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International Journal of Laboratory... Apr 2021Congenital fibrinogen disorders (CFDs) are classified as afibrinogenemia or hypofibrinogenemia (Hypo), dysfibrinogenemia (Dys), or hypodysfibrinogenemia (Hypodys),...
INTRODUCTION
Congenital fibrinogen disorders (CFDs) are classified as afibrinogenemia or hypofibrinogenemia (Hypo), dysfibrinogenemia (Dys), or hypodysfibrinogenemia (Hypodys), according to functional and antigenic fibrinogen concentrations. However, in routine laboratory tests, plasma fibrinogen levels are mostly measured using the functional Clauss method and not as an antigenic level. Therefore, it is difficult to discriminate CFD from acquired hypofibrinogenemia (aHypo). To establish a screening method for CFD, we investigated the parameters of clot waveform analysis (CWA) from the Clauss method.
METHODS
We compared fibrinogen concentrations determined using Clauss and prothrombin time (PT)-derived methods for 67 aHypo and CFD cases (19 Dys, 4 Hypodys, and 1 Hypo determined using antigen levels and DNA sequence analysis) with a CS-2400 instrument, and the CWA parameters, dH and Min1, were analyzed automatically with an on-board algorithm. dH and Min1 are the maximum change in transmittance at the end of coagulation and the maximum velocity of transmittance change during coagulation, respectively.
RESULTS
Clauss/PT-derived ratios detected 18 cases of Dys and Hypodys but no Hypo cases, whereas Clauss/dH plus Clauss/Min1 ratios were calculated from fibrinogen concentration using the Clauss method and CWA parameters detected 21 cases of Dys and Hypodys and one Hypo case. Moreover, the Clauss/PT-derived ratio and Clauss/dH plus Clauss/Min1 ratio detected 22 cases of Dys and Hypodys cases and one Hypo case.
CONCLUSION
This report demonstrates that CWA parameters of the Clauss method, Clauss/dH plus Clauss/Min1 ratio, screened Dys patients with a higher rate, whereas Clauss/PT-derived ratios did not.
Topics: Adolescent; Adult; Afibrinogenemia; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Child; Diagnostic Tests, Routine; Female; Fibrinogen; Humans; Male; Mass Screening; Middle Aged; Prothrombin Time; Young Adult
PubMed: 33030793
DOI: 10.1111/ijlh.13358 -
Thrombosis Research Oct 2020
Topics: Afibrinogenemia; Blood Coagulation Tests; Fibrinogen; Hemostatics; Humans; Prothrombin Time
PubMed: 32788118
DOI: 10.1016/j.thromres.2020.07.023 -
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 -
Zhonghua Nei Ke Za Zhi Apr 2020
Topics: Afibrinogenemia; Asian People; Humans; Pedigree
PubMed: 32209199
DOI: 10.3760/cma.j.cn112138-20190730-00525 -
Polish Archives of Internal Medicine Dec 2019Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual...
Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on chromosome 4q28. It is estimated that congenital fibrinogen disorder accounts for 8% of rare coagulation factor deficiencies. Most of congenital fibrinogen disorders are suspected in individuals with bleeding tendency or coincidentally discovered, for instance prior to surgery. Fibrinogen disorders could be also found in patients with thrombotic events, impaired wound healing, and recurrent spontaneous abortions. Afibrinogenemia manifests as mild to severe bleeding, while hypofibrinogenemia is often asymptomatic. Dysfibrinogenemia, a qualitative fibrinogen disorder, is associated with bleeding, thrombosis, or with no symptoms. Recent recommendations issued by the International Society on Thrombosis and Haemostasis in 2018 do not encourage routine evaluation of thrombin time or other coagulation tests in patients with suspected congenital fibrinogen disorders, highlighting the value of fibrinogen antigen measurement and genetic analysis, added to the key finding, that is, reduced fibrinogen concentration determined with a coagulometric assay. The current review summarizes practical issues in diagnostic workup and clinical management of patients with afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia from a perspective of internists who may encounter patients with reduced fibrinogen concentration in everyday practice. Despite the fact that hematologists are in front line for the management of patients with bleeding tendency, internists should be aware of the clinical and laboratory findings in patients with inherited fibrinogen disorders including the risk of thromboembolism and management prior to invasive procedures.
Topics: Adult; Afibrinogenemia; Blood Coagulation Tests; Female; Fibrinogen; Genetic Predisposition to Disease; Genetic Testing; Hemorrhage; Humans; Male; Middle Aged; Poland; Thrombosis; Young Adult
PubMed: 31797863
DOI: 10.20452/pamw.15082 -
Blood Cells, Molecules & Diseases Feb 2021Congenital fibrinogen disorders are characterized by heterogeneous clinical manifestations with mutations in the fibrinogen gene cluster. We aimed to describe the...
INTRODUCTION
Congenital fibrinogen disorders are characterized by heterogeneous clinical manifestations with mutations in the fibrinogen gene cluster. We aimed to describe the molecular genetics and clinical manifestations of fibrinogen abnormalities and perform genotype-phenotype correlations.
MATERIALS AND METHODS
Genetic analysis of fibrinogen genes was performed by direct sequencing. The effect of the specific missense variants on fibrinogen structure and function was analyzed using PROVEAN and PolyPhen-2 algorithms and was predicted by protein modeling.
RESULTS
Thirteen mutations, including five novel mutations, were identified in the three fibrinogen genes. There was poor correlation between genotypes and phenotypes. All but one of the novel mutations in subjects were predicted to be deleterious. Protein modeling predicted that multiple ienteractions with surrounding residues for novel variants were likely to result in congenital fibrinogen disorders.
