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Blood Jun 2021Due 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... (Clinical Trial)
Clinical Trial
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.
Topics: Adolescent; Adult; Afibrinogenemia; Age Factors; Cerebral Hemorrhage; Child; Child, Preschool; Factor VIII; Female; Fibrinogen; Humans; Male; Middle Aged; Quality of Life; Risk Factors; Thrombosis
PubMed: 33512441
DOI: 10.1182/blood.2020009472 -
Journal of Thrombosis and Haemostasis :... Oct 2006Hereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of... (Review)
Review
Hereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of immunoreactive protein; and type II deficiencies (dysfibrinogenemia and hypodysfibrinogenemia, i.e. qualitative defects), showing normal or altered antigen levels associated with reduced coagulant activity. While dysfibrinogenemias are in most cases autosomal dominant disorders, type I deficiencies are generally inherited as autosomal recessive traits. Patients affected by congenital afibrinogenemia or severe hypofibrinogenemia may experience bleeding manifestations varying from mild to severe. This review focuses on the genetic bases of type I fibrinogen deficiencies, which are invariantly represented by mutations within the three fibrinogen genes (FGA, FGB, and FGG) coding for the three polypeptide chains Aalpha, Bbeta, and gamma. From the inspection of the mutational spectrum of these disorders, some conclusions can be drawn: (i) genetic defects are scattered throughout the three fibrinogen genes, with only few sites appearing to represent relative mutational hot spots; (ii) several different types of genetic lesions and pathogenic mechanisms have been described in affected individuals (including gross deletions, point mutations causing premature termination codons, missense mutations affecting fibrinogen assembly/secretion, and uniparental isodisomy associated with a large deletion); (iii) the possibility to express recombinant fibrinogen mutants in eukaryotic cells is rapidly shedding light into the molecular mechanisms responsible for physiologic and pathologic properties of the molecule; (iv) though mutation analysis of the fibrinogen cluster does not yield precise information for predicting genotype/phenotype correlations, it still provides a valuable tool for diagnosis confirmation, identification of potential carriers, and prenatal diagnosis.
Topics: Adolescent; Adult; Afibrinogenemia; Child; Child, Preschool; DNA Mutational Analysis; Female; Fibrinogen; Gene Deletion; Genotype; Hemostasis; Humans; Infant; Infant, Newborn; Male; Phenotype; Point Mutation
PubMed: 16999847
DOI: 10.1111/j.1538-7836.2006.02094.x -
International Journal of Molecular... Dec 2021Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are... (Review)
Review
Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240-410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats.
Topics: Blood Coagulation; Blood Coagulation Tests; Fibrinogen; Hemorrhage; Humans; Mutation; Thrombosis
PubMed: 35008554
DOI: 10.3390/ijms23010132 -
Scientific Reports Jun 2023Systemic juvenile idiopathic arthritis (SJIA) is a chronic inflammatory disease of childhood with elevated serum IL-6 levels. As an inhibitor of IL-6R, tocilizumab (TCZ)...
Systemic juvenile idiopathic arthritis (SJIA) is a chronic inflammatory disease of childhood with elevated serum IL-6 levels. As an inhibitor of IL-6R, tocilizumab (TCZ) has been approved to treat SJIA patients. TCZ-induced hypofibrinogenemia has been only reported in adult cases and limited small case series with rheumatoid arthritis or giant cell arteritis. Here, we describe the incidence of TCZ-induced hypofibrinogenemia in SJIA patients and its possible influence on bleeding risk. SJIA patients with TCZ treatment in Shenzhen Children's hospital were retrospectively reviewed. Only those with the data on serum fibrinogen levels were included. Data on clinical manifestations, laboratory parameters, management, and sJADAS10-ESR score were collected. Laboratory data were extracted following the start of TCZ therapy at 2, 4, 8, 12, and 24 weeks thereafter. Seventeen SJIA patients with TCZ treatment were included. Thirteen (76.47%, 13/17) had hypofibrinogenemia. The lowest serum fibrinogen levels were even below 1.5 g/L in seven (41.17%, 7/17) patients. Among four patients without MTX treatment, two had obvious hypofibrinogenemia. Although five patients had already stopped steroid treatment 24 weeks after TCZ treatment, three of them still had hypofibrinogenemia. Only P14 had mild nasal mucosal bleeding occasionally. Coagulation tests were regularly performed in eight patients, of these, six had hypofibrinogenemia, which occurred following one to four doses of TCZ; continuation of TCZ treatment hadn't further aggravated hypofibrinogenemia. Serum fibrinogen levels were not decreased consistently with the improvement of sJADAS10-ESR score in more than half of these eight patients. Factor XIII was detected in six patients and none was identified with Factor XIII deficiency. TCZ alone may induce hypofibrinogenemia in SJIA patients. Continuation of TCZ treatment may be safe for most SJIA patients. But for SJIA patients with indications of surgery or complicated with MAS, the risk of hemorrhage should be regularly evaluated during TCZ treatment. The association between TCZ-induced hypofibrinogenemia and factor XIII deficiency remains uncertain.Trial registration: Not applicable; this was a retrospective study.
