Advanced Search

Submit Manuscript

Volume 30, No 2, Feb 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 2, February 2020: 119-132   |  Open Access

ORIGINAL ARTICLES

Transferrin plays a central role in coagulation balance by interacting with clotting factors

Xiaopeng Tang 1,2, Zhiye Zhang1, Mingqian Fang 1,2, Yajun Han1, Gan Wang1, Sheng Wang3, Min Xue 1,2, Yaxiong Li4, Li Zhang4, Jian Wu4,Biqing Yang5, James Mwangi 1,2, Qiumin Lu1, Xiaoping Du6 and Ren Lai 1,7,8,9,10

1 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, 650223 Kunming, Yunnan, China; 2Kunming College of Life Science, University of Chinese Academy of Sciences, 650204 Kunming, Yunnan, China; 3Key Laboratory of Molecular Biophysics, Huazhong University of Science and Technology, Ministry of Education, College of Life Science and Technology, 430070 Wuhan, Hubei, China; 4Department of Cardiovascular Surgery, Yan’an Affiliated Hospital of Kunming Medical University, 650041 Kunming, Yunnan, China; 5Department of Laboratory, Dehong People’s Hospital, 678400 Dehong, Yunnan, China; 6Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA; 7Institute for Drug Discovery and Development, Chinese Academy of Sciences, 201203 Shanghai, China; 8KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223 Kunming, Yunnan, China; 9Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223 Kunming, Yunnan, China and 10Center for Biosafety Mega-Science, Chinese Academy of Sciences, 430071 Wuhan, Hubei, China
 Correspondence: Ren Lai (rlai@mail.kiz.ac.cn)These authors contributed equally: Xiaopeng Tang, Zhiye Zhang, Mingqian Fang, Yajun Han

Coagulation balance is maintained through fine-tuned interactions among clotting factors, whose physiological concentrations vary substantially. In particular, the concentrations of coagulation proteases (pM to nM) are much lower than their natural inactivator antithrombin (AT, ~ 3 μM), suggesting the existence of other coordinators. In the current study, we found that transferrin (normal plasma concentration ~40 μM) interacts with fibrinogen, thrombin, factor XIIa (FXIIa), and AT with different affinity to maintain coagulation balance. Normally, transferrin is sequestered by binding with fibrinogen (normal plasma concentration ~10 μM) at a molar ratio of 4:1. In atherosclerosis, abnormally up-regulated transferrin interacts with and potentiates thrombin/FXIIa and blocks AT’s inactivation effect on coagulation proteases by binding to AT, thus inducing hypercoagulability. In the mouse model, transferrin overexpression aggravated atherosclerosis, whereas transferrin inhibition via shRNA knockdown or treatment with anti-transferrin antibody or designed peptides interfering with transferrin-thrombin/FXIIa interactions alleviated atherosclerosis. Collectively, these findings identify that transferrin is an important clotting regulator and an adjuster in the maintenance of coagulation balance and modifies the coagulation cascade.


https://doi.org/10.1038/s41422-019-0260-6

FULL TEXT | PDF

Browse 773