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

Rita Marchi; Héctor Rojas; Michael Meyer; Oscar Castillo; Arlette De Sáez Ruiz; John W. Weisel

doi:10.1160/TH10-03-0179

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(04): 627-634
DOI: 10.1160/TH10-03-0179

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Rita Marchi

¹Centro de Medicina Experimental, Laboratorio Biología del Desarrollo de la Hemostasia, Instituto Venezolano de Investigaciones Científicas, Caracas, República Bolivariana de Venezuela

,

Héctor Rojas

²Centro de Biofísica y Bioquímica, Laboratorio de Fisiología Celular, Instituto Venezolano de Investigaciones Científicas, Caracas, República Bolivariana de Venezuela

,

Michael Meyer

³University of Applied Sciences, Department of Medical Engineering and Biotechnology, Jena, Germany

,

Oscar Castillo

¹Centro de Medicina Experimental, Laboratorio Biología del Desarrollo de la Hemostasia, Instituto Venezolano de Investigaciones Científicas, Caracas, República Bolivariana de Venezuela

,

Arlette De Sáez Ruiz

⁴Banco Metropolitano de Sangre del Distrito Capital, Caracas, República Bolivariana de Venezuela

,

John W. Weisel

⁵Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

› Author Affiliations

Abstract

Summary

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 x10^–9 cm² compared to 6 ± 0.5 x10^–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.

Keywords

Mutation - abnormal fibrinogen - clots - permeation - viscoelastic properties - scanning electron microscopy - confocal microscopy

Full Text

References

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