Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/153773
Title: Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods
Authors: Lau, Wai-Hoe
White, Nathan J.
Yeo, Tsin Wen
Gruen, Russell L.
Pervushin, Konstantin
Keywords: Science::Medicine
Issue Date: 2021
Source: Lau, W., White, N. J., Yeo, T. W., Gruen, R. L. & Pervushin, K. (2021). Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods. Scientific Reports, 11(1), 15691-. https://dx.doi.org/10.1038/s41598-021-94401-3
Project: NIM/05/2016
Journal: Scientific Reports
Abstract: Plasma fibrinogen is an important coagulation factor and susceptible to post-translational modification by oxidants. We have reported impairment of fibrin polymerization after exposure to hypochlorous acid (HOCl) and increased methionine oxidation of fibrinogen in severely injured trauma patients. Molecular dynamics suggests that methionine oxidation poses a mechanistic link between oxidative stress and coagulation through protofibril lateral aggregation by disruption of AαC domain structures. However, experimental evidence explaining how HOCl oxidation impairs fibrinogen structure and function has not been demonstrated. We utilized polymerization studies and two dimensional-nuclear magnetic resonance spectrometry (2D-NMR) to investigate the hypothesis that HOCl oxidation alters fibrinogen conformation and T₂ relaxation time of water protons in the fibrin gels. We have demonstrated that both HOCl oxidation of purified fibrinogen and addition of HOCl-oxidized fibrinogen to plasma fibrinogen solution disrupted lateral aggregation of protofibrils similarly to competitive inhibition of fibrin polymerization using a recombinant AαC fragment (AαC 419-502). DOSY NMR measurement of fibrinogen protons demonstrated that the diffusion coefficient of fibrinogen increased by 17.4%, suggesting the oxidized fibrinogen was more compact and fast motion in the prefibrillar state. 2D-NMR analysis reflected that water protons existed as bulk water (T₂) and intermediate water (T₂ᵢ) in the control plasma fibrin. Bulk water T₂ relaxation time was increased twofold and correlated positively with the level of HOCl oxidation. However, T₂ relaxation of the oxidized plasma fibrin gels was dominated by intermediate water. Oxidation induced thinner fibers, in which less water is released into the bulk and water fraction in the hydration shell was increased. We have confirmed that T₂ relaxation is affected by the self-assembly of fibers and stiffness of the plasma fibrin gel. We propose that water protons can serve as an NMR signature to probe oxidative rearrangement of the fibrin clot.
URI: https://hdl.handle.net/10356/153773
ISSN: 2045-2322
DOI: 10.1038/s41598-021-94401-3
Rights: © 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
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