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Identification of the factor XII contact activation site enables sensitive coagulation diagnostics

Heestermans, Marco; Naudin, Clément; Mailer, Reiner K.; Konrath, Sandra; Klaetschke, Kristin; Jämsä, Anne; Frye, Maike; Deppermann, Carsten; Pula, Giordano; Kuta, Piotr; Friese, Manuel A.; Gelderblom, Mathias; Sickmann, Albert; Preston, Roger J.S.; Nofer, Jerzy Roch; Rose-John, Stefan; Butler, Lynn M.; Salomon, Ophira; Stavrou, Evi X.; Renné, Thomas

Authors

Marco Heestermans

Clément Naudin

Reiner K. Mailer

Sandra Konrath

Kristin Klaetschke

Anne Jämsä

Maike Frye

Carsten Deppermann

Piotr Kuta

Manuel A. Friese

Mathias Gelderblom

Albert Sickmann

Roger J.S. Preston

Jerzy Roch Nofer

Stefan Rose-John

Lynn M. Butler

Ophira Salomon

Evi X. Stavrou

Thomas Renné



Abstract

Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317–Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317–Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317–Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.

Citation

Heestermans, M., Naudin, C., Mailer, R. K., Konrath, S., Klaetschke, K., Jämsä, A., Frye, M., Deppermann, C., Pula, G., Kuta, P., Friese, M. A., Gelderblom, M., Sickmann, A., Preston, R. J., Nofer, J. R., Rose-John, S., Butler, L. M., Salomon, O., Stavrou, E. X., & Renné, T. (2021). Identification of the factor XII contact activation site enables sensitive coagulation diagnostics. Nature communications, 12(1), Article 5596. https://doi.org/10.1038/s41467-021-25888-7

Journal Article Type Article
Acceptance Date Aug 31, 2021
Online Publication Date Aug 22, 2021
Publication Date Dec 1, 2021
Deposit Date Jun 4, 2025
Publicly Available Date Jun 20, 2025
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 12
Issue 1
Article Number 5596
DOI https://doi.org/10.1038/s41467-021-25888-7
Keywords Blood proteins; Diagnostic markers; Thrombosis
Public URL https://hull-repository.worktribe.com/output/4619752

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Copyright Statement
© The Author(s) 2021.
Open Access 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.





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