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, Thomas Renné*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number5596
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 1 Dec 2021

Funding

FundersFunder number
National Institutes of Health
National Heart, Lung, and Blood InstituteR01HL137695
U.S. Department of Veterans AffairsBX003851
Deutsche ForschungsgemeinschaftA11/SFB 877, B8/SFB 841, P6/KFO 306

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