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

Author

Listed:
  • Marco Heestermans

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Clément Naudin

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
    The Arctic University of Norway
    Clinical Chemistry and Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institute)

  • Reiner K. Mailer

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Sandra Konrath

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Kristin Klaetschke

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Anne Jämsä

    (Karolinska University Hospital)

  • Maike Frye

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Carsten Deppermann

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Giordano Pula

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Piotr Kuta

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Manuel A. Friese

    (Institute for Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf)

  • Mathias Gelderblom

    (University Medical Center Hamburg-Eppendorf)

  • Albert Sickmann

    (Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V.)

  • Roger J. S. Preston

    (Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland)

  • Jerzy-Roch Nofer

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Stefan Rose-John

    (Institute of Biochemistry, University of Kiel)

  • Lynn M. Butler

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
    The Arctic University of Norway
    Clinical Chemistry and Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institute)

  • Ophira Salomon

    (Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel and Sackler Faculty of Medicine, University of Tel Aviv)

  • Evi X. Stavrou

    (Louis Stokes Veterans Administration Medical Center
    Hematology and Oncology Division, Case Western Reserve University School of Medicine)

  • Thomas Renné

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
    Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center)

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.

Suggested Citation

  • 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 Gel, 2021. "Identification of the factor XII contact activation site enables sensitive coagulation diagnostics," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25888-7
    DOI: 10.1038/s41467-021-25888-7
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    Cited by:

    1. Pengfei Xu & Yingjie Zhang & Junyan Guo & Huihui Li & Sandra Konrath & Peng Zhou & Liming Cai & Haojie Rao & Hong Chen & Jian Lin & Zhao Cui & Bingyang Ji & Jianwei Wang & Nailin Li & De-Pei Liu & Tho, 2024. "A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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