Topics: Child; Adult; Humans; Arthritis, Juvenile; Retrospective Studies; Afibrinogenemia; Factor XIII Deficiency; Disseminated Intravascular Coagulation; Fibrinogen; Treatment Outcome
PubMed: 37270663
DOI: 10.1038/s41598-023-36246-6 -
Genes Jul 2021Congenital fibrinogen disorders are very rare in dogs. Cases of afibrinogenemia have been reported in Bernese Mountain, Bichon Frise, Cocker Spaniel, Collie, Lhasa Apso,...
Congenital fibrinogen disorders are very rare in dogs. Cases of afibrinogenemia have been reported in Bernese Mountain, Bichon Frise, Cocker Spaniel, Collie, Lhasa Apso, Viszla, and St. Bernard dogs. In the present study, we examined four miniature wire-haired Dachshunds with afibrinogenemia and ascertained their pedigree. Homozygosity mapping and a genome-wide association study identified a candidate genomic region at 50,188,932-64,187,680 bp on CFA15 harboring (), (), and (). Sanger sequencing of all three genes in two cases and validation of the -associated mutation (:g.6296delT, NC_006597.3:g.52240694delA, rs1152388481) in pedigree members showed a perfect co-segregation with afibrinogenemia-affected phenotypes, obligate carriers, and healthy animals. In addition, the rs1152388481 variant was validated in 393 Dachshunds and samples from 33 other dog breeds. The rs1152388481 variant is predicted to modify the protein sequence of both transcripts (FGA201:p.Ile486Met and FGA-202:p.Ile555Met) leading to proteins truncated by 306 amino acids. The present data provide evidence for a novel truncating frameshift mutation that is very likely to explain the cases of severe bleeding due to afibrinogenemia in a Dachshund family. This mutation has already been spread in Dachshunds through carriers before cases were ascertained. Genetic testing allows selective breeding to prevent afibrinogenemia-affected puppies in the future.
Topics: Afibrinogenemia; Animals; Dog Diseases; Dogs; Female; Fibrinogen; Frameshift Mutation; Genome-Wide Association Study; Male; Pedigree
PubMed: 34356081
DOI: 10.3390/genes12071065 -
International Journal of Molecular... May 2021Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations... (Review)
Review
Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).
Topics: Afibrinogenemia; Endoplasmic Reticulum; Hepatocytes; Humans; Kupffer Cells; Liver; Microscopy, Electron, Transmission; Mutation; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency
PubMed: 34071368
DOI: 10.3390/ijms22115778 -
Orphanet Journal of Rare Diseases Apr 2022Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder. How to stratify high risk patients is one of the current challenges for the treatment of HLH....
Fulfillment status of hypertriglyceridemia and hypofibrinogenemia in children with hemophagocytic lymphohistiocytosis and risks of multiple organ dysfunction syndrome and early mortality.
BACKGROUND
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder. How to stratify high risk patients is one of the current challenges for the treatment of HLH. HLH patients usually fulfill multiple but not all eight diagnostic criteria. Different combinations of the fulfilled criteria may naturally cluster into previously undescribed subsets or phenotypes that may have different pathophysiology and demonstrate different risks for a poor outcome. The objectives of this study were to identify HLH subgroups according to the fulfillment of diagnostic criteria and evaluate the risk of multiple organ dysfunction syndrome (MODS) and 30-day mortality for subgroups. We retrospectively collect medical records of patients with discharge diagnosis of HLH between June 2015 and October 2018 from a tertiary children's hospital in China. Latent class analysis was used to identify class defining variables from HLH diagnostic items, and subgroups were defined according to different combinations of the class defining variables.
RESULTS
Triglyceride and fibrinogen were identified as the class defining variables. When evaluated in combinations, patients with hypertriglyceridemia and normal fibrinogen levels during hospitalization had the lowest risks for MODS (27.8%, OR = 1) and 30-day mortality (18.8%, OR = 1), and patients with normal triglyceride and hypofibrinogenemia had the highest risks for MODS (86.2%, OR = 16.24, P = 0.0002) and 30-day mortality (57.1%, OR = 5.78, P = 0.0187). The fulfillment status of hypertriglyceridemia and hypofibrinogenemia within 72 h of hospital admission was also associated with the risk of adverse outcomes.
CONCLUSIONS
The fulfillment status of hypertriglyceridemia and hypofibrinogenemia were associated with the risks of MODS and 30-day mortality among pediatric HLH patients. Further studies are needed to validate this association and investigate its clinical utility in the severity evaluation for HLH.
