Identification of the factor XII contact activation site enables sensitive coagulation diagnostics.pdf (4.42 MB)
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Identification of the factor XII contact activation site enables sensitive coagulation diagnostics

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posted on 22.06.2022, 16:42 by Marco Heestermans, Clément Naudin, Reiner K Mailer, Sandra Konrath, Kristin Klaetschke, Anne Jämsä, Maike Frye, Carsten Deppermann, Giordano Pula, Piotr Kuta, Manuel A Friese, Mathias Gelderblom, Albert Sickmann, Roger PrestonRoger Preston, Jerzy-Roch Nofer, Stefan Rose-John, Lynn M Butler, Ophira Salomon, Evi X Stavrou, Thomas Renné
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.

Funding

National Institutes of Health (R01 HL137695), the Department of Veterans Affairs (Merit Review Award BX003851)

Oscar D. Ratnoff Endowed Professorship

German Research Foundation (grants A11/SFB 877, P6/KFO 306, and B8/SFB 841)

History

Comments

The original article is available at https://www.nature.com/

Published Citation

Heestermans M. et al. Identification of the factor XII contact activation site enables sensitive coagulation diagnostics. Nat Commun. 2021;12(1):5596

Publication Date

22 September 2021

PubMed ID

34552086

Department/Unit

  • Irish Centre for Vascular Biology
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Health Professions Education
  • Vascular Biology

Publisher

Nature Pub. Group

Version

  • Published Version (Version of Record)