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Ugeskrift For Laeger Jan 2024Congenital fibrinogen disorders are rare pathologies of the haemostasis, comprising afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia and hypodysfibrinogenaemia.... (Review)
Review
Congenital fibrinogen disorders are rare pathologies of the haemostasis, comprising afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia and hypodysfibrinogenaemia. Phenotypic manifestations are variable, patients may be asymptomatic or suffer from bleeding or thrombosis. Most of congenital fibrinogen disorders are coincidentally discovered. Fibrinogen concentrate is used to treat bleeding, whereas low-molecular weight heparin is most often administered for the treatment of thrombotic complications. The aim of this review is to provide an update of the knowledge of congenital fibrinogen disorders for Danish physicians.
Topics: Humans; Fibrinogen; Afibrinogenemia; Hemorrhage; Hemostasis; Hemostatics; Thrombosis
PubMed: 38235772
DOI: 10.61409/V04230274 -
Hereditas Jan 2024Fibrinogen plays pivotal roles in multiple biological processes. Genetic mutation of the fibrinogen coding genes can result in congenital fibrinogen disorders (CFDs). We...
BACKGROUND
Fibrinogen plays pivotal roles in multiple biological processes. Genetic mutation of the fibrinogen coding genes can result in congenital fibrinogen disorders (CFDs). We identified a novel heterozygous missense mutation, FGG c.1168G > T (NCBI NM_000509.6), and conducted expression studies and functional analyses to explore the influence on fibrinogen synthesis, secretion, and polymerization.
METHODS
Coagulation tests were performed on the patients to detect the fibrinogen concentration. Whole-exome sequencing (WES) and Sanger sequencing were employed to detect the novel mutation. Recombinant fibrinogen-producing Chinese hamster ovary (CHO) cell lines were built to examine the recombinant fibrinogen synthesis and secretion by western blotting and enzyme-linked immunosorbent assay (ELISA). The functional analysis of fibrinogen was performed by thrombin-catalyzed fibrin polymerization assay. In silico molecular analyses were carried out to elucidate the potential molecular mechanisms.
RESULTS
The clinical manifestations, medical history, and laboratory tests indicated the diagnosis of hypodysfibrinogenemia with bleeding phenotype in two patients. The WES and Sanger sequencing revealed that they shared the same heterozygous missense mutation, FGG c.1168G > T. In the expression studies and functional analysis, the missense mutation impaired the recombinant fibrinogen's synthesis, secretion, and polymerization. Furthermore, the in silico analyses indicated novel mutation led to the hydrogen bond substitution.
CONCLUSION
The study highlighted that the novel heterozygous missense mutation, FGG c.1168G > T, would change the protein secondary structure, impair the "A: a" interaction, and consequently deteriorate the fibrinogen synthesis, secretion, and polymerization.
Topics: Animals; Cricetinae; Humans; Afibrinogenemia; CHO Cells; Cricetulus; Fibrinogen; Mutation; Mutation, Missense; Phenotype
PubMed: 38233949
DOI: 10.1186/s41065-024-00308-0 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Nov 2023To analyze the phenotype and genotype of two pedigrees with inherited fibrinogen (Fg) deficiency caused by two heterozygous mutations. We also preliminarily probed the...
To analyze the phenotype and genotype of two pedigrees with inherited fibrinogen (Fg) deficiency caused by two heterozygous mutations. We also preliminarily probed the molecular pathogenesis. The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and plasma fibrinogen activity (Fg∶C) of all family members (nine people across three generations and three people across two generations) were measured by the clotting method. Fibrinogen antigen (Fg:Ag) was measured by immunoturbidimetry. Direct DNA sequencing was performed to analyze all exons, flanking sequences, and mutated sites of FGA, FGB, and FGG for all members. Thrombin-catalyzed fibrinogen polymerization was performed. ClustalX 2.1 software was used to analyze the conservatism of the mutated sites. MutationTaster, PolyPhen-2, PROVEAN, SIFT, and LRT online bioinformatics software were applied to predict pathogenicity. Swiss PDB Viewer 4.0.1 was used to analyze the changes in protein spatial structure and molecular forces before and after mutation. The Fg∶C of two probands decreased (1.28 g/L and 0.98 g/L, respectively). The Fg∶Ag of proband 1 was in the normal range of 2.20 g/L, while it was decreased to 1.01 g/L in proband 2. Through genetic analysis, we identified a heterozygous missense mutation (c.293C>A; p.BβAla98Asp) in exon 2 of proband 1 and a heterozygous nonsense mutation (c.1418C>G; p.BβSer473*) in exon 8 of proband 2. The conservatism analysis revealed that Ala98 and Ser473 presented different conservative states among homologous species. Online bioinformatics software predicted that p.BβAla98Asp and p.BβSer473* were pathogenic. Protein models demonstrated that the p.BβAla98Asp mutation influenced hydrogen bonds between amino acids, and the p.BβSer473* mutation resulted in protein truncation. The dysfibrinogenemia of proband 1 and the hypofibrinogenemia of proband 2 appeared to be related to the p.BβAla98Asp heterozygous missense mutation and the p.BβSer473* heterozygous nonsense mutation, respectively. This is the first ever report of these mutations.
