Identification of the factor XII contact activation site enables sensitive coagulation diagnostics.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 09 2021
22 09 2021
Historique:
received:
04
06
2020
accepted:
31
08
2021
entrez:
23
9
2021
pubmed:
24
9
2021
medline:
21
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34552086
doi: 10.1038/s41467-021-25888-7
pii: 10.1038/s41467-021-25888-7
pmc: PMC8458485
doi:
Substances chimiques
Antibodies
0
Peptides
0
Factor XII
9001-30-3
Factor XIIa
EC 3.4.21.38
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5596Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL137695
Pays : United States
Organisme : BLRD VA
ID : I01 BX003851
Pays : United States
Informations de copyright
© 2021. The Author(s).
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