Therapeutic doses of recombinant factor VIIa in hemophilia generates thrombin in platelet-dependent and -independent mechanisms.
endothelial cell protein C receptor
factor VIIa
hemophilia
hemostasis
platelets
thrombin generation
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:
08 2020
08 2020
Historique:
received:
10
03
2020
revised:
09
04
2020
accepted:
14
04
2020
pubmed:
3
5
2020
medline:
15
5
2021
entrez:
3
5
2020
Statut:
ppublish
Résumé
In hemophilia bypass therapy, a platelet-dependent mechanism is believed to be primarily responsible for recombinant factor VIIa (rFVIIa)'s hemostatic effect. rFVIIa may also possibly interact with other cells through its binding to endothelial cell protein C receptor (EPCR) or cell surface phospholipids. We aim to investigate the relative contribution of platelet-dependent and platelet-independent mechanisms in rFVIIa-mediated thrombin generation in hemophilic conditions at the injury site. Platelets were depleted in acquired and genetic hemophilia mice using anti-platelet antibodies. The mice were subjected to the saphenous vein injury, and the hemostatic effect of pharmacological concentrations of rFVIIa was evaluated by measuring thrombin generation at the injury site. Administration of anti-mouse CD42 antibodies to mice depleted platelets by more than 95%. As expected, hemophilia mice, compared with wild-type mice, generated only a small fraction of thrombin at the injury site. The depletion of platelets in hemophilia mice further reduced thrombin generation. However, when pharmacological doses of rFVIIa were administered to hemophilia mice, substantial amounts of thrombin were generated even in the platelet-depleted hemophilia mice. No differences in thrombin generation were detected among FVIII Our data suggest that pharmacological concentrations of rFVIIa generate thrombin in hemophilia in both platelet-dependent and platelet-independent mechanisms.
Sections du résumé
BACKGROUND
In hemophilia bypass therapy, a platelet-dependent mechanism is believed to be primarily responsible for recombinant factor VIIa (rFVIIa)'s hemostatic effect. rFVIIa may also possibly interact with other cells through its binding to endothelial cell protein C receptor (EPCR) or cell surface phospholipids.
OBJECTIVES
We aim to investigate the relative contribution of platelet-dependent and platelet-independent mechanisms in rFVIIa-mediated thrombin generation in hemophilic conditions at the injury site.
METHODS
Platelets were depleted in acquired and genetic hemophilia mice using anti-platelet antibodies. The mice were subjected to the saphenous vein injury, and the hemostatic effect of pharmacological concentrations of rFVIIa was evaluated by measuring thrombin generation at the injury site.
RESULTS
Administration of anti-mouse CD42 antibodies to mice depleted platelets by more than 95%. As expected, hemophilia mice, compared with wild-type mice, generated only a small fraction of thrombin at the injury site. The depletion of platelets in hemophilia mice further reduced thrombin generation. However, when pharmacological doses of rFVIIa were administered to hemophilia mice, substantial amounts of thrombin were generated even in the platelet-depleted hemophilia mice. No differences in thrombin generation were detected among FVIII
CONCLUSIONS
Our data suggest that pharmacological concentrations of rFVIIa generate thrombin in hemophilia in both platelet-dependent and platelet-independent mechanisms.
Identifiants
pubmed: 32359012
doi: 10.1111/jth.14881
pmc: PMC7415704
mid: NIHMS1600163
pii: S1538-7836(22)01610-5
doi:
Substances chimiques
Recombinant Proteins
0
recombinant FVIIa
AC71R787OV
Factor VIIa
EC 3.4.21.21
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
1911-1921Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL107483
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL124055
Pays : United States
Organisme : NHLBI NIH HHS
ID : HL107483
Pays : United States
Organisme : Baxalta, currently a part of Takeda
ID : H15-28004
Pays : International
Organisme : NHLBI NIH HHS
ID : HL107483
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
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