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

Author:

Heestermans MarcoORCID,Naudin ClémentORCID,Mailer Reiner K.,Konrath Sandra,Klaetschke Kristin,Jämsä Anne,Frye MaikeORCID,Deppermann Carsten,Pula Giordano,Kuta Piotr,Friese Manuel A.ORCID,Gelderblom Mathias,Sickmann Albert,Preston Roger J. S.,Nofer Jerzy-Roch,Rose-John StefanORCID,Butler Lynn M.,Salomon Ophira,Stavrou Evi X.ORCID,Renné ThomasORCID

Abstract

AbstractContact 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.

Funder

Deutsche Forschungsgemeinschaft

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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