitocondrial , Variações do Número de Cópias de DNA , Dinâmica Mitocondrial , Inflamação/veterinária , Suplementos Nutricionais , Fígado/metabolismo , Leite/metabolismo , Dieta/veterinária , Expressão Gênica , Fibrinogênio/efeitos adversos , Fibrinogênio/metabolismo , RNA Mensageiro/metabolismo , Proteínas Mitocondriais/metabolismo , Telômero , Doenças dos Bovinos/metabolismoRESUMO
BACKGROUND: A low plasma fibrinogen level influences blood component transfusion. Thromboelastometry provides clinical guidance for fibrinogen replacement in liver transplantation (LT). OBJECTIVES: We hypothesized that infusions of fibrinogen concentrate to reach an A10FibTem value of 11 mm during LT could reduce red blood cell (RBC) and other component and fluid requirements in comparison to standard care. METHODS: This randomized, blinded, multicenter trial in 3 hospitals enrolled 189 LT-scheduled patients allocated to an intervention target (A10FibTem, 11 mm) or a standard target (A10FibTem, 8 mm); 176 patients underwent LT with fibrinogen replacement. Data were analyzed by intention-to-treat (intervention group, 91; control group, 85). Blood was extracted, and fibrinogen kits were prepared to bring each patient's fibrinogen level to the assigned target at the start of LT, after portal vein clamping, and after graft reperfusion. The main outcome was the proportion of patients requiring RBC transfusion during LT or within 24 hours. RESULTS: The proportion of patients requiring RBCs did not differ between the groups: intervention, 74.7% (95% CI, 65.5%-83.3%); control, 72.9% (95% CI, 62.2%-82.0%); absolute difference, 1.8% (95% CI, -11.1% to 14.78%) (P = .922). Thrombotic events occurred in 4% of the patients in both groups; reoperation and retransplantation rates and mortality did not differ. Nearly 70% of the patients in both groups required fibrinogen concentrate to reach the target. Using an 11-mm A10FibTem target increased the maximum clot firmness without affecting safety. However, this change provided no clinical benefits. CONCLUSION: The similar low plasma fibrinogen concentrations could explain the lack of significant between-group outcomes.
Assuntos
Hemostáticos , Transplante de Fígado , Humanos , Fibrinogênio/efeitos adversos , Transplante de Fígado/efeitos adversos , Tromboelastografia , Transfusão de Componentes SanguíneosRESUMO
BACKGROUND: Congenital fibrinogen deficiency (CFD) is a rare coagulation disorder placing patients at increased bleeding risk. Human fibrinogen concentrate (HFC) represents current standard of care for fibrinogen replacement in CFD, however, limited data are available on HFC for prophylactic administration before/during surgery. Here, we report results and dosing considerations for HFC treatment in perioperative bleeding management in adult, adolescent, and pediatric patients with CFD. STUDY DESIGN AND METHODS: FORMA-02/FORMA-04 were multinational, prospective, open-label, uncontrolled Phase 3 HFC efficacy/safety studies for surgical bleeding prophylaxis in adult/adolescent (≥12 years) and pediatric patients (<12 years) respectively. HFC dosing was calculated to achieve pre-established target fibrinogen plasma levels. Overall hemostatic efficacy was assessed as success/failure by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) according to objective criteria. RESULTS: Twelve patients (≥12 years, N = 9; <12 years, N = 3) received HFC for surgical prophylaxis (15 surgeries; 13 minor, 2 major). Eleven minor surgeries in patients aged ≥12 years required a median of 1 infusion (range; 1-5), with a mean (±SD) dose of 93.50 mg/kg [±41.43] and two minor surgeries in patients <12 years required 1 infusion (91.55 mg/kg [±23.40]). The major surgery in an adult patient required eight infusions (225.3 mg/kg total dose). The major surgery in a pediatric patient required six infusions (450.4 mg/kg). All surgeries were rated successful by the IDMEAC. DISCUSSION: In adults/adolescents and pediatric patients with fibrinogen deficiency, HFC treatment for hemostatic management during/after minor and major surgery was successful, with efficacy comparable across the different age groups.
