title: A novel missense mutation in the FGB g. 3354 T>A (p. Y41N), fibrinogen Caracas VIII.
abstract: 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.
authors.affiliation: Centro de Medicina Experimental, Laboratorio Biología del Desarrollo de la Hemostasia, Instituto Venezolano de Investigaciones Científicas, Caracas, República Bolivariana de Venezuela. rmarchi@ivic.gob.ve
authors.forename: Rita
authors.initials: R
authors.lastname: Marchi
authors.forename: Héctor
authors.initials: H
authors.lastname: Rojas
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Oscar
authors.initials: O
authors.lastname: Castillo
authors.forename: Arlette
authors.initials: A
authors.lastname: De Sáez Ruiz
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D001216:Asparagine / Q000235:genetics; D002460:Cell Line; D004252:DNA Mutational Analysis; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005337:Fibrin / Q000737:chemistry / Q000378:metabolism*; D015241:Fibrinogens, Abnormal / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D020125:Mutation, Missense / Q000235:genetics; D011485:Protein Binding; D013918:Thrombin Time; D014443:Tyrosine / Q000235:genetics
chemical_list: D015241:Fibrinogens, Abnormal; C560184:fibrinogen Caracas VIII; D014443:Tyrosine; D001216:Asparagine; D005337:Fibrin