CONCLUSION
This study in a relatively large cohort of Chinese patients with congenital fibrinogen disorders enabled the identification of five new fibrinogen missense mutations. In silico modeling may represent a valuable tool for understanding amino acid residues from novel variants leading to congenital fibrinogen disorders, but it should be followed by functional studies. Clinical presentation of fibrinogen disorders was variable, possibly due to genetic and environmental modifiers.
Topics: Adult; Afibrinogenemia; Aged; Asian People; China; Female; Fibrinogen; Genetic Association Studies; Humans; Male; Middle Aged; Models, Molecular; Mutation; Mutation, Missense; Point Mutation; Young Adult
PubMed: 32877852
DOI: 10.1016/j.bcmd.2020.102489 -
European Journal of Haematology Oct 2019Inherited dysfibrinogenemia is a rare disorder, for which clinical studies related to the risk of bleeding or thrombosis and the type of causative mutation are scanty.
OBJECTIVES
Inherited dysfibrinogenemia is a rare disorder, for which clinical studies related to the risk of bleeding or thrombosis and the type of causative mutation are scanty.
MATERIALS AND METHODS
We analyzed the laboratory, clinical, and genotypic features of 50 patients with inherited dysfibrinogenemia belonging to 19 unrelated families.
RESULTS
In all the index cases, fibrinogen activity by Clauss method was below the normal range, while it was observed in 57.9% only by PT-derived method. In three families, hypodysfibrinogenemia was evident, associated with three novel mutations (Ter492Gln in FGB, Cys365Asp, and Leu370Phe in FGG). Three additional novel mutations were also identified (Arg114Lys in FGA, Ile131Thr and Trp234Arg in FGG). Bleeding symptoms assessed by ISTH-BAT scored at least 1 in 30% of patients and, significant bleeding symptoms were mainly present in female patients, especially associated with pregnancy. Two patients with FGB Arg44Cys suffered from venous thromboembolism, and two with FGA Arg35His had ischemic stroke at older age.
CONCLUSIONS
This study confirms the heterogeneity of clinical features in inherited dysfibrinogenemia, due to the wide spectrum of the causative mutations. Larger multicenter studies are needed to assess the definitive correlation of some mutations with bleeding or thrombosis.
Topics: Adolescent; Adult; Afibrinogenemia; Aged; Alleles; Amino Acid Substitution; Blood Coagulation; Blood Coagulation Tests; Child; Child, Preschool; DNA Mutational Analysis; Female; Fibrinogen; Genotype; Hemorrhage; Humans; Male; Middle Aged; Mutation; Risk Assessment; Risk Factors; Thrombosis; Young Adult
PubMed: 31314131
DOI: 10.1111/ejh.13296 -
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 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Nov 2023To explore the coagulation deficit and genetic basis for a Chinese pedigree affected with Congenital dysfibrinogenemia (CD).
OBJECTIVE
To explore the coagulation deficit and genetic basis for a Chinese pedigree affected with Congenital dysfibrinogenemia (CD).
METHODS
Peripheral venous blood samples of the proband and her family members (including 4 individuals from three generations) were subjected to routine blood test and assays of liver and kidney functions and viral hepatitis to exclude related diseases. Clauss method and DFg-PT method were used to determine the fibrinogen activity (Fg:C), and an immunoturbidimetric assay was used to determine the level of fibrinogen antigen (Fg:Ag). All of the exons (22 in total) and their flanking sequences of the FGA, FGB and FGG genes were amplified by PCR and directly sequenced. Variants in the coding regions of the three genes and transcriptional splicing sites were screened by using Mutation Surveyor software.
RESULTS
The Clauss method showed that Fg:C was significantly reduced in the proband and her father, whilst her mother and son were normal. With the DFg-PT method, the proband, her parents and son were all within the normal range. The Fg:C/Fg:Ag ratio of the proband and her father was lower than 0.7, whilst her mother and son were above 0.7. No significant change in the prothrombin time, activated partial thromboplastin clotting time and thrombin time was noted. Two genetic variants were detected, which included a homozygous missense variant in the FGA gene [c.991A>G (p.Thr331Ala)], which was predicted to be benign, and a heterozygous missense variant of the γ chain of the FGG gene [c.1211C>G (p.Ser404Phe)], which is located in a conserved region and unreported in the CLINVAR/HGMD/EXAC/1000G databases and literature.
CONCLUSION
This pedigree has conformed to the autosomal dominant inheritance of CD. The c.1211C>T (p.Ser404Phe) missense variant of the γ chain of the FGG gene probably underlay the pathogenesis of CD in this pedigree. The variant was unreported previously and named as "Fibrinogen Harbin II Ser404Phe".
Topics: Female; Humans; Afibrinogenemia; East Asian People; Fibrinogen; Mothers; Mutation; Pedigree
PubMed: 37906135
DOI: 10.3760/cma.j.cn511374-20220112-00027 -
International Journal of Molecular... Feb 2021The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the...
The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bβ chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among and mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure-function relationship of fibrin to support hemostasis.
Topics: Adult; Afibrinogenemia; Aged; Aged, 80 and over; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Fibrinogen; Genotype; Humans; Male; Middle Aged; Mutation; Phenotype; Prothrombin; Structure-Activity Relationship; Thrombelastography; Thrombin
PubMed: 33668986
DOI: 10.3390/ijms22052286