EPCR deficiency or function-blocking antibody protects against joint bleeding–induced pathology in hemophilia mice

We recently showed that clotting factor VIIa (FVIIa) binding to endothelial cell protein C receptor (EPCR) induces anti-inflammatory signaling and protects vascular barrier integrity. Inflammation and vascular permeability are thought to be major contributors to the development of hemophilic arthrop...

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Bibliographic Details
Published in:Blood 2020-06, Vol.135 (25), p.2211-2223
Main Authors: Magisetty, Jhansi, Pendurthi, Usha R., Esmon, Charles T., Rao, L. Vijaya Mohan
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal - therapeutic use
Cytokines - physiology
Endothelial Protein C Receptor - antagonists & inhibitors
Endothelial Protein C Receptor - deficiency
Endothelial Protein C Receptor - immunology
Endothelial Protein C Receptor - physiology
Factor VIIa - therapeutic use
Hemarthrosis - drug therapy
Hemarthrosis - etiology
Hemarthrosis - physiopathology
Hemarthrosis - prevention & control
Hemophilia A - complications
Hemophilia A - drug therapy
Hemophilia A - genetics
Mice
Mice, Knockout
Plenary Paper
Punctures - adverse effects
Rats
Recombinant Proteins - therapeutic use
Synovitis - etiology
Synovitis - prevention & control
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Summary:We recently showed that clotting factor VIIa (FVIIa) binding to endothelial cell protein C receptor (EPCR) induces anti-inflammatory signaling and protects vascular barrier integrity. Inflammation and vascular permeability are thought to be major contributors to the development of hemophilic arthropathy following hemarthrosis. The present study was designed to investigate the potential influence of FVIIa interaction with EPCR in the pathogenesis of hemophilic arthropathy and its treatment with recombinant FVIIa (rFVIIa). For this, we first generated hemophilia A (FVIII−/−) mice lacking EPCR (EPCR−/−FVIII−/−) or overexpressing EPCR (EPCR++ FVIII−/−). Joint bleeding was induced in FVIII−/−, EPCR−/−FVIII−/−, and EPCR++FVIII−/− mice by needle puncture injury. Hemophilic synovitis was evaluated by monitoring joint bleeding, change in joint diameter, and histopathological analysis of joint tissue sections. EPCR deficiency in FVIII−/− mice significantly reduced the severity of hemophilic synovitis. EPCR deficiency attenuated the elaboration of interleukin-6, infiltration of macrophages, and neoangiogenesis in the synovium following hemarthrosis. A single dose of rFVIIa was sufficient to fully prevent the development of milder hemophilic synovitis in EPCR−/−FVIII−/− mice. The development of hemophilic arthropathy in EPCR-overexpressing FVIII−/− mice did not significantly differ from that of FVIII−/− mice, and 3 doses of rFVIIa partly protected against hemophilic synovitis in these mice. Consistent with the data that EPCR deficiency protects against developing hemophilic arthropathy, administration of a single dose of EPCR-blocking monoclonal antibodies markedly reduced hemophilic synovitis in FVIII−/− mice subjected to joint bleeding. The present data indicate that EPCR could be an attractive new target to prevent joint damage in hemophilia patients. •EPCR deficiency protects against hemophilic joint disease by reducing joint bleeding.•Administration of a single dose of EPCR-blocking antibody attenuates the progression of hemophilic arthropathy in hemophilia A mouse model. [Display omitted]
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2019003824