{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T11:19:18Z","timestamp":1793272758688,"version":"4.5.0"},"reference-count":78,"publisher":"American Society of Hematology","issue":"24","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,6,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Recombinant factor FVIIa (rFVIIa) is used as a hemostatic agent to treat bleeding disorders in hemophilia patients with inhibitors and other groups of patients. Our recent studies showed that FVIIa binds endothelial cell protein C receptor (EPCR) and induces protease-activated receptor 1 (PAR1)-mediated biased signaling. The importance of FVIIa-EPCR-PAR1\u2013mediated signaling in hemostasis is unknown. In the present study, we show that FVIIa induces the release of extracellular vesicles (EVs) from endothelial cells both in vitro and in vivo. Silencing of EPCR or PAR1 in endothelial cells blocked the FVIIa-induced generation of EVs. Consistent with these data, FVIIa treatment enhanced the release of EVs from murine brain endothelial cells isolated from wild-type (WT), EPCR-overexpressing, and PAR1-R46Q\u2013mutant mice, but not EPCR-deficient or PAR1-R41Q\u2013mutant mice. In vivo studies revealed that administration of FVIIa to WT, EPCR-overexpressing, and PAR1-R46Q\u2013mutant mice, but not EPCR-deficient or PAR1-R41Q\u2013mutant mice, increased the number of circulating EVs. EVs released in response to FVIIa treatment exhibit enhanced procoagulant activity. Infusion of FVIIa-generated EVs and not control EVs to platelet-depleted mice increased thrombin generation at the site of injury and reduced blood loss. Administration of FVIIa-generated EVs or generation of EVs endogenously by administering FVIIa augmented the hemostatic effect of FVIIa. Overall, our data reveal that FVIIa treatment, through FVIIa-EPCR-PAR1 signaling, releases EVs from the endothelium into the circulation, and these EVs contribute to the hemostatic effect of FVIIa.<\/jats:p>","DOI":"10.1182\/blood.2020008417","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T10:02:32Z","timestamp":1612778552000},"page":"3428-3442","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":44,"title":["Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect"],"prefix":"10.1182","volume":"137","author":[{"given":"Kaushik","family":"Das","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shabbir A.","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles T.","family":"Esmon","sequence":"additional","affiliation":[{"name":"Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-2547","authenticated-orcid":false,"given":"John H.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2099-0585","authenticated-orcid":false,"given":"L. 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