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

Cell Res. 2020 Feb;30(2):119-132. doi: 10.1038/s41422-019-0260-6.

Xiaopeng Tang ^# ¹ ², Zhiye Zhang ^# ¹, Mingqian Fang ^# ¹ ², Yajun Han ^# ¹, Gan Wang ¹, Sheng Wang ³, Min Xue ¹ ², Yaxiong Li ⁴, Li Zhang ⁴, Jian Wu ⁴, Biqing Yang ⁵, James Mwangi ¹ ², Qiumin Lu ¹, Xiaoping Du ⁶, Ren Lai ⁷ ⁸ ⁹ ¹⁰ ¹¹

Affiliations

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.
2 Kunming College of Life Science, University of Chinese Academy of Sciences, 650204, Kunming, Yunnan, China.
3 Key Laboratory of Molecular Biophysics, Huazhong University of Science and Technology, Ministry of Education, College of Life Science and Technology, 430070, Wuhan, Hubei, China.
4 Department of Cardiovascular Surgery, Yan'an Affiliated Hospital of Kunming Medical University, 650041, Kunming, Yunnan, China.
5 Department of Laboratory, Dehong People's Hospital, 678400, Dehong, Yunnan, China.
6 Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
7 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. [email protected].
8 Institute for Drug Discovery and Development, Chinese Academy of Sciences, 201203, Shanghai, China. [email protected].
9 KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China. [email protected].
10 Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China. [email protected].
11 Center for Biosafety Mega-Science, Chinese Academy of Sciences, 430071, Wuhan, Hubei, China. [email protected].
# Contributed equally.

PMID: 31811276 DOI: 10.1038/s41422-019-0260-6

Abstract

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.

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HY-P3267

Transferrins

≥99.0%, Iron Transportor

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