Abstract
BackgroundAbnormal fibrinogens can be caused by clinically silent hereditary mutations. A new case was detected accidentally in an 11-year-old girl when routine pre-operative coagulation tests were performed for nasal turbinate surgery.MethodsThe fibrinogen genes FGA, FGG and FGB were sequenced using standard protocols. The kinetics of fibrin formation were followed by turbidity at 350 nm. Purified fibrinogen was incubated with plasmin, and the degradation products analyzed by SDS/PAGE. The formation of fibrinogen-albumin complexes was analyzed by immunobloting. Fibrin structure was examined in a Nikon Eclipse TE 2000-U laser microscope. Secretion of the variant protein was analyzed directly by reverse phase-electrospray time of flight-mass spectrometry (TOF-MS).ResultsDNA sequencing revealed a novel heterozygous g. 3057 C > T mutation in the FGA that predicts a p. Arg104 > Cys substitution, in the proband and her father. Both patients were asymptomatic with low functional and antigen fibrinogen concentrations. The proband’s plasma fibrinogen polymerization was almost normal, with a 12% decrease in the final turbidity, while, the father’s fibrin formation had a diminished slope and final turbidity (2.5× and 40%, respectively). Aα Arg104 is located at a plasmin cleavage site in the coiled-coil region of fibrinogen. However, the father’s fibrinogen plasmin degradation was normal. Although the exchanged Cys introduces an unpaired –SH, immunoblotting showed no fibrinogen-albumin complexes. Furthermore, the plasma clot structure observed by confocal microscopy appeared almost normal. TOF-MS showed that the variant Aα chain was underrepresented in plasma and made up only about 25% of the total.ConclusionsThe low expression of the Aα Arg104 > Cys chain in circulation could account for the observed hypodysfibrinogenemia.
Highlights
Abnormal fibrinogens can be caused by clinically silent hereditary mutations
Once the coagulation cascade is initiated, thrombin is formed and catalyzes the conversion of fibrinogen into soluble fibrin monomers that polymerize spontaneously, forming a three-dimensional network that becomes further stabilized by activated factor XIII (FXIIIa)
The coiled coil is delineated by two disulfide rings and its central region has a kink in Marchi et al BMC Hematology (2017) 17:22 its structure that acts as the primary attack site for plasmin [3]
Summary
Abnormal fibrinogens can be caused by clinically silent hereditary mutations. A new case was detected accidentally in an 11-year-old girl when routine pre-operative coagulation tests were performed for nasal turbinate surgery. Fibrinogen is the central protein of blood coagulation. Once the coagulation cascade is initiated, thrombin is formed and catalyzes the conversion of fibrinogen into soluble fibrin monomers that polymerize spontaneously, forming a three-dimensional network that becomes further stabilized by activated factor XIII (FXIIIa). Fibrinogen is a 340 kDa glycoprotein synthetized in the liver and normally circulates in plasma at 160–400 mg/dl [2]. It is composed of two sets of three different polypeptides chains (Aα, Bβ,γ), arranged in three nodules: the Nterminal of the six chains converge at the center forming the globular E region. The coiled coil is delineated by two disulfide rings and its central region has a kink in Marchi et al BMC Hematology (2017) 17:22 its structure that acts as the primary attack site for plasmin [3]
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