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Seminars in Thrombosis and Hemostasis Nov 2022Fibrinogen is a complex protein that plays a key role in the blood clotting process. It is a hexamer composed of two copies of three distinct chains: Aα, Bβ, and γ...
Fibrinogen is a complex protein that plays a key role in the blood clotting process. It is a hexamer composed of two copies of three distinct chains: Aα, Bβ, and γ encoded by three genes, , and clustered on the long arm of chromosome 4. Congenital fibrinogen disorders (CFDs) are divided into qualitative deficiencies (dysfibrinogenemia, hypodysfibrinogenemia) in which the mutant fibrinogen molecule is present in the circulation and quantitative deficiencies (afibrinogenemia, hypofibrinogenemia) with no mutant molecule present in the bloodstream. Phenotypic manifestations are variable, patients may be asymptomatic, or suffer from bleeding or thrombosis. Causative mutations can occur in any of the three fibrinogen genes and can affect one or both alleles. Given the large number of studies reporting on novel causative mutations for CFDs since the review on the same topic published in 2016, we performed an extensive search of the literature and list here 120 additional mutations described in both quantitative and qualitative disorders. The visualization of causative single nucleotide variations placed on the coding sequences of , and eveals important structure function insight for several domains of the fibrinogen molecule.
Topics: Humans; Fibrinogen; Afibrinogenemia; Mutation; Hemorrhage; Exons; Hemostatics
PubMed: 35073585
DOI: 10.1055/s-0041-1742170 -
Scientific Reports Jan 2022Plasma fibrinogen is commonly examined by Clauss fibrinogen assay, which cannot distinguish between quantitative and qualitative fibrinogen anomalies. However, our...
Plasma fibrinogen is commonly examined by Clauss fibrinogen assay, which cannot distinguish between quantitative and qualitative fibrinogen anomalies. However, our previously reported Clauss fibrinogen assay utilizing clot waveform analysis (Clauss-CWA) provides additional information that contributes to the classification of fibrinogen anomalies. In this study, we adopted the Clauss-CWA method for an autoanalyzer to automatically measure the antigenic estimate (eAg) of fibrinogen in addition to the functional amount (Ac), and to thus provide the Ac/eAg ratio as a qualitative indicator. Performance was validated by receiver operating characteristics (ROC) and precision recall (PR) curve analyses using a patient cohort, consisting of a training cohort (n = 519) and a validation cohort (n = 523), both of which contained cases of congenital (hypo)dysfibrinogenemia as qualitative defects. We obtained an optimal cutoff of 0.65 for Ac/eAg by ROC curve analysis of the training cohort, offering superior sensitivity (> 0.9661) and specificity (1.000). This cutoff was validated in the validation cohort, providing positive predictive value > 0.933 and negative predictive value > 0.998. PR curve analysis also showed that Clauss-CWA provided excellent performance for detecting qualitative fibrinogen anomalies. The Clauss-CWA method may represent a useful approach for detecting qualitative fibrinogen abnormalities in routine laboratory testing.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Clinical Laboratory Techniques; Female; Fibrinogen; Humans; Infant; Infant, Newborn; Male; Middle Aged; Plasma; ROC Curve; Young Adult
PubMed: 35064141
DOI: 10.1038/s41598-021-04464-5 -
Clinica Chimica Acta; International... Mar 2022Congenital dysfibrinogenemia is characterized by qualitatively abnormal fibrinogens with resultant blood coagulation dysfunction. The clinical manifestations are high... (Review)
Review
BACKGROUND
Congenital dysfibrinogenemia is characterized by qualitatively abnormal fibrinogens with resultant blood coagulation dysfunction. The clinical manifestations are high heterogeneity. Treatment for dysfibrinogenemia should be personalized. Here, we reported four congenital dysfibrinogenemia patients with the major surgery, in order to discuss the treatment and diagnosis of congenital dysfibrinogenemia.
METHODS
We reported four asymptomatic congenital dysfibrinogenemia patients with the major surgery (valve replacement, brain surgery, tumorectomy, hysterectomy) in our study. Routine coagulation tests, hepatorenal function and gene analysis, thrombelastogram were performed.
RESULTS
Four congenital dysfibrinogenemia patients all showed prolonged TT, low level of activity fibrinogen and normal fibrinogen antigen. Case1 showed a heterozygous mutation in exon 2 of the FGA, c.1223G > C, which turns the codon for residue Aα Gly13 into Arg (p. Gly13Arg). DNA sequencing of case2 showed that a heterozygous mutation in exon 8 of the FGG (c.5877G > A) with being responsible for the Arg → His substitution at position 301 of the γ chain (p. Arg301His). Case3 and case 4 failed to do genetic testing for other reason. Four congenital dysfibrinogenemia patients were asymptomatic in the daily life. Personal and family history revealed no abnormal bleeding or thrombotic events. These four patients did not receive special treatment and management before surgery. They all had a smooth operation.
