{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T02:50:37Z","timestamp":1774061437525,"version":"3.50.1"},"reference-count":58,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Recurrent spontaneous or trauma-related bleeding into joints in hemophilia leads to hemophilic arthropathy (HA), a debilitating joint disease. Treatment of HA consists of preventing joint bleeding by clotting factor replacement, and in extreme cases, orthopedic surgery. We recently showed that administration of endothelial cell protein C receptor (EPCR) blocking monoclonal antibodies (mAb) markedly reduced the severity of HA in factor VIII (FVIII)\u2212\/\u2212 mice. EPCR blocking inhibits activated protein C (APC) generation and EPCR-dependent APC signaling. The present study was aimed to define the role of inhibition of APC anticoagulant activity, APC signaling, or both in suppressing HA. FVIII\u2212\/\u2212 mice were treated with a single dose of isotype control mAb, MPC1609 mAb, that inhibits anticoagulant, and signaling properties of APC, or MAPC1591 mAb that only blocks the anticoagulant activity of APC. Joint bleeding was induced by needle puncture injury. HA was evaluated by monitoring joint bleeding, change in joint diameter, and histopathological analysis of joint tissue sections for synovial hypertrophy, macrophage infiltration, neoangiogenesis, cartilage degeneration, and chondrocyte apoptosis. No significant differences were observed between MPC1609 and MAPC1591 in inhibiting APC anticoagulant activity in\u00a0vitro and equally effective in correcting acute bleeding induced by the saphenous vein incision\u00a0in FVIII\u2212\/\u2212 mice. Administration of MAPC1591, and not MPC1609, markedly reduced the severity of HA. MAPC1591 inhibited joint bleed\u2013induced inflammatory cytokine interleukin-6 expression and vascular leakage in joints, whereas MPC1609 had no significant effect. Our data show that an mAb that selectively inhibits APC\u2019s anticoagulant activity without compromising its cytoprotective signaling offers a therapeutic potential alternative to treat HA.<\/jats:p>","DOI":"10.1182\/blood.2021013119","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T18:59:02Z","timestamp":1644519542000},"page":"2830-2841","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":22,"title":["Selective inhibition of activated protein C anticoagulant activity protects against hemophilic arthropathy in mice"],"prefix":"10.1182","volume":"139","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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijay","family":"Kondreddy","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiva","family":"Keshava","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaushik","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles T.","family":"Esmon","sequence":"additional","affiliation":[{"name":"Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7138-9362","authenticated-orcid":false,"given":"Usha R.","family":"Pendurthi","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2099-0585","authenticated-orcid":false,"given":"L. 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