The impact of fibrinogen carbamylation on fibrin clot formation and stability

Research output: Contribution to journalArticlepeer-review

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The impact of fibrinogen carbamylation on fibrin clot formation and stability. / Binder, Veronika ; Bergum, Brith ; Jaisson, Stephane; Gillery, Philippe; Scavenius, Carsten; Spriet, Endy; Nyhaug, Anne Karin; Roberts, Helen; Chapple, Iain; Hellvard, Annelie; Delaleu, Nicolas ; Mydel, Piotr .

In: Thrombosis and Haemostasis, Vol. 117, No. 5, 28.11.2017, p. 899-910.

Research output: Contribution to journalArticlepeer-review

Harvard

Binder, V, Bergum, B, Jaisson, S, Gillery, P, Scavenius, C, Spriet, E, Nyhaug, AK, Roberts, H, Chapple, I, Hellvard, A, Delaleu, N & Mydel, P 2017, 'The impact of fibrinogen carbamylation on fibrin clot formation and stability', Thrombosis and Haemostasis, vol. 117, no. 5, pp. 899-910. https://doi.org/10.1160/TH16-09-0704

APA

Binder, V., Bergum, B., Jaisson, S., Gillery, P., Scavenius, C., Spriet, E., Nyhaug, A. K., Roberts, H., Chapple, I., Hellvard, A., Delaleu, N., & Mydel, P. (2017). The impact of fibrinogen carbamylation on fibrin clot formation and stability. Thrombosis and Haemostasis, 117(5), 899-910. https://doi.org/10.1160/TH16-09-0704

Vancouver

Binder V, Bergum B, Jaisson S, Gillery P, Scavenius C, Spriet E et al. The impact of fibrinogen carbamylation on fibrin clot formation and stability. Thrombosis and Haemostasis. 2017 Nov 28;117(5):899-910. https://doi.org/10.1160/TH16-09-0704

Author

Binder, Veronika ; Bergum, Brith ; Jaisson, Stephane ; Gillery, Philippe ; Scavenius, Carsten ; Spriet, Endy ; Nyhaug, Anne Karin ; Roberts, Helen ; Chapple, Iain ; Hellvard, Annelie ; Delaleu, Nicolas ; Mydel, Piotr . / The impact of fibrinogen carbamylation on fibrin clot formation and stability. In: Thrombosis and Haemostasis. 2017 ; Vol. 117, No. 5. pp. 899-910.

Bibtex

@article{d3e1c2c5d515447b8f47f7159cd9d2a7,
title = "The impact of fibrinogen carbamylation on fibrin clot formation and stability",
abstract = "Carbamylation is a non-enzymatic post-translational modification induced upon exposure of free amino groups to urea-derived cyanate leading to irreversible changes of protein charge, structure and function. Levels of carbamylated proteins increase significantly in chronic kidney disease and carbamylated albumin is considered as an important biomarker indicating mortality risk. High plasma concentrations and long half-life make fibrinogen a prime target for carbamylation. As aggregation and cross-linking of fibrin monomers rely on lysine residues, it is likely that carbamylation impacts fibrinogen processing. In this study we investigated carbamylation levels of fibrinogen from kidney disease patients as well as the impact of carbamylation on fibrinogen cleavage by thrombin, fibrin polymerisation and cross-linking in vitro. In conjunction, all these factors determine clot structure and stability and thus control biochemical and mechanical properties. LC-MS/MS analyses revealed significantly higher homocitrulline levels in patient fibrinogen than in fibrinogen isolated from control plasma. In our in vitro studies we found that although carbamylation does not affect thrombin cleavage per se, it alters fibrin polymerisation kinetics and impairs cross-linking and clot degradation. In addition, carbamylated fibrin clots had reduced fiber size and porosity associated with decreased mechanical stability. Using mass spectroscopy, we discovered that N-terminally carbamylated fibrinopeptide A was generated in this process and acted as a strong neutrophil chemoattractant potentially mediating recruitment of inflammatory cells to sites of fibrin(ogen) turnover. Taken together, carbamylation of fibrinogen seems to play a role in aberrant fibrin clot formation and might be involved in haemostatic disorders associated with chronic inflammatory diseases.",
keywords = "fibrinogen, carbamylation, fibrin structure",
author = "Veronika Binder and Brith Bergum and Stephane Jaisson and Philippe Gillery and Carsten Scavenius and Endy Spriet and Nyhaug, {Anne Karin} and Helen Roberts and Iain Chapple and Annelie Hellvard and Nicolas Delaleu and Piotr Mydel",
year = "2017",
month = nov,
day = "28",
doi = "10.1160/TH16-09-0704",
language = "English",
volume = "117",
pages = "899--910",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "Schattauer",
number = "5",

