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Emicizumab is a humanized anti\u2010FIXa\/FX bispecific monoclonal antibody that mimicks FVIIIa cofactor function. In recent clinical trials in haemophilia A patients, once\u2010weekly subcutaneous administration of emicizumab was remarkably effective in preventing bleeding events, but the mechanisms controlling the regulation of emicizumab\u2010mediated haemostasis remain to be explored. We investigated the role of <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content>\u2010mediated reactions in these circumstances. <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content> dose\u2010dependently depressed thrombin generation (<jats:styled-content style=\"fixed-case\">TG<\/jats:styled-content>) initiated by emicizumab in FVIII\u2010deficient plasmas, and in normal plasmas preincubated with an anti\u2010FVIII antibody (FVIII\u2010depleted). FVIIIa\u2010independent FXa generation with emicizumab was not affected by the presence of <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content>, protein S and <jats:styled-content style=\"fixed-case\">FV<\/jats:styled-content>. The results suggested that <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content>\u2010induced down\u2010regulation of emicizumab\u2010dependent <jats:styled-content style=\"fixed-case\">TG<\/jats:styled-content> was accomplished by direct inactivation of <jats:styled-content style=\"fixed-case\">FV<\/jats:styled-content>a. The addition of <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content> to emicizumab mixed with FVIII\u2010depleted FV\u2010deficient plasma in the presence of various concentrations of exogenous FV demonstrated similar attenuation of <jats:styled-content style=\"fixed-case\">TG<\/jats:styled-content>, irrespective of specific <jats:styled-content style=\"fixed-case\">FV<\/jats:styled-content> concentrations. Emicizumab\u2010related <jats:styled-content style=\"fixed-case\">TG<\/jats:styled-content> in FVIII\u2010depleted FV<jats:sub>Leiden<\/jats:sub> plasma was decreased by <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content> more than that observed with native FV<jats:sub>Leiden<\/jats:sub> plasma. The findings indicated that emicizumab\u2010driven haemostasis was down regulated by <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content>\u2010mediated <jats:styled-content style=\"fixed-case\">FV<\/jats:styled-content>a inactivation in plasma from haemophilia A patients without or with <jats:styled-content style=\"fixed-case\">FV<\/jats:styled-content> defects.<\/jats:p>","DOI":"10.1111\/bjh.15525","type":"journal-article","created":{"date-parts":[[2018,8,20]],"date-time":"2018-08-20T16:39:36Z","timestamp":1534783176000},"page":"257-266","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Emicizumab\u2010mediated haemostatic function in patients with haemophilia A is down\u2010regulated by activated protein C through inactivation of activated factor V"],"prefix":"10.1111","volume":"183","author":[{"given":"Koji","family":"Yada","sequence":"first","affiliation":[{"name":"Department of Paediatrics Nara Medical University Kashihara Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2415-2194","authenticated-orcid":false,"given":"Keiji","family":"Nogami","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Nara Medical University Kashihara Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Shinozawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics of Coagulation Disorders Tokyo Medical University Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehisa","family":"Kitazawa","sequence":"additional","affiliation":[{"name":"Research Division Chugai Pharmaceutical Co., Ltd. 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