Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
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Identification of the factor XII contact activation site enables sensitive coagulation diagnostics. / 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.
In: NAT COMMUN, Vol. 12, No. 1, 22.09.2021, p. 5596 - 5613.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
AU - Heestermans, Marco
AU - Naudin, Clément
AU - Mailer, Reiner K
AU - Konrath, Sandra
AU - Klaetschke, Kristin
AU - Jämsä, Anne
AU - Frye, Maike
AU - Deppermann, Carsten
AU - Pula, Giordano
AU - Kuta, Piotr
AU - Friese, Manuel A
AU - Gelderblom, Mathias
AU - Sickmann, Albert
AU - Preston, Roger J S
AU - Nofer, Jerzy-Roch
AU - Rose-John, Stefan
AU - Butler, Lynn M
AU - Salomon, Ophira
AU - Stavrou, Evi X
AU - Renné, Thomas
N1 - © 2021. The Author(s).
PY - 2021/9/22
Y1 - 2021/9/22
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-021-25888-7
DO - 10.1038/s41467-021-25888-7
M3 - SCORING: Journal article
C2 - 34552086
VL - 12
SP - 5596
EP - 5613
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -