Transferrin plays a central role in coagulation balance by interacting with clotting factors
Authors: Jian Wu
Min Xue
Sheng Wang
Li Zhang
Yaxiong Li
Mingqian Fang
James Mwangi
Xiaopeng Tang
Qiumin Lu
Zhiye Zhang
Ren Lai
Xiaoping Du
Biqing Yang
Yajun Han
Gan Wang
Journal: Cell Research (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Coagulation balance; Transferrin; Fibrinogen; Thrombin; Factor XIIa
Affiliations: 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., Kunming College of Life Science, University of Chinese Academy of Sciences, 650204, Kunming, Yunnan, China., Key Laboratory of Molecular Biophysics, Huazhong University of Science and Technology, Ministry of Education, College of Life Science and Technology, 430070, Wuhan, Hubei, China., Department of Cardiovascular Surgery, Yan'an Affiliated Hospital of Kunming Medical University, 650041, Kunming, Yunnan, China., Department of Laboratory, Dehong People's Hospital, 678400, Dehong, Yunnan, China., Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA., 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. ., Institute for Drug Discovery and Development, Chinese Academy of Sciences, 201203, Shanghai, China. ., KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China. ., Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China. ., Center for Biosafety Mega-Science, Chinese Academy of Sciences, 430071, Wuhan, Hubei, China. .

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. 

Retracted: No

PubPeer comments:
 Figure 6B. The TH16-0.2 and FX 18-5 panels look more similar to each other than expected, in both time points. Although the blood perfusion in the artery is quite different in both treatments, especially in the 10 min time point, the background of all four panels is unexpectedly similar. Could the authors please clarify? ![file] Here is an enlargement. Image made a bit lighter to bring out details. ![file] (concern brought to my attention through another reader). , 
 #1 In this experiment, carotid arteries were exposed by cervical incision, and separated from the adherent tissue and vagus nerve. A PVDF membrane was under the carotid arteries to continuously monitor blood flow by laser speckle perfusion imaging, such as 5-10 min. The PVDF membrane will be replaced if it is soaked and dirty, but the membrane is not replaced if it is clean. As shown in Figure 6B, we did not replace the background PVDF membrane and use the same PVDF membrane for both TH16-0.2 and FX18-5 groups, and thus the background looks similar. In fact, you can find that the backgrounds are some different between TH16-0.2 and FX18-5 groups because the same PVDF membrane was soaked and used for different time. The soaked and used time was longer in FX18-5 than that in TH16-0.2. **Finally, we have to emphasize that all the backgrounds are from PVDF membranes, not any tissues or organs. ** ,