{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:36:30Z","timestamp":1791315390005,"version":"4.3.1"},"reference-count":80,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Drug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K\u2013dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.<\/jats:p>","DOI":"10.1182\/blood.2019004234","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T01:25:39Z","timestamp":1588814739000},"page":"898-908","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":13,"title":["A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle"],"prefix":"10.1182","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8459-2557","authenticated-orcid":false,"given":"Xuejie","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caihong","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center for Integrative Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Yun","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Ingram","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6418-2921","authenticated-orcid":false,"given":"Zhenyu","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"Research Center for Integrative Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrel W.","family":"Stafford","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; 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