Topics: Afibrinogenemia; Child; Fibrinogen; Humans; Hypertriglyceridemia; Lymphohistiocytosis, Hemophagocytic; Multiple Organ Failure; Retrospective Studies; Triglycerides
PubMed: 35410268
DOI: 10.1186/s13023-022-02315-8 -
American Journal of Hematology Dec 2008Fibrinogen is essential for the formation of a fibrin clot. Acquired and congenital disorders of fibrinogen may result in decreased concentration or altered function of... (Review)
Review
Fibrinogen is essential for the formation of a fibrin clot. Acquired and congenital disorders of fibrinogen may result in decreased concentration or altered function of fibrinogen, often leading to an increased risk of bleeding. Routine coagulation testing and specialized laboratory investigations can guide diagnosis in patients suspected of having a fibrinogen abnormality. This article summarizes the types of laboratory assays that are used to assess fibrinogen disorders, and key abnormalities found in different types of fibrinogen disorders.
Topics: Afibrinogenemia; Blood Coagulation Tests; Fibrinogens, Abnormal; Humans
PubMed: 18951466
DOI: 10.1002/ajh.21293 -
Vascular Health and Risk Management 2009Afibrinogenemia is a rare bleeding disorder with an estimated prevalence of 1:1,000,000. It is an autosomal recessive disease resulting from mutations in any of the 3... (Review)
Review
Afibrinogenemia is a rare bleeding disorder with an estimated prevalence of 1:1,000,000. It is an autosomal recessive disease resulting from mutations in any of the 3 genes that encode the 3 polypeptide chains of fibrinogen and are located on the long arm of chromosome 4. Spontaneous bleeding, bleeding after minor trauma and excessive bleeding during interventional procedures are the principal manifestations. We review the management of afibrinogenemia. Replacement therapy is the mainstay of treatment of bleeding episodes in these patients and plasma-derived fibrinogen concentrate is the agent of choice. Cryoprecipitate and fresh frozen plasma are alternative treatments that should be used only when fibrinogen concentrate is not available. Secondary prophylactic treatment may be considered after life-threatening bleeding whereas primary prophylactic treatment is not currently recommended. We also discuss alternative treatment options and the management of surgery, pregnancy and thrombosis in these patients. The development of new tests to identify higher risk patients and of safer replacement therapy will improve the management of afibrinogenemia in the future.
Topics: Afibrinogenemia; Blood Coagulation; Blood Coagulation Tests; Blood Component Transfusion; Coagulants; Factor VIII; Female; Fibrinogen; Hemorrhage; Humans; Male; Mutation; Postoperative Hemorrhage; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Treatment Outcome
PubMed: 19851522
DOI: 10.2147/vhrm.s5305 -
Journal of Thrombosis and Haemostasis :... Jun 2015Congenital dysfibrinogenemia is a qualitative congenital fibrinogen disorder characterized by normal antigen levels of a dysfunctional fibrinogen. The diagnosis is... (Review)
Review
Congenital dysfibrinogenemia is a qualitative congenital fibrinogen disorder characterized by normal antigen levels of a dysfunctional fibrinogen. The diagnosis is usually based on discrepancies between fibrinogen activity and antigen levels, but could require more specialized techniques for the assessment of fibrinogen function, owing to some limitations in routine assays. Molecular abnormalities, which are frequently heterozygous missense mutations localized in exon 2 of FGA and exon 8 of FGG, lead to defects in one or more phases of fibrinogen to fibrin conversion, fibrin network formation, and other important functions of fibrinogen. The clinical phenotype is highly heterogeneous, from no manifestations to bleeding and/or thrombotic events. Asymptomatic propositi and relatives with the predisposing genotype are at risk of developing adverse outcomes during the natural course of the disease. Correlations between genotype and phenotype have not yet been clearly established, with the exception of some abnormal fibrinogens that severely increase the risk of thrombosis. Functional analysis of polymerization and fibrinolysis, structural studies of the fibrin network and the viscoelastic properties of fibrin clot could help to predict the phenotype of congenital dysfibrinogenemia, but have not yet been evaluated in detail. The management is essentially based on personal and family history; however, even individuals who are still asymptomatic and without a family history should be carefully assessed and monitored. Particular situations, such as pregnancy, delivery, and surgery, require a multidisciplinary approach.
Topics: Afibrinogenemia; Animals; Blood Coagulation; Blood Coagulation Tests; DNA Mutational Analysis; Female; Fibrinogens, Abnormal; Genetic Predisposition to Disease; Humans; Male; Molecular Diagnostic Techniques; Mutation; Phenotype; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Hematologic; Prognosis; Risk Factors; Thrombosis
PubMed: 25816717
DOI: 10.1111/jth.12916