Assuntos
Afibrinogenemia , Hemostáticos , Adolescente , Adulto , Afibrinogenemia/tratamento farmacológico , Perda Sanguínea Cirúrgica/prevenção & controle , Criança , Fibrinogênio/efeitos adversos , Humanos , Estudos ProspectivosRESUMO
The etiologies of chronic obstructive pulmonary disease (COPD) remain unclear. Cadmium (Cd) causes both pulmonary fibrosis and emphysema; however, the predictors for Cd exposure and the mechanisms by which Cd causes COPD remain unknown. We demonstrated that Cd burden was increased in lung tissue from subjects with COPD and this was associated with cigarette smoking. Fibrinogen levels increased markedly in lung tissue of patients with smoked COPD compared with never-smokers and control subjects. Fibrinogen concentration also correlated positively with lung Cd load, but inversely with the predicted % of FEV1 and FEV1/FVC. Cd enhanced the secretion of fibrinogen in a cdc2-dependent manner, whereas fibrinogen further mediated Cd-induced peptidylarginine deiminase 2 (PAD2)-dependent macrophage activation. Using lung fibroblasts from CdCl2-treated Toll-like receptor 4 (TLR4) wild-type and mutant mice, we demonstrated that fibrinogen enhanced Cd-induced TLR4-dependent collagen synthesis and cytokine/chemokine production. We further showed that fibrinogen complexed with connective tissue growth factor (CTGF), which in turn promoted the synthesis of plasminogen activator inhibitor-2 (PAI-2) and fibrinogen and inhibited fibrinolysis in Cd-treated mice. The amounts of fibrinogen were increased in the bronchoalveolar lavage fluid (BALF) of Cd-exposed mice. Positive correlations were observed between fibrinogen with hydroxyproline. Our data suggest that fibrinogen is involved in Cd-induced macrophage activation and increases in fibrinogen in patients with COPD may be used as a marker of Cd exposure and predict disease progression.
Assuntos
Cádmio , Doença Pulmonar Obstrutiva Crônica , Animais , Cádmio/toxicidade , Fibrinogênio/efeitos adversos , Humanos , Pulmão/metabolismo , Ativação de Macrófagos , Camundongos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptor 4 Toll-LikeAssuntos
Coagulação Sanguínea , Fator VIII/uso terapêutico , Fibrinogênio/uso terapêutico , Transfusão de Sangue/instrumentação , Fator VIII/efeitos adversos , Fator VIII/química , Fibrinogênio/efeitos adversos , Fibrinogênio/química , Humanos , Masculino , Pessoa de Meia-Idade , Reação Transfusional/prevenção & controleRESUMO
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.
Assuntos
Transfusão de Sangue , Tratamento de Emergência/métodos , Fibrinogênio/administração & dosagem , Hemorragia/terapia , Hemostáticos/administração & dosagem , Ensaios Clínicos Controlados como Assunto , Fibrinogênio/efeitos adversos , Hemorragia/mortalidade , Hemostáticos/efeitos adversos , Mortalidade Hospitalar , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto , Resultado do TratamentoRESUMO
Due to the patients' underlying illness, in combination with circuit-induced coagulopathy, as well as PLT dysfunction, children supported by ECMO are a risk of receiving large volumes of blood components. Given the increasing use of modified blood products and newer biologics, it is unknown whether these products have equal efficacy and safety, in ECMO. The majority of guidance for transfusion therapy is based on expert opinion alone, and research on indications for RBC, plasma, and PLT transfusions for children on ECMO should be a priority.
