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.