CONCLUSIONS
Misdiagnosis and unnecessary infusion bring huge health risks to patients. Correct diagnosis of congenital dysfibrinogenemia is the key to avoid misdiagnosis or unnecessary infusion. Asymptomatic patients with congenital dysfibrinogenemia do not need cryoprecipitate or fibrinogen input before major surgery.
Topics: Afibrinogenemia; Blood Coagulation Tests; Female; Fibrinogen; Fibrinogens, Abnormal; Humans; Sequence Analysis, DNA
PubMed: 35063457
DOI: 10.1016/j.cca.2022.01.009 -
International Journal of Molecular... Jan 2022Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and...
Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and structural analysis of 4 novel variants located in the gene coding for fibrinogen Bβ chain-heterozygous missense BβY416C and BβA68S, homozygous nonsense BβY345*, and heterozygous nonsense BβW403* mutations. The cases were identified by coagulation screening tests and further investigated by various methods. Fibrin polymerization had abnormal development with decreased maximal absorbance in all patients. Plasmin-induced fibrin degradation revealed different lytic phases of BβY416C and BβW403* than those of the control. Fibrinopeptide cleavage measured by reverse phase high pressure liquid chromatography of BβA68S showed impaired release of fibrinopeptide B. Morphological properties, studied through scanning electron microscopy, differed significantly in the fiber thickness of BβY416C, BβA68S, and BβW403*, and in the fiber density of BβY416C and BβW403*. Finally, homology modeling of BβA68S showed that mutation caused negligible alternations in the protein structure. In conclusion, all mutations altered the correct fibrinogen function or structure that led to congenital fibrinogen disorders.
Topics: Adolescent; Afibrinogenemia; Aged; Blood Coagulation; Blood Coagulation Tests; DNA Mutational Analysis; Female; Fibrinogen; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant, Newborn; Male; Middle Aged; Models, Molecular; Mutation; Phenotype; Protein Conformation; Structure-Activity Relationship
PubMed: 35054908
DOI: 10.3390/ijms23020721 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Jan 2022To improve the understanding and diagnosis and treatment of congenital dysfibrinogenemia (CD) through analyzing the clinical data of a pediatric patient and his pedigree.
OBJECTIVE
To improve the understanding and diagnosis and treatment of congenital dysfibrinogenemia (CD) through analyzing the clinical data of a pediatric patient and his pedigree.
METHODS
The clinical manifestations, laboratory findings and treatment of a case of CD diagnosed at West China Second University Hospital, Sichuan University and those of its pedigree members were analyzed, and genetic tracing and follow-up were conducted on the patient and its pedigree.
RESULTS
The child has no clinical manifestations at the time of admission. Coagulation function examination showed normal prothrombin time (PT), normal activated partial thrombin time (APTT), significantly prolonged thrombin time (TT), fibrinogen activity (Fg: C<0.5 g/L) measured with the Clauss method, and fibrinogen antigen (Fg: Ag) measured at 2.8 g/L with PT algorithm. Gene sequencing results showed that heterozygous missense mutation c.901C>T (p.Arg301Cys) in exon 8 of gene. Combined with the family history, the child was diagnosed with CD. During the follow-up of 4 months, the patient did not present bleeding, abnormal coagulation or thrombosis, and the coagulation function did not show significant changes compared with the findings obtained on admission.
CONCLUSION
The diagnosis of CD is confirmed mainly based on genetic testing and the treatment is characterized by the principle of precise individualized treatment. No special treatment is needed for patients presenting no clinical manifestations. However, it is important to provide thorough prenatal diagnosis and follow-up services for female patients planning for pregnancy so as to prevent miscarriage and complications caused by postpartum coagulation dysfunction.
Topics: Afibrinogenemia; Child; Female; Fibrinogen; Heterozygote; Humans; Mutation; Pedigree
PubMed: 35048620
DOI: 10.12182/20220160201 -
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 -
Diagnostics (Basel, Switzerland) Nov 2021Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia... (Review)
Review
Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management.
Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.
PubMed: 34829490
DOI: 10.3390/diagnostics11112140 -
Journal of Interventional Cardiac... Aug 2022We report our single-center experience with percutaneous left atrial appendage closure (LAAC) in patients with non-valvular atrial fibrillation (NVAF) and primary...
BACKGROUND OR PURPOSE
We report our single-center experience with percutaneous left atrial appendage closure (LAAC) in patients with non-valvular atrial fibrillation (NVAF) and primary hemostasis disorders (HD).
METHODS
Consecutive patients with primary HD who underwent a percutaneous LAAC were included. Baseline characteristics, procedural data, and clinical outcomes were prospectively collected and compared with the overall LAAC cohort without HD.
