Pharmacological reduction of coagulation factor XI reduces macrophage accumulation and accelerates deep vein thrombosis resolution in a mouse model of venous thrombosis.
contact activation
factor XI
thrombosis
vein
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:
09 2022
09 2022
Historique:
revised:
10
05
2022
received:
14
09
2021
accepted:
25
05
2022
pubmed:
1
6
2022
medline:
17
8
2022
entrez:
31
5
2022
Statut:
ppublish
Résumé
Deep vein thrombosis (DVT) and post-thrombotic syndrome (PTS) remain highly prevalent despite modern medical therapy. Contact activation is a promising target for safe antithrombotic anticoagulation. The anti-factor XI (FXI) monoclonal antibody 14E11 reduces circulating levels of FXI without compromising hemostasis. The human recombinant analog, AB023, is in clinical development. The role of FXI in mediation of inflammation during DVT resolution is unknown. Investigate the effects of pharmacological targeting of FXI with 14E11 in an experimental model of venous thrombosis. Adult wild-type CD1 mice were treated with subcutaneous anti-FXI antibody (14E11, 5 mg/kg) versus saline prior to undergoing surgical constriction of the inferior vena cava (IVC). Mice were evaluated at various time points to assess thrombus weight and volume, as well as histology analysis, ferumoxytol enhanced magnetic resonance imaging (Fe-MRI), and whole blood flow cytometry. 14E11-treated mice had reduced thrombus weights and volumes after IVC constriction on day 7 compared to saline-treated mice. 14E11 treatment reduced circulating monocytes by flow cytometry and macrophage content within thrombi as evaluated by histologic staining and Fe-MRI. Collagen deposition was increased at day 3 while CD31 and smooth muscle cell actin expression was increased at day 7 in the thrombi of 14E11-treated mice compared to saline-treated mice. Pharmacologic targeting of FXI enhances the early stages of experimental venous thrombus resolution in wild-type CD1 mice, and may be of interest for future clinical evaluation of the antibody in DVT and PTS.
Sections du résumé
BACKGROUND
Deep vein thrombosis (DVT) and post-thrombotic syndrome (PTS) remain highly prevalent despite modern medical therapy. Contact activation is a promising target for safe antithrombotic anticoagulation. The anti-factor XI (FXI) monoclonal antibody 14E11 reduces circulating levels of FXI without compromising hemostasis. The human recombinant analog, AB023, is in clinical development. The role of FXI in mediation of inflammation during DVT resolution is unknown.
OBJECTIVES
Investigate the effects of pharmacological targeting of FXI with 14E11 in an experimental model of venous thrombosis.
METHODS
Adult wild-type CD1 mice were treated with subcutaneous anti-FXI antibody (14E11, 5 mg/kg) versus saline prior to undergoing surgical constriction of the inferior vena cava (IVC). Mice were evaluated at various time points to assess thrombus weight and volume, as well as histology analysis, ferumoxytol enhanced magnetic resonance imaging (Fe-MRI), and whole blood flow cytometry.
RESULTS
14E11-treated mice had reduced thrombus weights and volumes after IVC constriction on day 7 compared to saline-treated mice. 14E11 treatment reduced circulating monocytes by flow cytometry and macrophage content within thrombi as evaluated by histologic staining and Fe-MRI. Collagen deposition was increased at day 3 while CD31 and smooth muscle cell actin expression was increased at day 7 in the thrombi of 14E11-treated mice compared to saline-treated mice.
CONCLUSION
Pharmacologic targeting of FXI enhances the early stages of experimental venous thrombus resolution in wild-type CD1 mice, and may be of interest for future clinical evaluation of the antibody in DVT and PTS.
Identifiants
pubmed: 35638310
doi: 10.1111/jth.15777
pmc: PMC9580566
mid: NIHMS1812283
pii: S1538-7836(22)02095-5
doi:
Substances chimiques
Antibodies, Monoclonal
0
Factor XI
9013-55-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2035-2045Subventions
Organisme : NIAID NIH HHS
ID : R01 AI157037
Pays : United States
Organisme : CSRD VA
ID : IK2 CX001720
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144113
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL101972
Pays : United States
Organisme : NIH HHS
ID : R01HL144113
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL140025
Pays : United States
Organisme : NIH HHS
ID : R01AI157037
Pays : United States
Informations de copyright
© 2022 International Society on Thrombosis and Haemostasis. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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