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.
Highlights
Atherosclerosis (AS) is recognized as a chronic inflammatory disease in which plaque accumulates along arteries, leading to serious cardiovascular problems, including heart attack and ischemic stroke.[1,2] Recent studies have suggested a procoagulant state in early AS and an association of AS with venous thrombosis,[3,4] but the underlying mechanisms remain elusive
Factor XII is a coagulation protein that is essential for surface-activated blood coagulation and its deficiency confers susceptibility to thrombosis according to previous report.[12]
Enhanced enzymatic activity of thrombin and factor XIIa (FXIIa) is associated with elevated transferrin in AS To investigate the mechanism responsible for AS-associated hypercoagulability, the enzymatic activities of several coagulation factors, including FVIIa, FXIa, FXIIa, kallikrein, and thrombin, were compared between plasma from healthy volunteers and atherosclerotic patients who have coronary heart disease (CHD) and display angiographically visible luminal narrowing (Supplementary information, Table S1)
Summary
Atherosclerosis (AS) is recognized as a chronic inflammatory disease in which plaque accumulates along arteries, leading to serious cardiovascular problems, including heart attack and ischemic stroke.[1,2] Recent studies have suggested a procoagulant state in early AS and an association of AS with venous thrombosis,[3,4] but the underlying mechanisms remain elusive. Nineteen clotting factors have been identified to participate in the coagulation cascade and to maintain thrombohemorrhagic balance.[13,14,15,16] They include the fibrinogen family (fibrinogen (factor I), factor V, factor VIII, and factor XIII),[17] vitamin K-dependent family ((factor II, thrombin), factor VII, factor IX and factor X),[18,19] contact family (factor XI, factor XII, high molecular weight kininogen (HMWK), and prekallikrein (PK)),[20,21] tissue factor (factor III), calcium, Von Willebrand factor (vWf), antithrombin (AT), heparin cofactor-II, protein C, and protein S.13,20,22–24 They resemble a coagulation cascade comprised of the intrinsic and the extrinsic pathways, which involve the conversion of each proenzyme into active enzyme by upstream activated clotting factors,[25] which converge in factor X activation, leading to fibrin activation.[22,26,27] Nineteen clotting factors have been identified to participate in the coagulation cascade and to maintain thrombohemorrhagic balance.[13,14,15,16] They include the fibrinogen family (fibrinogen (factor I), factor V, factor VIII, and factor XIII),[17] vitamin K-dependent family ((factor II, thrombin), factor VII, factor IX and factor X),[18,19] contact family (factor XI, factor XII, high molecular weight kininogen (HMWK), and prekallikrein (PK)),[20,21] tissue factor (factor III), calcium, Von Willebrand factor (vWf), antithrombin (AT), heparin cofactor-II, protein C, and protein S.13,20,22–24 They resemble a coagulation cascade comprised of the intrinsic and the extrinsic pathways, which involve the conversion of each proenzyme into active enzyme by upstream activated clotting factors,[25] which converge in factor X activation, leading to fibrin activation.[22,26,27]
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