Topics: Humans; Afibrinogenemia; Codon, Nonsense; Pedigree; Phenotype; Fibrinogen; Genotype
PubMed: 38185523
DOI: 10.3760/cma.j.issn.0253-2727.2023.11.008 -
Thrombosis Research Feb 2024
Topics: Humans; Fibrinogen; Afibrinogenemia; Mutation; Fibrinogens, Abnormal
PubMed: 38159325
DOI: 10.1016/j.thromres.2023.12.012 -
Thrombosis Research Jan 2024Lung transplantation is associated with high proportion of transfusion. Monitoring of coagulopathy using viscoelastic tests could aid in the perioperative management of...
INTRODUCTION
Lung transplantation is associated with high proportion of transfusion. Monitoring of coagulopathy using viscoelastic tests could aid in the perioperative management of bleeding. The aim of the study was to assess the predictive cut-off values for thrombocytopenia and hypofibrinogenemia using the new thromboelastography analyzer, ClotPro.
METHODS
We retrospectively enrolled 65 patients who underwent lung transplantation and were sampled for both viscoelastic assays and conventional coagulation assays simultaneously during the procedure. We characterized the correlation between the EX-test (extrinsic pathway) and platelet count as well as between the FIB-test (extrinsic pathway after platelet inhibition) and fibrinogen concentration. Then, we used ROC curve analysis to determine the optimal EX-test and FIB-test values for predicting thrombocytopenia and hypofibrinogenemia.
RESULTS
All the amplitude values of the EX-test (A5, A10, A20, MCF) showed correlation with platelets count (Spearman's rank correlation coefficient ranging from 0.75 to 0.77, all p < 0.0001). We also observed a strong correlation between the amplitude values of the FIB-test (A5, A10, A20 and MCF) and the fibrinogen concentration (Spearman's rank correlation coefficient ranging from 0.68 to 0.71, all p < 0.0001). The AUCs of the EX-test values for thrombocytopenia <100 G/L and <80 G/L ranged from 0.80 to 0.93. Similarly, the AUCs of the FIB-test values for hypofibrinogenemia <1.5 g/L and <2 g/L ranged from 0.74 to 0.83. These results indicate that only the five-minute parameter of thromboelastometry is sufficient for detecting thrombocytopenia and hypofibrinogenemia in patients undergoing lung transplantation. The proposed cut off values for the EX-test to predict thrombocytopenia <80 G/L showed high sensitivity (>86 %), high specificity (>89 %) and high negative predictive value (>95 %). FIB-test cut off values predictive of fibrinogen below 1.5 g/L showed sensitivity (>78 %), specificity (>55 %) and negative predictive value (>88 %).
CONCLUSIONS
Our study provided preliminary results that are useful for developing a ClotPro-based algorithm to guide transfusion in lung transplantation. Future interventional studies will be necessary to validate these cut-off values of ClotPro for guiding transfusion.
Topics: Humans; Thrombelastography; Afibrinogenemia; Retrospective Studies; Thrombocytopenia; Fibrinogen; Thrombosis; Lung Transplantation
PubMed: 38128338
DOI: 10.1016/j.thromres.2023.11.029 -
International Journal of Antimicrobial... Feb 2024Tigecycline has been widely used for multi-drug-resistant bacterial infections in China. Although many studies have reported the risk factors for tigecycline-induced...
BACKGROUND
Tigecycline has been widely used for multi-drug-resistant bacterial infections in China. Although many studies have reported the risk factors for tigecycline-induced hypofibrinogenaemia, it remains unknown whether valproic acid or voriconazole in combination with tigecycline is associated with the decrease in fibrinogen, as both drugs could lead to coagulation disorders. The aim of this study was to develop a nomogram for the prediction of tigecycline-induced hypofibrinogenaemia.
METHODS
This was a multi-centre retrospective case-control study. The primary outcome was the accurate prediction of tigecycline-induced hypofibrinogenaemia. Nomograms were developed from logistic regression models with least absolute shrinkage and selection operator regression for variable selection. Model performance was assessed via calibration plots, and models were validated internally using bootstrapping on a validation cohort.
