{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T11:19:21Z","timestamp":1793272761839,"version":"4.5.0"},"reference-count":50,"publisher":"American Society of Hematology","issue":"25","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,6,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2212\/\u2212) mice lacking EPCR (EPCR\u2212\/\u2212FVIII\u2212\/\u2212) or overexpressing EPCR (EPCR++ FVIII\u2212\/\u2212). Joint bleeding was induced in FVIII\u2212\/\u2212, EPCR\u2212\/\u2212FVIII\u2212\/\u2212, and EPCR++FVIII\u2212\/\u2212 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\u2212\/\u2212 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\u2212\/\u2212FVIII\u2212\/\u2212 mice. The development of hemophilic arthropathy in EPCR-overexpressing FVIII\u2212\/\u2212 mice did not significantly differ from that of FVIII\u2212\/\u2212 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\u2212\/\u2212 mice subjected to joint bleeding. The present data indicate that EPCR could be an attractive new target to prevent joint damage in hemophilia patients.<\/jats:p>","DOI":"10.1182\/blood.2019003824","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T22:34:28Z","timestamp":1586990068000},"page":"2211-2223","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":27,"title":["EPCR deficiency or function-blocking antibody protects against joint bleeding\u2013induced pathology in hemophilia mice"],"prefix":"10.1182","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8917-7168","authenticated-orcid":false,"given":"Jhansi","family":"Magisetty","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7138-9362","authenticated-orcid":false,"given":"Usha R.","family":"Pendurthi","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles T.","family":"Esmon","sequence":"first","affiliation":[{"name":"Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2099-0585","authenticated-orcid":false,"given":"L. 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