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

Abstract

Coagulation balance is maintained through fine-tuning interactions among clotting factors. Physiological concentrations of clotting factors are huge difference. Especially, coagulation proteases concentration (pM to nM) is much lower than their natural inactivator antithrombin III (AT-III, [~]3 M). Here we show that transferrin (normal plasma concentration [~]40 M) interacts with fibrinogen, thrombin, FXIIa and AT-III with different affinity to maintain coagulation balance. Normally, transferrin is sequestered by binding with fibrinogen (normal plasma concentration [~]10 M) with a molar ratio of 4:1. In atherosclerosis, abnormally up-regulated transferrin interacts with and potentiates thrombin/FXIIa and blocks AT-IIIs inactivation on coagulation proteases by binding to AT-III, and thus induces hypercoagulability. In mouse models, transferrin-overexpression aggravated atherosclerosis while transferrin-knockdown, anti-transferrin antibody or designed peptides interfering transferrin-thrombin/FXIIa interactions alleviated it. Collectively, these findings identify transferrin as a clotting factor and an adjuster for maintaining coagulation balance and modify the coagulation cascade.