Assuntos
Transfusão de Sangue/métodos , Oxigenação por Membrana Extracorpórea , Transfusão de Componentes Sanguíneos/efeitos adversos , Transfusão de Componentes Sanguíneos/métodos , Criança , Pré-Escolar , Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/métodos , Fator VIII/efeitos adversos , Fator VIII/imunologia , Fibrinogênio/efeitos adversos , Fibrinogênio/imunologia , Humanos , Lactente , Recém-Nascido , Plasma , Transfusão de Plaquetas/efeitos adversos , Transfusão de Plaquetas/métodosRESUMO
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.
Assuntos
Afibrinogenemia/tratamento farmacológico , Hemorragia Cerebral/prevenção & controle , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Fibrinogênio/administração & dosagem , Fibrinogênio/efeitos adversos , Qualidade de Vida , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Trombose/induzido quimicamenteRESUMO
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.
Assuntos
Afibrinogenemia/terapia , Transfusão de Sangue , Varizes Esofágicas e Gástricas/terapia , Fator VIII/administração & dosagem , Fibrinogênio/metabolismo , Hemorragia Gastrointestinal/terapia , Hipertensão Portal/terapia , Cirrose Hepática/terapia , Afibrinogenemia/sangue , Afibrinogenemia/diagnóstico , Afibrinogenemia/mortalidade , Biomarcadores/sangue , Transfusão de Sangue/mortalidade , Estado Terminal , Regulação para Baixo , Varizes Esofágicas e Gástricas/sangue , Varizes Esofágicas e Gástricas/diagnóstico , Varizes Esofágicas e Gástricas/mortalidade , Fator VIII/efeitos adversos , Feminino , Fibrinogênio/administração & dosagem , Fibrinogênio/efeitos adversos , Hemorragia Gastrointestinal/sangue , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/mortalidade , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/diagnóstico , Hipertensão Portal/mortalidade , Unidades de Terapia Intensiva , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Fibrinogen-like protein 1 (FGL1) was recently identified as a major ligand of lymphocyte-activation gene-3 (LAG-3) on activated T cells and serves as an immune suppressive molecule for regulation of immune homeostasis. However, whether FGL1 has therapeutic potential for use in the T cell-induced the autoimmune disease, rheumatoid arthritis (RA), is still unknown. Here, we attempted to evaluate the effect of FGL1 protein on arthritis progression. We also evaluated potential adverse events in a collagen-induced arthritis (CIA) mouse model. We first confirmed that soluble Fgl1 protein could specifically bind to surface Lag-3 receptor on 3T3-Lag-3 cells and further inhibit interleukin (IL-2) and interferon gamma (IFNγ) secretion from activated primary mouse T cells by 95% and 43%, respectively. Intraperitoneal administration of Fgl1 protein significantly decreased the inflammatory cytokine level (i.e., IL-1ß and IL-6) in local paw tissue, and prevented joint inflammation, cellular infiltration, bone deformation and attenuated collagen-induced arthritis progression in vivo. We further demonstrated that exogenous Fgl1 does not cause obvious adverse events during treatment by monitoring body weight and liver weight, and assessing the morphology of several organs (i.e., heart, liver, spleen, lung and kidney) by pathological studies. We expect that Fgl1 protein may be suitable to serve as a potential therapeutic agent for treatment of RA or even other types of T cell-induced autoimmune or inflammatory diseases in the future.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Fibrinogênio/farmacologia , Animais , Antígenos CD/metabolismo , Feminino , Fibrinogênio/efeitos adversos , Fibrinogênio/metabolismo , Fibrinogênio/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Células NIH 3T3 , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
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.
Assuntos
Afibrinogenemia/tratamento farmacológico , Anafilaxia/etiologia , Fibrinogênio/efeitos adversos , Hipersensibilidade/etiologia , Afibrinogenemia/imunologia , Afibrinogenemia/patologia , Anafilaxia/patologia , Criança , Feminino , Fibrinogênio/administração & dosagem , Fibrinogênio/antagonistas & inibidores , Humanos , Hipersensibilidade/patologia , Mutação , PrognósticoRESUMO
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.
