A novel missense mutation in the FGB g. 3354 T > A (p. Y41N), fibrinogen caracas VIII

Centro de Medicina Experimental, Laboratorio Biología del Desarrollo de la Hemostasia, Instituto Venezolano de Investigaciones Científicas, Caracas, República Bolivariana de Venezuela.
Thrombosis and Haemostasis (Impact Factor: 4.98). 02/2011; 105(4):627-34. DOI: 10.1160/TH10-03-0179
Source: PubMed


A novel dysfibrinogenaemia with a replacement of Tyr by Asn at Bβ41 has been discovered (fibrinogen Caracas VIII). An asymptomatic 39-year-old male was diagnosed as having dysfibrinogenaemia due to a mildly prolonged thrombin time (+ 5.8 seconds); his fibrinogen concentration was in the low normal range, both by Clauss and gravimetric determination, 1.9 g/l and 2.1 g/l, respectively. The plasma polymerization process was slightly impaired, characterised by a mildly prolonged lag time and a slightly increased final turbidity. Permeation through the patients' clots was dramatically increased, with the Darcy constant around four times greater than that of the control (22 ± 2 x 10(-9) cm² compared to 6 ± 0.5 x 10(-9) cm² in controls). The plasma fibrin structure of the patient, by scanning electron microscopy, featured a mesh composed of thick fibres (148 ± 50 nm vs. 120 ± 31 nm in controls, p<0.05) and larger pores than those of the control fibrin clot. The viscoelastic properties of the clot from the patient were also altered, as the storage modulus (G', 310 ± 30) was much lower than in the control (831 ± 111) (p ≤0.005). The interaction of the fibrin clot with a monolayer of human microvascular endothelial cells, by confocal laser microscopy, revealed that the patients' fibrin network had less interaction with the cells. These results demonstrate the significance of the amino terminal end of the β chain of fibrin in the polymerisation process and its consequences on the clot organisation on the surface of endothelial cells.

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Available from: Hector Rojas, Apr 29, 2014
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    • "We identified TSH as an independent predictor of low clot permeability in this disease, which suggests that thyroid function affects structure/function of fibrinogen and has profound influence on coagulation. Substantial body of evidence supports the notion that even if the fibrinogen concentrations measured with Clauss method are normal, alterations to its structure dramatically influence the properties of the final fibrin product [26]. Interestingly, we have also observed prothrombotic plasma fibrin clot phenotype in hypothyroid subjects with K s that tended to be lower than in controls (p = 0.05). "
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    ABSTRACT: Introduction Available data on fibrin clot properties and fibrinolysis in hyperthyroidism and hypothyroidism are inconsistent. Our objective was to assess the impact of effective treatment of hyper- and hypothyroidism on fibrin clot characteristics. Material and Methods In a case-control study, ex vivo plasma fibrin clot permeability (Ks) and efficiency of fibrinolysis were assessed in 35 consecutive hyperthyroid and 35 hypothyroid subjects versus 30 controls. All measurements were performed before and after 3 months of thyroid function normalizing therapy. Results At baseline, hyperthyroid, but not hypothyroid, patients had lower Ks than controls (p < 0.0001). Hyperthyroid and hypothyroid groups compared with controls had prolonged clot lysis time (CLT), and lower rate of D-dimer release from clots (D-Drate) (all p < 0.05). The regression analysis adjusted for fibrinogen showed that in hyperthyroid patients, pre-treatment thyroid stimulating hormone (TSH) independently predicted Ks, while thrombin activatable fibrinolysis inhibitor (TAFI) antigen predicted CLT. In hypothyroid individuals a similar regression model showed that TSH independently predicts CLT. After 3 months of thyroid function normalizing therapy, 32 (91.4%) hyperthyroid and 30 (85.7%) hypothyroid subjects achieved euthyroidism and had improved fibrin clot properties (all p < 0.05), with normalization of Ks in hyperthyroid and lysability in hypothyroid patients. Conclusions Both hyper- and mild-to-moderate hypothyroidism are associated with prothrombotic plasma fibrin clot phenotype and restoration of euthyroidism improves clot phenotype. Abnormal fibrin clot phenotype might contribute to thromboembolic risk in thyroid disease.
    Full-text · Article · Aug 2014 · Thrombosis Research
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    ABSTRACT: There is evidence that clot structure can be modulated by endothelial cells, wherein the fibrinogen αC domain plays a major role in the fibrin-cell interaction. The spatial distribution of fibrin fibers from fibrinogen Caracas V and Caracas I, with heterozygous mutation in the αC domain (Aα Ser432Cys and Aα Ser466stop, respectively) on human dermal microvasculature endothelial cells (HMEC-1), was studied by laser scanning confocal microscopy. In order to assess fibrin-cell interaction and the role of the αC domain, preliminary experiments were done with inert microspheres and RGD peptide included in the clotting reaction, and forming clots with fibrinogen fragment X (fibrinogen without αC domain). Groups of stressed fibers were observed near the cell surface and were related to fibrin-cell interactions, which were abolished by the RGD peptide, and by the absence of the αC domain. The fibrin network of fibrinogen Caracas V and Caracas I was very different from that of normal fibrinogen. In general, patient's clots were characterized by very thin, tightly packed fibrin fibers, with a substantially reduced network porosity. Near the cell's surface, both abnormal fibrinogens formed a very fine meshwork, with stressed fibers 'anchored' to the cell surface, a pattern that was lost far from the cell surface. The structure of normal and patient clots performed in the absence of cells resembled that observed far from the cell surface, concluding that Caracas V and Caracas I fibrin was modulated by the presence of endothelial cells.
    No preview · Article · Dec 2011 · Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis
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    ABSTRACT: Routine coagulation tests on a 14year-old male with frequent epistaxis showed a prolonged thrombin time together with diminished functional (162mg/dl) and gravimetric (122mg/dl) fibrinogen concentrations. His father showed similar aberrant results and sequencing of the three fibrinogen genes revealed a novel heterozygous nonsense mutation in the FGB gene c.1105C>T, which converts the codon for residue Bβ 339Q to stop, causing deletion of Bβ chain residues 339-461. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and RP-HPLC (reverse-phase high-pressure liquid chromatography) of purified fibrinogen showed only normal Aα, Bβ, and γ chains, indicating that molecules with the truncated 37,990Da β chain were not secreted into plasma. Functional analysis showed impaired fibrin polymerization, fibrin porosity, and elasticity compared to controls. By laser scanning confocal microscopy the patient's fibers were slightly thinner than normal. Electrospray ionization mass spectrometry (ESI MS) presented normal sialylation of the oligosaccharide chains, and liver function tests showed no evidence of liver dysfunction that might explain the functional abnormalities.
    No preview · Article · Dec 2012 · Blood Cells Molecules and Diseases
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