Factor XIII cross-links fibrin(ogen) independent of fibrin polymerization in experimental acute liver injury.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
06 05 2021
06 05 2021
Historique:
received:
04
06
2020
accepted:
18
01
2021
pubmed:
12
2
2021
medline:
15
12
2021
entrez:
11
2
2021
Statut:
ppublish
Résumé
Intravascular fibrin clot formation follows a well-ordered series of reactions catalyzed by thrombin cleavage of fibrinogen leading to fibrin polymerization and cross-linking by factor XIIIa (FXIIIa). Extravascular fibrin(ogen) deposits are observed in injured tissues; however, the mechanisms regulating fibrin(ogen) polymerization and cross-linking in this setting are unclear. The objective of this study was to determine the mechanisms of fibrin polymerization and cross-linking in acute liver injury induced by acetaminophen (APAP) overdose. Hepatic fibrin(ogen) deposition and cross-linking were measured following APAP overdose in wild-type mice, mice lacking the catalytic subunit of FXIII (FXIII-/-), and in FibAEK mice, which express mutant fibrinogen insensitive to thrombin-mediated fibrin polymer formation. Hepatic fibrin(ogen) deposition was similar in APAP-challenged wild-type and FXIII-/- mice, yet cross-linking of hepatic fibrin(ogen) was dramatically reduced (>90%) by FXIII deficiency. Surprisingly, hepatic fibrin(ogen) deposition and cross-linking were only modestly reduced in APAP-challenged FibAEK mice, suggesting that in the APAP-injured liver fibrin polymerization is not strictly required for the extravascular deposition of cross-linked fibrin(ogen). We hypothesized that the oxidative environment in the injured liver, containing high levels of reactive mediators (eg, peroxynitrite), modifies fibrin(ogen) such that fibrin polymerization is impaired without impacting FXIII-mediated cross-linking. Notably, fibrin(ogen) modified with 3-nitrotyrosine adducts was identified in the APAP-injured liver. In biochemical assays, peroxynitrite inhibited thrombin-mediated fibrin polymerization in a concentration-dependent manner without affecting fibrin(ogen) cross-linking over time. These studies depict a unique pathology wherein thrombin-catalyzed fibrin polymerization is circumvented to allow tissue deposition and FXIII-dependent fibrin(ogen) cross-linking.
Identifiants
pubmed: 33569603
pii: S0006-4971(21)00352-9
doi: 10.1182/blood.2020007415
pmc: PMC8109015
doi:
Substances chimiques
Analgesics, Non-Narcotic
0
Acetaminophen
362O9ITL9D
Fibrin
9001-31-4
Fibrinogen
9001-32-5
Factor XIII
9013-56-3
Thrombin
EC 3.4.21.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2520-2531Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK120289
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK121423
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM092715
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105099
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211098
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL143403
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112778
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology.
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