Assuntos
Fibrinogênio/administração & dosagem , Hemorragia/terapia , Hemostáticos/administração & dosagem , Coagulantes/administração & dosagem , Coagulantes/efeitos adversos , Fator VIII/administração & dosagem , Fibrinogênio/efeitos adversos , Hemorragia/etiologia , Hemostáticos/efeitos adversos , Humanos , Testes Imediatos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Transfusion therapy in hemorrhaging trauma patients is associated with the development of thromboembolic events. It is unknown whether current resuscitation strategies, including large volumes of plasma and early administration of procoagulant therapy, increases this risk. METHODS: A systematic search was conducted in MEDLINE, PubMed, and Embase. Studies were screened by two independent reviewers and included if they reported on thromboembolic events in patients with severe trauma (injury severity score ≥16) who received transfusion of at least 1 unit of red blood cells. The ratio by which blood products were transfused, as well as use of procoagulant or antifibrinolytic medication, was recorded. RESULTS: A total of 40 studies with 11.074 bleeding trauma patients were included, in which 1.145 thromboembolic events were reported, yielding an incidence of 10% thromboembolic events. In studies performing routine screening for thromboembolic complications, the incidence ranged from 12% to 23%. The risk of thromboembolic events was increased after administration of tranexamic acid (TXA; odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.1; p < 0.001) and fibrinogen concentrate (OR, 2.1; 95% CI, 1.0-4.2; p = 0.04). Blood product ratio, the use of prothrombin complex concentrate or recombinant factor VIIa were not associated with thromboembolic events. CONCLUSION: This systematic review identified an incidence of thromboembolic events of 10% in severely injured bleeding trauma patients. The use of TXA and fibrinogen concentrate was associated with the development of thromboembolic complications.
Assuntos
Antifibrinolíticos/efeitos adversos , Fatores de Coagulação Sanguínea/administração & dosagem , Transfusão de Componentes Sanguíneos , Fibrinogênio/efeitos adversos , Plasma , Tromboembolia , Ácido Tranexâmico/efeitos adversos , Ferimentos e Lesões , Antifibrinolíticos/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Fator VIIa/uso terapêutico , Fibrinogênio/uso terapêutico , Hemorragia/sangue , Hemorragia/terapia , Humanos , Proteínas Recombinantes/uso terapêutico , Tromboembolia/sangue , Tromboembolia/induzido quimicamente , Ácido Tranexâmico/uso terapêutico , Índices de Gravidade do Trauma , Ferimentos e Lesões/sangue , Ferimentos e Lesões/terapiaRESUMO
OBJECTIVE: To date, the use of a fibrinogen concentrate (FC) administered in children with inherited fibrinogen deficiency is poorly documented. Treatment modalities may differ from those of adults. The aim of this study was to investigate the pharmacokinetics (PK), efficacy (bleeding/surgery) and safety of a triple-secured FC (FibCLOT, LFB, France) in young patients aged of 12 years or less. METHODS: This was a prospective, non-comparative, multicentre, phase 2-3 study. Estimated PK parameters were based on population PK modelling. Target fibrinogen levels were 1.2 and 1.0 g/L for major and minor events, respectively. In vivo recovery (IVR) was calculated at study entry to tailor the dose. RESULTS: Sixteen afibrinogenaemia patients were treated with FC: 12 included in the PK study (6 aged ≤ 6 years and 6 aged 7-12 years). IVR at 1 hour post-infusion (geometric mean [coefficient of variation]) was 1.91 [20%] mg/dL per mg/kg and results were similar between the two age groups (1.87 [14%]) and (1.96 [27%]) with no statistical differences. Estimated half-life (t 1/2) was 49.0 hours [12%] with no observed differences between groups (46.6 hours [10%] and 51.6 hours [12%]). Overall efficacy was rated as excellent/good in 96.9% of 32 bleeds and in 100% of 11 surgeries. Most of the events (39/43, 90.7%) were managed with one infusion. There was no serious adverse drug reaction. CONCLUSION: Individually tailored dosing was efficacious in children who exhibited a lower IVR and shorter t 1/2 than those previously reported in adolescent and adult patients emphasising the importance of individualised dose optimisation.
