Sustained depletion of FXIII-A by inducing acquired FXIII-B deficiency.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
17 12 2020
17 12 2020
Historique:
received:
21
01
2020
accepted:
06
07
2020
pubmed:
18
7
2020
medline:
7
4
2021
entrez:
18
7
2020
Statut:
ppublish
Résumé
The activated form of coagulation factor XIII (FXIII-A2B2), FXIII-A*, is a hemostatic enzyme essential for inhibiting fibrinolysis by irreversibly crosslinking fibrin and antifibrinolytic proteins. Despite its importance, there are no modulatory therapeutics. Guided by the observation that humans deficient in FXIII-B have reduced FXIII-A without severe bleeding, we hypothesized that a suitable small interfering RNA (siRNA) targeting hepatic FXIII-B could safely decrease FXIII-A. Here we show that knockdown of FXIII-B with siRNA in mice and rabbits using lipid nanoparticles resulted in a sustained and controlled decrease in FXIII-A. The concentration of FXIII-A in plasma was reduced by 90% for weeks after a single injection and for more than 5 months with repeated injections, whereas the concentration of FXIII-A in platelets was unchanged. Ex vivo, crosslinking of α2-antiplasmin and fibrin was impaired and fibrinolysis was enhanced. In vivo, reperfusion of carotid artery thrombotic occlusion was also enhanced. Re-bleeding events were increased after challenge, but blood loss was not significantly increased. This approach, which mimics congenital FXIII-B deficiency, provides a potential pharmacologic and experimental tool to modulate FXIII-A2B2 activity.
Identifiants
pubmed: 32678423
pii: S0006-4971(20)77870-5
doi: 10.1182/blood.2020004976
pmc: PMC9710420
doi:
Substances chimiques
RNA, Small Interfering
0
Factor XIII
9013-56-3
factor XIIIb
97089-56-0
Factor XIIIa
EC 2.3.2.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2946-2954Subventions
Organisme : NCI NIH HHS
ID : R01 CA204058
Pays : United States
Organisme : CIHR
ID : MSH-130166
Pays : Canada
Organisme : CIHR
ID : FDN-148370
Pays : Canada
Informations de copyright
© 2020 by The American Society of Hematology.
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