Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lys...

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Autores principales:	Helen R McPherson, Cedric Duval, Stephen R Baker, Matthew S Hindle, Lih T Cheah, Nathan L Asquith, Marco M Domingues, Victoria C Ridger, Simon DA Connell, Khalid M Naseem, Helen Philippou, Ramzi A Ajjan, Robert AS Ariëns
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	blood coagulation fibrinogen bleeding thrombosis vascular biology Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c1db5394e1864b85a4927dd251608dff
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spelling	oai:doaj.org-article:c1db5394e1864b85a4927dd251608dff2021-11-25T12:34:39ZFibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis10.7554/eLife.687612050-084Xe68761https://doaj.org/article/c1db5394e1864b85a4927dd251608dff2021-10-01T00:00:00Zhttps://elifesciences.org/articles/68761https://doaj.org/toc/2050-084XFibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short, stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.Helen R McPhersonCedric DuvalStephen R BakerMatthew S HindleLih T CheahNathan L AsquithMarco M DominguesVictoria C RidgerSimon DA ConnellKhalid M NaseemHelen PhilippouRamzi A AjjanRobert AS AriënseLife Sciences Publications Ltdarticleblood coagulationfibrinogenbleedingthrombosisvascular biologyMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	blood coagulation fibrinogen bleeding thrombosis vascular biology Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	blood coagulation fibrinogen bleeding thrombosis vascular biology Medicine R Science Q Biology (General) QH301-705.5 Helen R McPherson Cedric Duval Stephen R Baker Matthew S Hindle Lih T Cheah Nathan L Asquith Marco M Domingues Victoria C Ridger Simon DA Connell Khalid M Naseem Helen Philippou Ramzi A Ajjan Robert AS Ariëns Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis
description	Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short, stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.
format	article
author	Helen R McPherson Cedric Duval Stephen R Baker Matthew S Hindle Lih T Cheah Nathan L Asquith Marco M Domingues Victoria C Ridger Simon DA Connell Khalid M Naseem Helen Philippou Ramzi A Ajjan Robert AS Ariëns
author_facet	Helen R McPherson Cedric Duval Stephen R Baker Matthew S Hindle Lih T Cheah Nathan L Asquith Marco M Domingues Victoria C Ridger Simon DA Connell Khalid M Naseem Helen Philippou Ramzi A Ajjan Robert AS Ariëns
author_sort	Helen R McPherson
title	Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis
title_short	Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis
title_full	Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis
title_fullStr	Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis
title_full_unstemmed	Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis
title_sort	fibrinogen αc-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/c1db5394e1864b85a4927dd251608dff
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Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis

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