Coagulation factor VIII regulates von Willebrand factor homeostasis invivo.
ADAMTS-13
coagulation factor VIII
proteolysis
regulation
thrombosis
von Willebrand factor
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
12 2023
12 2023
Historique:
received:
16
06
2023
revised:
02
09
2023
accepted:
06
09
2023
pmc-release:
01
12
2024
medline:
27
11
2023
pubmed:
20
9
2023
entrez:
19
9
2023
Statut:
ppublish
Résumé
Coagulation factor VIII (FVIII) and von Willebrand factor (VWF) circulate as a noncovalent complex, but each has its distinct functions. Binding of FVIII to VWF results in a prolongation of FVIII's half-life in circulation and modulates FVIII's immunogenicity during hemophilia therapy. However, the biological effect of FVIII and VWF interaction on VWF homeostasis is not fully understood. To determine the effect of FVIII in VWF proteolysis and homeostasis in vivo. Mouse models, recombinant FVIII infusion, and patients with hemophilia A on a high dose FVIII for immune tolerance induction therapy or emicizumab for bleeding symptoms were included to address this question. An intravenous infusion of a recombinant B-domain less FVIII (BDD-FVIII) (40 and 160 μg/kg) into wild-type mice significantly reduced plasma VWF multimer sizes and its antigen levels; an infusion of a high but not low dose of BDD-FVIII into Adamts13 Our results demonstrate the pivotal role of FVIII as a cofactor regulating VWF proteolysis and homeostasis under various (patho)physiological conditions.
Sections du résumé
BACKGROUND
Coagulation factor VIII (FVIII) and von Willebrand factor (VWF) circulate as a noncovalent complex, but each has its distinct functions. Binding of FVIII to VWF results in a prolongation of FVIII's half-life in circulation and modulates FVIII's immunogenicity during hemophilia therapy. However, the biological effect of FVIII and VWF interaction on VWF homeostasis is not fully understood.
OBJECTIVES
To determine the effect of FVIII in VWF proteolysis and homeostasis in vivo.
METHODS
Mouse models, recombinant FVIII infusion, and patients with hemophilia A on a high dose FVIII for immune tolerance induction therapy or emicizumab for bleeding symptoms were included to address this question.
RESULTS
An intravenous infusion of a recombinant B-domain less FVIII (BDD-FVIII) (40 and 160 μg/kg) into wild-type mice significantly reduced plasma VWF multimer sizes and its antigen levels; an infusion of a high but not low dose of BDD-FVIII into Adamts13
CONCLUSION
Our results demonstrate the pivotal role of FVIII as a cofactor regulating VWF proteolysis and homeostasis under various (patho)physiological conditions.
Identifiants
pubmed: 37726033
pii: S1538-7836(23)00701-8
doi: 10.1016/j.jtha.2023.09.004
pmc: PMC10842601
mid: NIHMS1936522
pii:
doi:
Substances chimiques
Factor VIII
9001-27-8
von Willebrand Factor
0
Hemostatics
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3477-3489Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL156073
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL146991
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL164016
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM130423
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL074124
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL142012
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157975
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL139420
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144552
Pays : United States
Informations de copyright
Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interests X.L.Z. is a consultant and a member of the advisory boards for Alexion, Apollo, GC Biopharma, Sanofi, Stago, and Takeda. X.L.Z. is also the cofounder of Clotsolution. W.C. holds equity in Ivygen. All other authors have declared no relevant conflict.
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