Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature communications, 2021-09, Vol.12 (1), p.5596-5596, Article 5596

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.