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

• Published in: Nature communications Vol. 12; no. 1; p. 5596
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.09.2021; Nature Publishing Group; MDPI; Nature Portfolio
• Subjects: 13/56; 13/95; 14/1; 631/92/612/1221; 64/60; 692/53/2421; 692/699/75/593/567; 82/80; Antibodies; Blood clots; Blood coagulation; Clinical medical disciplines: 750; Clotting; Coagulation; Coagulation factor XII; Coagulation factors; Diagnostic systems; Epidermal growth factor; Hematologi: 775; Hematology: 775; Humanities and Social Sciences; Kallikrein; Klinisk medisinske fag: 750; Medical disciplines: 700; Medicin och hälsovetenskap; Medicine; Medisinske Fag: 700; Molecular weight; multidisciplinary; Mutants; Peptides; Plasma; Plasma kallikrein; Plasmin; Reagents; Residues; Science; Science (multidisciplinary); Standardization; Thrombin; Thromboplastin; Thrombosis; VDP
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25888-7

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. Blood coagulation is started by contact to surfaces and this is the principle for a commonly used diagnostic clotting test, aPTT. Here, the authors identify the structure in coagulation factor XII that initiates surface-driven coagulation and use the information to develop improved aPTT assays.