Fibrin monomers derived from thrombogenic dysfibrinogenemia, Naples-type variant (BβAla68Thr), showed almost entirely normal polymerization

Kamijo, Tomu; Nagata, Kazuhiro; Taira, Chiaki; Higuchi, Yumiko; Arai, Shinpei; Okumura, Nobuo

doi:10.1016/j.thromres.2018.10.004

Cited by 4 publications

(5 citation statements)

References 9 publications

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“…One possible mechanism could be the regulation of active thrombin in the plasma through thrombin binding to the fibrinogen, which helps sequester thrombin and decrease the feedback reaction that enhances thrombin production and has been referred to as “antithrombin I.” 20 However, reduced thrombin binding to fibrinogen could lead to an increase in active thrombin levels, which could eventually cause excessive coagulation or even thrombosis. 8 16…”

Section: Discussionmentioning

confidence: 99%

“…The clinical presentation of congenital fibrinogen deficiency is diverse and includes various symptoms such as asymptomatic cases, bleeding, thrombosis, recurrent miscarriages in women, and so on. 8 In contrast to the bleeding tendency observed in afibrinogenemia, approximately 55% of patients with dysfibrinogenemia remain asymptomatic, while 25% exhibit a mild bleeding tendency, and nearly 20% are at risk of developing arteriovenous thrombosis. 9 The mechanisms for the risk of thrombosis in patients with dysfibrinogenemia include increased thrombin levels due to defective binding with fibrinogen (fibrinogens Malmo, Naples, New York I, Pamplona II, and Poitiers), altered structure, and stability of fibrinogen, as well as the impaired function of the tissue plasminogen activator-medicated fibrinolysis (fibrinogens Argenteuil, Chapel Hill III, Date, New York I, Nijmegen, Pamplona II, and Paris V).…”

Section: Discussionmentioning

confidence: 99%

“…20 However, reduced thrombin binding to fibrinogen could lead to an increase in active thrombin levels, which could eventually cause excessive coagulation or even thrombosis. 8,16 In a study by Ceznerová, a 17-year-old female presented with mild posttraumatic cutaneous bleeding. 15 After conducting DNA sequencing, a heterozygous mutation was found in position c.292G > T in exon 2 of the FGB gene, which resulted in the amino acid substitution BßAla68Ser.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Fibrinogen Mutation p.BβAla68Asp Causes an Inherited Dysfibrinogenemia

Jia,

Zeng,

Zheng

et al. 2023

Hamostaseologie

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Objective Our study aimed to analyze the phenotype and genotype of a pedigree with inherited dysfibrinogenemia, and preliminarily elucidate the probable pathogenesis. Methods The one-stage clotting method was used to test the fibrinogen activity (FIB:C), whereas immunoturbidimetry was performed to quantify the fibrinogen antigen (FIB:Ag). Furthermore, DNA sequence analysis was conducted to confirm the site of mutation. Conservation analysis and protein model analysis were performed using online bioinformatics software. Results The FIB:C and FIB:Ag of the proband were 1.28 and 2.20 g/L, respectively. Gene analysis revealed a heterozygous c.293C > A (p.BßAla68Asp) mutation in FGB. Bioinformatics and modeling analysis suggested that the missense mutation could potentially have a deleterious effect on fibrinogen. Conclusion The BßAla68Asp mutation in exon 2 of FGB may account for the reduced FIB:C levels observed in the pedigree. To our knowledge, this point mutation is the first report in the world.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Novel Fibrinogen Mutation p.BβAla68Asp Causes an Inherited Dysfibrinogenemia

Jia,

Zeng,

Zheng

et al. 2023

Hamostaseologie

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“…This variant showed a fibrinogen value obtained using the PT‐derived method that was smaller than the fibrinogen Ag value, just as dH in the Clauss method was small, so the Clauss/PT‐derived ratio did not differ from that of the aHypo group. For the heterozygous variant of BβA68T, it was reported that fibrin polymerization was almost the same as the normal control, 22 there was no large discrepancy between the fibrinogen values measured using the Clauss and PT‐derived methods.…”

Section: Discussionmentioning

confidence: 82%

Screening method for congenital dysfibrinogenemia using clot waveform analysis with the Clauss method

Arai

Kamijo

Hayashi

et al. 2020

Int J Lab Hematology

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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.

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“…The clinical phenotype of fibrinogen Naples (BβA68T) is associated with thrombosis in the homozygous state due to defective thrombin binding and its increased concentration in the circulation [ 13 ]. Patients in a heterozygous state were reported asymptomatic (Yonekawa et al, 16th Congress of International Society on Thrombosis and Haemostasis, Florence, 1997, PS-2550) [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Characterization of Four Novel Fibrinogen Mutations in FGB Causing Congenital Fibrinogen Disorder

Ceznerová

Kaufmanová

Sovová

et al. 2022

IJMS

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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 FGB 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.

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Fibrin monomers derived from thrombogenic dysfibrinogenemia, Naples-type variant (BβAla68Thr), showed almost entirely normal polymerization

Cited by 4 publications

References 9 publications

A Novel Fibrinogen Mutation p.BβAla68Asp Causes an Inherited Dysfibrinogenemia

A Novel Fibrinogen Mutation p.BβAla68Asp Causes an Inherited Dysfibrinogenemia

Screening method for congenital dysfibrinogenemia using clot waveform analysis with the Clauss method

Structural and Functional Characterization of Four Novel Fibrinogen Mutations in FGB Causing Congenital Fibrinogen Disorder

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