}

RIS

TY - JOUR

T1 - The impact of fibrinogen carbamylation on fibrin clot formation and stability

AU - Binder, Veronika

AU - Bergum, Brith

AU - Jaisson, Stephane

AU - Gillery, Philippe

AU - Scavenius, Carsten

AU - Spriet, Endy

AU - Nyhaug, Anne Karin

AU - Roberts, Helen

AU - Chapple, Iain

AU - Hellvard, Annelie

AU - Delaleu, Nicolas

AU - Mydel, Piotr

PY - 2017/11/28

Y1 - 2017/11/28

N2 - Carbamylation is a non-enzymatic post-translational modification induced upon exposure of free amino groups to urea-derived cyanate leading to irreversible changes of protein charge, structure and function. Levels of carbamylated proteins increase significantly in chronic kidney disease and carbamylated albumin is considered as an important biomarker indicating mortality risk. High plasma concentrations and long half-life make fibrinogen a prime target for carbamylation. As aggregation and cross-linking of fibrin monomers rely on lysine residues, it is likely that carbamylation impacts fibrinogen processing. In this study we investigated carbamylation levels of fibrinogen from kidney disease patients as well as the impact of carbamylation on fibrinogen cleavage by thrombin, fibrin polymerisation and cross-linking in vitro. In conjunction, all these factors determine clot structure and stability and thus control biochemical and mechanical properties. LC-MS/MS analyses revealed significantly higher homocitrulline levels in patient fibrinogen than in fibrinogen isolated from control plasma. In our in vitro studies we found that although carbamylation does not affect thrombin cleavage per se, it alters fibrin polymerisation kinetics and impairs cross-linking and clot degradation. In addition, carbamylated fibrin clots had reduced fiber size and porosity associated with decreased mechanical stability. Using mass spectroscopy, we discovered that N-terminally carbamylated fibrinopeptide A was generated in this process and acted as a strong neutrophil chemoattractant potentially mediating recruitment of inflammatory cells to sites of fibrin(ogen) turnover. Taken together, carbamylation of fibrinogen seems to play a role in aberrant fibrin clot formation and might be involved in haemostatic disorders associated with chronic inflammatory diseases.

AB - Carbamylation is a non-enzymatic post-translational modification induced upon exposure of free amino groups to urea-derived cyanate leading to irreversible changes of protein charge, structure and function. Levels of carbamylated proteins increase significantly in chronic kidney disease and carbamylated albumin is considered as an important biomarker indicating mortality risk. High plasma concentrations and long half-life make fibrinogen a prime target for carbamylation. As aggregation and cross-linking of fibrin monomers rely on lysine residues, it is likely that carbamylation impacts fibrinogen processing. In this study we investigated carbamylation levels of fibrinogen from kidney disease patients as well as the impact of carbamylation on fibrinogen cleavage by thrombin, fibrin polymerisation and cross-linking in vitro. In conjunction, all these factors determine clot structure and stability and thus control biochemical and mechanical properties. LC-MS/MS analyses revealed significantly higher homocitrulline levels in patient fibrinogen than in fibrinogen isolated from control plasma. In our in vitro studies we found that although carbamylation does not affect thrombin cleavage per se, it alters fibrin polymerisation kinetics and impairs cross-linking and clot degradation. In addition, carbamylated fibrin clots had reduced fiber size and porosity associated with decreased mechanical stability. Using mass spectroscopy, we discovered that N-terminally carbamylated fibrinopeptide A was generated in this process and acted as a strong neutrophil chemoattractant potentially mediating recruitment of inflammatory cells to sites of fibrin(ogen) turnover. Taken together, carbamylation of fibrinogen seems to play a role in aberrant fibrin clot formation and might be involved in haemostatic disorders associated with chronic inflammatory diseases.

KW - fibrinogen

KW - carbamylation

KW - fibrin structure

U2 - 10.1160/TH16-09-0704

DO - 10.1160/TH16-09-0704

M3 - Article

VL - 117

SP - 899

EP - 910

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 5

ER -