RESULTS
In total, 2362 patients were screened, of which 611 were eligible for inclusion in this study. These 611 patients were divided into the training cohort (n=488) and the validation cohort (n=123). Predictors included in the nomogram for the total population were total dose, age, fibrinogen, prothrombin time (PT), comorbidity, and concomitant use of voriconazole. Total dose, fibrinogen, PT, activated partial thromboplastin time, white blood cell count, and concomitant use of voriconazole were selected to predict hypofibrinogenaemia in patients with malignant haematologic diseases. Both models were calibrated adequately, and their predictions were correlated with the observed outcome. The cut-offs for treatment duration in the total population and the subgroup were 10 and 6 days, respectively.
CONCLUSIONS
Tigecycline in combination with voriconazole could increase the risk of hypofibrinogenaemia, and tigecycline-induced hypofibrinogenaemia is more likely to occur in patients with malignant haematologic diseases.
Topics: Humans; Tigecycline; Nomograms; Afibrinogenemia; Retrospective Studies; Case-Control Studies; Voriconazole; Fibrinogen
PubMed: 38104947
DOI: 10.1016/j.ijantimicag.2023.107062 -
Paediatric Anaesthesia Jul 2024Newer generation viscoelastic tests, TEG6s, offer point-of-care hemostatic therapy in adult patients. However, their efficacy in estimating fibrinogen levels in... (Comparative Study)
Comparative Study
BACKGROUND
Newer generation viscoelastic tests, TEG6s, offer point-of-care hemostatic therapy in adult patients. However, their efficacy in estimating fibrinogen levels in pediatric patients undergoing cardiac surgery is not well established.
AIMS
This study evaluates TEG6s for estimating fibrinogen levels in pediatric cardiac surgery patients and its predictive capability for post-bypass hypofibrinogenemia.
METHODS
A single-center, retrospective study on pediatric patients (under 18 years) who underwent cardiac surgery with cardiopulmonary bypass from August 2020 and November 2022. Blood samples for estimated whole blood functional fibrinogen level via TEG6s (Haemonetics Inc.) and concurrent laboratory-measured plasma fibrinogen via von Clauss assay were collected at pre- and post-cardiopulmonary bypass.
RESULTS
Paired data for TEG6s estimated functional fibrinogen levels and plasma fibrinogen were analyzed for 432 pediatric patients pre-bypass. It was observed that functional fibrinogen consistently overestimated plasma fibrinogen across all age groups with a mean difference of 138 mg/dL (95% confidence interval [CI]: 128-149 mg/dL). This positive bias in the pre-bypass data was confirmed by Bland-Altman analysis. Post-bypass, functional fibrinogen estimates were comparable to plasma fibrinogen in all patient groups with a mean difference of -6 mg/dL (95% CI: -20-8 mg/dL) except for neonates, where functional fibrinogen levels underestimated plasma fibrinogen with a mean difference of -38 mg/dL (95% CI: -64 to -12 mg/dL). The predictive accuracy of functional fibrinogen for detecting post-bypass hypofibrinogenemia (plasma fibrinogen ≤250 mg/dL) demonstrated overall fair accuracy in all patients, indicated by an area under the curve of 0.73 (95% CI: 0.65-0.80) and good accuracy among infants, with an area under the curve of 0.80 (95% CI: 0.70-0.90). Similar performance was observed in predicting critical post-bypass hypofibrinogenemia (plasma fibrinogen ≤200 mg/dL). Based on these analyses, optimal cutoffs for predicting post-bypass hypofibrinogenemia were established as a functional fibrinogen level ≤270 mg/dL and MA ≤15 mm.
CONCLUSION
This study demonstrates that whole blood functional fibrinogen, as estimated by TEG6s, tends to overestimate baseline plasma fibrinogen levels in pediatric age groups but aligns more accurately post-cardiopulmonary bypass, particularly in neonates and infants, suggesting its potential as a point-of-care tool in pediatric cardiac surgery. However, the variability in TEG6s performance before and after bypass highlights the need for careful interpretation of its results in clinical decision-making. Despite its contributions to understanding TEG6s in pediatric cardiac surgery, the study's design and inherent biases warrant cautious application of these findings in clinical settings.
Topics: Humans; Fibrinogen; Retrospective Studies; Infant; Cardiac Surgical Procedures; Child, Preschool; Female; Male; Child; Thrombelastography; Adolescent; Infant, Newborn; Cardiopulmonary Bypass; Afibrinogenemia; Blood Coagulation Tests
PubMed: 38071737
DOI: 10.1111/pan.14820 -
International Journal of Molecular... Nov 2023Variant identification underlying inherited dysfibrinogenemia quite exceptionally fails. We report on two dysfibrinogenemia cases whose underlying DNA variant could not...
Variant identification underlying inherited dysfibrinogenemia quite exceptionally fails. We report on two dysfibrinogenemia cases whose underlying DNA variant could not be identified by Sanger analysis. These failures result from two distinct mechanisms. The first case involved raw signal overcorrection by a built-in software, and the second constituted the first description of mosaicism for one of the fibrinogen genes. This mosaicism was subsequently identified by next-generation sequencing reanalysis of the sample.
