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

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 J. S. Preston, Jerzy-Roch Nofer, Stefan Rose-John, Lynn M. Butler, Ophira Salomon, Evi X. Stavrou and Thomas Renné ()
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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
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
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
Thomas Renné: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25888-7

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