Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γ Ala327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism

Hamano, Akiei; Mimuro, Jun; Aoshima, Motonori; Itoh, Takuya; Kitamura, Noboru; Nishinarita, Susumu; Takano, Katsuhiro; Ishiwata, Akira; Kashiwakura, Yuji; Niwa, Kazuki; Ono, Tomoko; Madoiwa, Seiji; Sugo, Teruko; Matsuda, Michio; Sakata, Yoichi

doi:10.1182/blood-2003-07-2569

Cited by 24 publications

(18 citation statements)

References 21 publications

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“…In addition, the γ/γ’ clots contained a large number of free fiber ends (see arrows in Figure 5B). Fiber ends are normally found at low levels in scanning electron micrographs of fibrin clots, and have been suggested to arise from early truncation of protofibril formation or lateral aggregation [28,29]. …”

Section: Resultsmentioning

confidence: 99%

The presence of γ′ chain impairs fibrin polymerization

Gersh

Nagaswami

Weisel

et al. 2009

Thrombosis Research

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Introduction A fraction of fibrinogen molecules contain an alternatively spliced variant chain called γ’. Plasma levels of this variant have been associated with both myocardial infarction and venous thrombosis. Because clot structure has been associated with cardiovascular risk, we examined the effect of γ’ chain on clot structure. Materials and Methods We expressed three fibrinogen variants in Chinese hamster ovary (CHO) cells: γ/γ homodimer, γ/γ’ heterodimer, and γ’/γ’ homodimer. We observed thrombin-catalyzed fibrinopeptide release by HPLC, fibrin polymerization by turbidity, and clot structure by scanning electron microscopy. We characterized post-translational modifications by mass spectrometry. Results Fibrinopeptide A was released at the same rate for all three fibrinogens, while fibrinopeptide B was released faster from the γ’/γ’ homodimer. The rise in turbidity was slower and final absorbance was lower during polymerization of γ’-containing fibrinogens than for γ/γ fibrinogen. Micrographs showed that γ’/γ’ fibrin clots are composed of very thin fibers, while the diameter of γ/γ’ fibers is similar to γ/γ fibers. Further, the fiber networks formed from γ’-containing samples were non-uniform. Mass spectrometry showed heterogeneous addition of N-glycans and tyrosine sulfation in the γ’ chain. Conclusions The presence of γ’ chains slows lateral aggregation and alters fibrin structure. We suggest these changes are likely due to charge-charge repulsion, such that polymerization of the γ’/γ’ homodimer is more impaired than the heterodimer since these repulsions are partially offset by incorporation of γ chains in the γ/γ’ heterodimer.

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Section: Resultsmentioning

confidence: 99%

The presence of γ′ chain impairs fibrin polymerization

Gersh

Nagaswami

Weisel

et al. 2009

Thrombosis Research

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“…Two alleles were also shown to encode proteins of higher molecular weight than the wild type protein [49,50]. Eight alleles were shown, by the glycosidase-or tunicamycin-mediated restoration of normal molecular weight, to encode proteins carrying an additional N-glycan [27,30,31,33,36,38,45]. Finally, six studies documented the presence of an additional glycan on the corresponding protein by western blotting, glycosidase digestion and HPLC [26,28,29,34,41 ,51], and three others demonstrated the attachment of a glycan by western blotting, glycosidase digestion and site-directed mutagenesis [32,35,37,43,47].…”

Section: Previously Reported Gain-of-glycosylation Mutationsmentioning

confidence: 99%

Gain-of-glycosylation mutations

Vogt

Chuzhanova

et al. 2007

Current Opinion in Genetics & Development

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“…Of note, an amino acid mutation at 326 is associated with thrombosis in most cases, including a case with γCys326Ser, 1 case and 1 family with γCys326Tyr, and a family with γCys326Phe, except for 1 family with γCys326Ser [4,7,8,9,10]. In addition, a case of γAla327Thr also presented with thrombosis [11]. This strong tendency towards thrombosis with amino acid mutations at 326 and 327 suggests the importance of the steric structure at this site in fibrinogen in the mechanism of thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Hypodysfibrinogenemia with a Heterozygous Mutation of γCys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus

Ushijima

Komai²,

Masukawa³

et al. 2017

Cardiology

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We encountered a 45-year-old Japanese man who suffered from pulmonary thromboembolism and huge right ventricular thrombus after inferior vena cava (IVC) filter implantation without apparent thrombus in either the deep veins or inside the IVC filter. The biochemical data showed a discrepancy in the level of fibrinogen between the immunological and thrombin time methods, suggesting hypodysfibrinogenemia. The sequencing of the fibrinogen γ-chain gene (FGG) revealed a novel heterozygous missense mutation in exon 8 - a TGT to TCT transversion in codon 326 - resulting in an amino acid substitution of serine for cysteine (γCys326Ser). The characterization of the protein did not show known mechanisms for thrombosis in dysfibrinogenemia, such as dimer or albumin-binding complex formation. In summary, the current case with a life-threatening thrombotic event was found to have a novel heterozygous missense mutation resulting in γCys326Ser, which was suggested as a predisposing factor of the thrombosis. Known mechanisms responsible for thrombosis in the current case were not demonstrated, suggesting other mechanisms including superimposing inherited and/or acquired risk factors. When a patient presents with unusual thrombosis such as breakthrough pulmonary embolism and huge thrombus in the right ventricle, as in the current case, the laboratory process for heritable thrombophilia should be considered.

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Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γ Ala327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism

Cited by 24 publications

References 21 publications

The presence of γ′ chain impairs fibrin polymerization

The presence of γ′ chain impairs fibrin polymerization

Gain-of-glycosylation mutations

Hypodysfibrinogenemia with a Heterozygous Mutation of γCys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus

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Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γ Ala327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism

Cited by 24 publications

References 21 publications

The presence of γ′ chain impairs fibrin polymerization

The presence of γ′ chain impairs fibrin polymerization

Gain-of-glycosylation mutations

Hypodysfibrinogenemia with a Heterozygous Mutation of &#x03B3;Cys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus

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Hypodysfibrinogenemia with a Heterozygous Mutation of γCys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus