Fibrinogen Dusart presenting as recurrent thromboses in the hepatic portal system

Shen, Yu-Min; Trang, Vinh; Sarode, Ravindra; Brennan, Stephen O.

doi:10.1097/mbc.0000000000000045

Cited by 10 publications

(7 citation statements)

References 13 publications

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“…Indeed, the Christchurch and Dusart mutation (Aa554 Arg!Cys; six of six cases) are the two most thrombotic of all fibrinogen substitutions [12,18]. Interestingly, both of these variants have the potential to form inter molecular S-S linked complexes with themselves and with serum albumin and it has been speculated that this might contribute to the thrombotic phenotype [19,20]. This is an attractive idea as varying proportions of fibrinogen-albumin complexes in different individuals would help explain the variability of phenotype penetration.…”

Section: Discussionmentioning

confidence: 99%

Novel fibrinogen mutations (Aα17Gly→Cys and Aα381Ser→Phe) occurring with a 312Thr→Ala polymorphism

Brennan

Laurie²,

Mo³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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The aim of the study was to determine the molecular cause of dysfibrinogenaemia in a woman with a prolonged thrombin time. Functional fibrinogen abnormalities can be benign or may lead to bleeding or thrombotic conditions. In complex cases, phenotypes may be acquired or involve interplay between several coinherited mutations. The authors developed a new whole-protein time-of-flight mass spectrometry (TOF MS) approach to direct targeted DNA sequencing of the fibrinogen genes and determine the phase of multiple substitutions in a single individual. TOF MS analysis of the individual's fibrinogen indicated normal Bβ, γ, and alternately transcribed γ' chain isoforms, but aberrant Aα chain masses. Subsequent fibrinogen Aα gene (FGA) sequencing indicated the presence of three different mutations. Two of the substitutions, Aα17Gly→Cys (at the thrombin cleavage site) and Aα381Ser→Phe (in the αC connector) were novel and the third, Aα312Thr→Ala, was a known benign polymorphism. Accurate mass measurements of isolated control Aα chains showed the predicted Aα polypeptide at 66 132 Da and additional phosphorylated species at + 80 and + 160 Da. Patient's Aα chains on the other hand had masses of 66 103 and 66 241 Da indicating that she had one 312Ala allele (-30 Da) and one 312Thr allele which carried both the 17Gly→Cys (+ 46 Da) and 381Ser→Phe (+ 60) Da mutations. Cotransmission of these new mutations was confirmed by Aα chain TOF MS of plasma fibrinogen and targeted FGA nucleotide sequencing for 10 additional family members.

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Section: Discussionmentioning

confidence: 99%

Novel fibrinogen mutations (Aα17Gly→Cys and Aα381Ser→Phe) occurring with a 312Thr→Ala polymorphism

Brennan

Laurie²,

Mo³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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“…A few fibrinogen mutants, that is, fibrinogens Paris V, Caracas V, New York, Naples (in homozygous state), IJmuiden, Nijmegen, and Melun have been clearly associated with an increased susceptibility to both arterial and venous thrombosis, including splanchnic and cerebral territories. 43,44 Several mechanisms, often overlapping, account for the increased thrombotic risk. These include elevated levels of circulating thrombin due to an impaired binding to fibrinogen, 39 altered strength, permeability, and stability of the fibrin network, 45 or hypofibrinolysis resulting from a defective plasminogen and tissue-plasminogen activator binding to the abnormal fibrinogen molecule.…”

Section: Afibrinogenemia and Hypofibrinogenemiamentioning

confidence: 99%

Clinical Features and Management of Congenital Fibrinogen Deficiencies

Casini

Moerloose

Neerman-Arbez

2016

Semin Thromb Hemost

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Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (dysfibrinogenemia) or both (hypodysfibrinogenemia) of plasmatic fibrinogen. Afibrinogenemia is often diagnosed at birth following prolonged umbilical cord bleeding and is characterized by spontaneous bleeding in all tissues, while hypofibrinogenemic patients are more often asymptomatic. Spontaneous spleen ruptures, painful bone cysts, cardiovascular events, and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of dysfibrinogenemia are very heterogeneous, from absence of symptoms to major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis. Hypodysfibrinogenemic patients can suffer from both major bleeding and recurrent thrombosis. Pregnancy of women with congenital fibrinogen disorders is a high-risk situation. Owing to the absence of controlled randomized studies, clinical management is mainly based on expert consensus. For the treatment and/or the prevention of bleeding, plasma-derived fibrinogen concentrates are the optimal choice. Treatment of thrombosis may be challenging. More specifically, management strategies should be tailored to each patient, taking the personal and familial history of bleeding and thrombosis, the genotype, and the specific clinical situation into account.

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“…[ 15 ] Aα554Arg→Cys mutation and Aα532Ser→Cys mutation are associated with thrombotic manifestations; BβArg14Cys mutation should be responsible for inherited thrombophilia. [ 16 – 18 ]…”

Section: Discussionmentioning

confidence: 99%

A novel fibrinogen variant in a Chinese pedigree with congenital dysfibrinogenemia caused by FGA P. Arg38Thr mutation

Cai

Wang

et al. 2018

Medicine

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Rationale:Congenital dysfibrinogenemia (CD) is characterized by altered functional properties of the fibrinogen; people who suffer from CD often have a low activity of fibrinogen and the mutation in the genomic DNA.Patient concerns:A 6-year-old child was examined with a low activity of fibrinogen measured by Von Clauss method and PT-derived method which indicated a normal level of fibrinogen; this abnormality was also detected in her mother. The genomic DNA of all the family members was extracted, and all exons of 3 fibrinogen genes which encode fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG) were amplified by polymerase chain reaction (PCR), in addition, sanger sequencing, homologous sequence alignment and bioinformatics software were performed for the further analysis.Diagnoses:CD in this pedigree is associated with c.113G>C in the exon 2 of FGA which caused Arg38Thr mutation.Outcomes:The child and her mother showed a low plasma concentration of fibrinogen measured by Von Clauss method, whereas a normal result measured by PT-derived method; finally, c.113G>C in the exon 2 of FGA was detected in the pedigree which caused Arg38Thr mutation and it is the first report on a pedigree with CD caused by AαArg38Thr.Lessons:This case gives us the lesson that not all patients with CD showed typical symptoms and laboratory test results; the result of fibrinogen concentration and antigen which is tested by Von Clauss method and immunoturbidimetric assay is various according to the condition of each CD patient.

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Fibrinogen Dusart presenting as recurrent thromboses in the hepatic portal system

Cited by 10 publications

References 13 publications

Novel fibrinogen mutations (Aα17Gly→Cys and Aα381Ser→Phe) occurring with a 312Thr→Ala polymorphism

Novel fibrinogen mutations (Aα17Gly→Cys and Aα381Ser→Phe) occurring with a 312Thr→Ala polymorphism

Clinical Features and Management of Congenital Fibrinogen Deficiencies

A novel fibrinogen variant in a Chinese pedigree with congenital dysfibrinogenemia caused by FGA P. Arg38Thr mutation

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