Assuntos
Afibrinogenemia/tratamento farmacológico , Fibrinogênio/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Criança , Pré-Escolar , Cromatografia por Troca Iônica , Relação Dose-Resposta a Droga , Feminino , Fibrinogênio/efeitos adversos , Fibrinogênio/isolamento & purificação , Fibrinogênio/farmacocinética , Seguimentos , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Hemostasia/efeitos dos fármacos , Humanos , Lactente , Infusões Intravenosas , Masculino , Hemorragia Pós-Operatória/prevenção & controleRESUMO
BACKGROUND: Low level of fibrinogen is a risk factor of perioperative bleeding, which is a major complication in surgical patients. However, the safety and efficacy of fibrinogen supplementation with fibrinogen concentrate to minimize postoperative bleeding remains unclear. OBJECTIVES: The primary aim of this review was to investigate the effect of fibrinogen concentrate in postoperative blood loss in adult surgical patients. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Databases of MEDLINE, EMBASE and CENTRAL were searched from their start date until July 2019. ELIGIBILITY CRITERIA: All randomized clinical trials comparing intravenous fibrinogen concentrate and placebo in adult surgical patients were included, regardless of type of surgery. Observational studies, case reports, case series and non-systematic reviews were excluded. RESULTS: Thirteen trials (n = 900) were included in this review. In comparison to placebo, fibrinogen concentrate significantly reduced the first 12-hour postoperative blood loss, with a mean difference of -134.6 ml (95% CI -181.9 to -87.4). It also significantly increased clot firmness in thromboelastometry (FIBTEM) with a mean difference of 2.5 mm (95%CI 1.1 to 3.8). No significant differences were demonstrated in the adverse events associated with fibrinogen concentrate use, namely incidence of thromboembolism, myocardial infarction and acute kidney injury. CONCLUSIONS: In this meta-analysis of 13 randomized trials, low level of evidence and substantial heterogeneity with small sample size limit strong recommendation on the use of fibrinogen concentrate in adult surgical patients. However, its use is tolerable without any notable adverse events. TRIAL REGISTRATION: CRD42019149164.
Assuntos
Fibrinogênio , Hemostáticos , Adulto , Fibrinogênio/efeitos adversos , Humanos , Hemorragia Pós-Operatória/induzido quimicamente , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , TromboelastografiaRESUMO
BACKGROUND AND OBJECTIVE: The use of fibrinogen concentrate to treat or prevent major bleeding with regard to potential adverse reactions has not been free of controversy. Our objective was to perform a post-authorization safety study to describe the use of Clottafact® (LFB Biomedicaments) fibrinogen concentrate in real-life medical practice in Mexico. METHODS: This was a prospective, observational study that collected and evaluated information between January 2017 and June 2019 related to suspected serious adverse reactions (SUSARs) during and after Clottafact® infusion. RESULTS: Information from 40 subjects was analyzed; 43% were women (n = 17), mean age was 39.05 ± 26.8 years (range 0-91 years). The medical specialties included in this analysis were cardiac surgery - 52.5% of the cases, gynecology/obstetrics - 17.5%, general surgery and orthopedics - 12.5% each, and hematology and neurosurgery - 2.5%, respectively. Mean plasma fibrinogen levels before and after Clottafact® infusion were 2.58 g/L and 4.02 g/L; p = 0.001, respectively. The mean Clottafact® dose was 2.20 ± 0.77 g. One patient presented SUSARs (dry mouth and dysgeusia) with drug administration, which ceased after treatment discontinuation. CONCLUSIONS: In this real-life post-marketing study, the safety profile of Clottafact® was very similar to previous reports. Thus, Clottafact® shows a favorable safety profile in clinical practice.