RESULTS
Since 2013, among 229 LAAC, 17 patients (7%) had a primary HD: thrombocytopenia (n = 5), myelodysplastic syndrome (n = 6), von Willebrand syndrome (n = 4), type A hemophilia (n = 1), and dysfibrinogenemia (n = 1). The HD population's age ranged from 61 to 87 years, and the median CHADSVASc was 5. Periprocedural plasmatic management was required in 47% of patients. The immediate LAAC implantation success rate was 100%. Patients received a direct oral anticoagulant (DOA) (n = 9), dual antiplatelet (n = 6), aspirin (n = 1), or no therapy (n = 1) during the first six postoperative weeks, followed with single antiplatelet (n = 16) or no therapy (n = 1) during lifelong. After 20 months, the technical success rate and procedural success rate were 100% and 94%. Zero device-/procedure-related complication and only one life-threatening bleeding occurred. Compared to patients without HD (n = 212), a baseline history of bleeding was less frequent (53% vs 91%, p < 0.001), and more patients received a perioperative blood transfusion (47% vs 4%, p < 0.001) in the HD group. The efficacy and safety outcomes did not differ between HD and non-HD cohorts.
CONCLUSIONS
Percutaneous LAAC in primary HD carriers appeared as safe and as effective as in overall LAAC population for stroke and bleeding prevention at midterm follow-up. Percutaneous left atrial appendage closure in patients with atrial fibrillation and primary hemostasis disorders. The percutaneous LAAC in primary hemostasis disorders and AF carriers requires a multidisciplinary approach. Cardiologist, anesthesiologist, and hematologist discussion is a cornerstone to assess anticoagulant contraindication, LAAC feasibility, periprocedural management, and follow-up (high). This multidisciplinary care is illustrated by the case of a 61-year-old male with hemophilia type A and recurrent hemarthrosis. Pre-LAAC assessment confirmed procedural indication and cactus LAA anatomy (left). After plasmatic management with factor VIII infusion, a WATCHMAN™ no. 21 was successfully implanted (middle). During follow-up, without antithrombotic regime, no ischemic or hemorrhagic complication occurred (right). LAA, left atrial appendage; LAAC, left atrial appendage closure; TEE, transesophageal echocardiography. Percutaneous LAAC in primary HD carriers appeared as safe and as effective as in overall LAAC population for stroke and bleeding prevention at midterm follow-up.
Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Hemophilia A; Hemorrhage; Hemostasis; Humans; Male; Middle Aged; Stroke; Treatment Outcome
PubMed: 34822043
DOI: 10.1007/s10840-021-01073-0 -
Research and Practice in Thrombosis and... Dec 2021Afibrinogenemia and congenital dysfibrinogenemia (CD) are rare conditions with limited information available for appropriate management. Previous case reports have...
Afibrinogenemia and congenital dysfibrinogenemia (CD) are rare conditions with limited information available for appropriate management. Previous case reports have demonstrated the safe and efficacious use of fibrinogen replacement therapy (FRT) as a therapeutic approach to prevent hemorrhage and fetal loss in pregnant women with CD. In this case report, we present a 28-year-old pregnant woman who sought testing for CD given her family history. She denied any current or previous bleeding symptoms. Laboratory testing confirmed the diagnosis of CD. She was treated with FRT and prophylactic anticoagulation starting in her third trimester. She had preterm labor that prompted an urgent cesarean section with FRT support. This case adds to the sparse literature about fibrinogen disorders in pregnancy, and highlights the benefits, safety, and tolerability of FRT and prophylactic anticoagulation in pregnant women with CD. Finally, it emphasizes the importance of a multidisciplinary team approach for an uneventful delivery.
PubMed: 34816075
DOI: 10.1002/rth2.12619 -
Haemophilia : the Official Journal of... Nov 2021Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities...
INTRODUCTION
Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities of fibrinogen. Although the diagnosis of CFDs is based on antigenic and functional level of fibrinogen, few genotypes are clearly correlated with phenotype.
METHODS
In this study, we investigated all of the referred patients diagnosed as CFDs in Taiwan's population between 1995 and 2020. Clinical features, laboratory data and genetic defects were analysed. Functional fibrinogen level was determined by the Clauss method. Antigenic fibrinogen was measured by an enzyme-linked immunosorbent assay. Fibrinogen genes were assessed for mutations by polymerase chain reaction and sequencing.
RESULTS
A total of 18 patients from six unrelated families with CFDs were identified. One patient from a consanguineous family was diagnosed as afibrinogenemia type 1A with a novel homozygous frameshift mutation in FGB exon 4. The other five (83.3 %) index patients were all diagnosed as dysfibrinogenemia type 3A caused by two novel and one known mutation. Six (33.3 %) patients from three families had a novel mutation in FGB exon 8. The clinical features and laboratory data were highly variable among these patients with the same mutation.
CONCLUSIONS
Three novel mutations of CFDs causing afibrinogenemia and dysfibrinogenemia were identified. The point mutation in FGB exon 8 is also a common mutation in Taiwan's population. Considerable phenotypic variability among the patients with an identical mutation was observed.
Topics: Afibrinogenemia; Fibrinogen; Homozygote; Humans; Mutation; Taiwan
PubMed: 34460979
DOI: 10.1111/hae.14399