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Iron-deficiency and estrogen are associated with ischemic stroke by up-regulating transferrin to induce hypercoagulability
Open accessPreprint — published as 10.1161/circresaha.119.316453 · Paper page
Abstract
Summary: In the accompanying manuscript, transferrin has been demonstrated to maintain coagulation balance by interacting with clotting factors, suggesting that elevated transferrin causes thromboembolic diseases and factors up-regulating transferrin is associated with thrombosis. Here we show that transferrin and transferrin-thrombin/FXIIa complexes are elevated in plasma and cerebrospinal fluid of ischemic stroke (IS) patients with iron-deficiency anemia (IDA) history, IDA patients and venous thromboembolism patients using combined oral contraceptives (CC) as well as ID mice, suggesting an association of transferrin up-regulation with ID and CC. ID and estrogen up-regulated transferrin through hypoxia and estrogen response elements located at transferrin gene enhancer and promoter region, respectively. ID, exogenous transferrin/estrogen administration or transferrin over-expression promoted hypercoagulability and aggravated IS, while anti-transferrin antibody, transferrin knockdown or designed peptide inhibitors interfering transferrin-thrombin/FXIIa interaction exerted anti-IS effects in vivo . Collectively, the results reveal that factors (i.e., ID and CC) up-regulating transferrin are risk factors of thromboembolic diseases.
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Metadata
- Authors
- Tang, X., Fang, M., Cheng, R., Zhang, Z., Wang, Y., Shen, C., Han, Y., Lu, Q., Du, Y., Liu, Y., Sun, Z., Zhu, L., Mwangi, J., Xue, M., Long, C., & Lai, R.
- Affiliations
- Kunming Institute of Zoology (CN)
- Kunming Medical University (CN)
- Kunming Third People's Hospital (CN)
- General Hospital of Guangzhou Military Command (CN)
- First Affiliated Hospital of Kunming Medical University (CN)
- Corresponding author
- Lai, Ren
- ORCID
- Venue
- Circulation Research
- Publisher
- openRxiv
- Published
- 2019-05-23
- Volume
- 127
- Issue
- 5
- Pages
- 651-663
- ISSN
- 0009-7330 (ISSN-L)
- OpenAlex
- W3029930991
- Cited by
- 114
- References
- 1
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 19 · 2023: 22 · 2022: 21 · 2021: 10 · 2020: 6 · 2019: 1
- FWCI
- 9.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Circulation Research (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (331372208, 31630075, KFJ-BRP-008, XDB31000000, 81770464, 21761142002, 31640071, 31930015, 31770835)
- Chinese Academy of Sciences (XDA12040221, KFJ-BRP-008, XDA12020334, SAJC201606, QYZDJ-SSW-SMC012, XDB31000000)
- Ministry of Science and Technology of the People's Republic of China (2018YFA0801403)
- Natural Science Foundation of Yunnan Province (2015HA023, 2018ZF001)
- Youth Innovation Promotion Association (2017432)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Blood properties and coagulation
- Keywords
- iron deficiency, ischemic stroke, transferrin, estrogen, oral contraceptives, hypercoagulability, thrombin, factor XIIa, antithrombin III, platelet activation, hypoxia, estrogen response element, venous thromboembolism, cerebrospinal fluid
- MeSH terms
- Ischemic Stroke, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Blood Coagulation, Cell Line, Contraceptives, Oral, Hormonal, Disease Models, Animal, Estrogens, Female, Humans, Liver, Male, Mice, Inbred C57BL, Middle Aged, Prospective Studies, Risk Factors, Thrombin, Transferrin, Biomarkers, Up-Regulation, Factor XIIa, Case-Control Studies, Risk Assessment, Anemia, Iron-Deficiency, Thrombophilia, Young Adult
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