Topics: Humans; Mosaicism; Afibrinogenemia; Mutation, Missense; Algorithms; Mutation
PubMed: 38068874
DOI: 10.3390/ijms242316551 -
Ultrasound in Obstetrics & Gynecology :... Jun 2024Management of placenta accreta spectrum (PAS) with the placenta kept in situ aims to preserve fertility and minimize blood loss. However, this method is associated with... (Review)
Review
OBJECTIVE
Management of placenta accreta spectrum (PAS) with the placenta kept in situ aims to preserve fertility and minimize blood loss. However, this method is associated with a risk of coagulopathy and subsequent bleeding. The aim of this study was to evaluate the occurrence and pathophysiology of coagulopathy in cases of PAS managed conservatively.
METHODS
We reviewed our database for cases of PAS in which the placenta was kept in situ. In addition, we performed a systematic review of articles on PAS in which the placenta was left in situ and was complicated by coagulopathy. PubMed was searched for publications between 1980 and 2023. Our eligibility criteria included studies in which no additional interventions were performed other than keeping the placenta entirely in situ, and in which coagulopathy was reported.
RESULTS
After screening and selection of full-text articles, 10 studies were included in the review. A review of our databases yielded a case series of PAS managed conservatively with the placenta kept in situ. When adding our case series to the results of our systematic review, a total of 87 cases were found to have been managed conservatively, with 28 cases of coagulopathy. Of these, the time at which coagulopathy developed was known in 11 cases. The median time at development of coagulopathy was 58 (interquartile range, 50-67) days postpartum.
CONCLUSIONS
Our findings highlight that conservative management of PAS with the placenta in situ poses a risk of coagulopathy. Keeping the placenta in situ after delivery prolongs the risk factors that are integral to PAS. The pathophysiology behind coagulopathy is comparable with that of concealed placental abruption, due to the disrupted uteroplacental interface and the collection of blood in the placenta. Therefore, the presence of large placental lakes could be an indicator of developing coagulopathy. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Humans; Female; Placenta Accreta; Pregnancy; Conservative Treatment; Blood Coagulation Disorders; Postpartum Hemorrhage; Adult; Placenta
PubMed: 38030960
DOI: 10.1002/uog.27547 -
Journal of Cardiothoracic and Vascular... Jan 2024Cardiac surgery with cardiopulmonary bypass (CPB) is associated with hypofibrinogenemia and severe bleeding requiring transfusion. Guidelines recommend cryoprecipitate... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Cardiac surgery with cardiopulmonary bypass (CPB) is associated with hypofibrinogenemia and severe bleeding requiring transfusion. Guidelines recommend cryoprecipitate or fibrinogen concentrate (FC) for the treatment of acquired hypofibrinogenemia. This study compared cryoprecipitate and FC for the correction of acquired hypofibrinogenemia and the associated costs.
DESIGN
A single-center, prospective, randomized study evaluating patients with hypofibrinogenemia after cardiac surgery. The primary endpoint was direct treatment cost. Secondary endpoints included the change in fibrinogen level after FC and/or cryoprecipitate dosing.
SETTING
A single-center study in Astana, Kazakhstan.
PARTICIPANTS
Participants who underwent CPB from 2021 to 2022 and developed clinically significant bleeding and hypofibrinogenemia.
INTERVENTIONS
Patients were randomized to receive cryoprecipitate or FC.
MEASUREMENTS AND MAIN RESULTS
Eighty-eight adult patients with acquired hypofibrinogenemia (<2.0 g/L) after CPB were randomized to receive cryoprecipitate (N = 40) or FC (N = 48), with similar demographics between groups. Overall, mean ± SD 9.33 ± 0.94 units (range, 8-10) cryoprecipitate or 1.40 ± 0.49 g (1-2) FC was administered to the 2 groups. From before administration to 24 hours after, mean plasma fibrinogen increased by a mean ± SD of 125 ± 65 and 96 ± 65 mg/dL in the cryoprecipitate and FC groups, respectively. At 48 hours after administration, there was no significant difference in fibrinogen levels between groups. The mean direct cost of treatment with FC was significantly lower than with cryoprecipitate (p < 0.0001): $1,505.06 ± $152.40 and $631.75 ± $223.67 per patient for cryoprecipitate and FC, respectively.
CONCLUSION
Analysis of plasma fibrinogen concentration showed that cryoprecipitate and FC had comparable effectiveness. However, FC is advantageous over cryoprecipitate due to its ease of handling, lower cost, and high purity.
Topics: Adult; Humans; Fibrinogen; Afibrinogenemia; Prospective Studies; Hemostatics; Hemorrhage; Cardiac Surgical Procedures
PubMed: 38016817
DOI: 10.1053/j.jvca.2023.10.031