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Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications

BACKGROUND: Fibrinogen is an acute phase glycoprotein whose concentration increases in response to trauma. The newly synthesised protein is functionally enhanced and it is known that treatment with neuraminidase increases the rate of fibrin polymerisation. To explore this, we examined the difference...

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Autor principal: Brennan, Stephen O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661561/
https://www.ncbi.nlm.nih.gov/pubmed/26675134
http://dx.doi.org/10.1016/j.bbacli.2015.02.007
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author Brennan, Stephen O.
author_facet Brennan, Stephen O.
author_sort Brennan, Stephen O.
collection PubMed
description BACKGROUND: Fibrinogen is an acute phase glycoprotein whose concentration increases in response to trauma. The newly synthesised protein is functionally enhanced and it is known that treatment with neuraminidase increases the rate of fibrin polymerisation. To explore this, we examined the differences between the oligosaccharide structures of quiescent and acute phase fibrinogen. METHODS: A series of plasma samples was obtained from two individuals suffering an acute phase response. Fibrinogen chains were examined directly by ESI mass spectrometry before and after digestion with N-glycosidase F and β1,4 galactosidase. RESULTS: The Bβ and γ chains of acute phase fibrinogen showed a mass decrease of 162 Da (Gal) in some 50% of the molecules, and the Bβ chain showed an additional decrease corresponding to a further loss of NAcGlc. Incubation with N-glycosidase F normalised all isoform masses to that of the quiescent naked protein, confirming the N-linked oligosaccharide as the source of heterogeneity. β1,4 galactosidase treatment showed the structural difference was the absence of the penultimate Gal from the biantennary oligosaccharides, and mapping of tryptic glycopeptides confirmed these results showing that approximately half the chains lacked Gal. CONCLUSIONS AND IMPLICATIONS: The failure of incorporation Gal excludes the possibility of the hepatic NAcNeu Gal transferase capping the oligosaccharides with sialic acid. This has two desirable haemostatic outcomes: fibrin monomers will polymerise and form clots more rapidly, and two galactose residues can never be exposed diminishing uptake of the protein by the asialoglycoprotein receptor and ramping up concentration at a time of challenge.
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spelling pubmed-46615612015-12-15 Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications Brennan, Stephen O. BBA Clin Regular Article BACKGROUND: Fibrinogen is an acute phase glycoprotein whose concentration increases in response to trauma. The newly synthesised protein is functionally enhanced and it is known that treatment with neuraminidase increases the rate of fibrin polymerisation. To explore this, we examined the differences between the oligosaccharide structures of quiescent and acute phase fibrinogen. METHODS: A series of plasma samples was obtained from two individuals suffering an acute phase response. Fibrinogen chains were examined directly by ESI mass spectrometry before and after digestion with N-glycosidase F and β1,4 galactosidase. RESULTS: The Bβ and γ chains of acute phase fibrinogen showed a mass decrease of 162 Da (Gal) in some 50% of the molecules, and the Bβ chain showed an additional decrease corresponding to a further loss of NAcGlc. Incubation with N-glycosidase F normalised all isoform masses to that of the quiescent naked protein, confirming the N-linked oligosaccharide as the source of heterogeneity. β1,4 galactosidase treatment showed the structural difference was the absence of the penultimate Gal from the biantennary oligosaccharides, and mapping of tryptic glycopeptides confirmed these results showing that approximately half the chains lacked Gal. CONCLUSIONS AND IMPLICATIONS: The failure of incorporation Gal excludes the possibility of the hepatic NAcNeu Gal transferase capping the oligosaccharides with sialic acid. This has two desirable haemostatic outcomes: fibrin monomers will polymerise and form clots more rapidly, and two galactose residues can never be exposed diminishing uptake of the protein by the asialoglycoprotein receptor and ramping up concentration at a time of challenge. Elsevier 2015-03-04 /pmc/articles/PMC4661561/ /pubmed/26675134 http://dx.doi.org/10.1016/j.bbacli.2015.02.007 Text en © 2015 The Author http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular Article
Brennan, Stephen O.
Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications
title Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications
title_full Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications
title_fullStr Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications
title_full_unstemmed Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications
title_short Variation of fibrinogen oligosaccharide structure in the acute phase response: Possible haemorrhagic implications
title_sort variation of fibrinogen oligosaccharide structure in the acute phase response: possible haemorrhagic implications
topic Regular Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661561/
https://www.ncbi.nlm.nih.gov/pubmed/26675134
http://dx.doi.org/10.1016/j.bbacli.2015.02.007
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