Protein S Stimulates Inhibition of the Tissue Factor Pathway by Tissue Factor Pathway Inhibitor

Tissue factor (TF) plays an important role in hemostasis, inflammation, angiogenesis, and the pathophysiology of atherosclerosis and cancer. In this article we uncover a mechanism in which protein S, which is well known as the cofactor of activated protein C, specifically inhibits TF activity by pro...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (9), p.3106-3111
Main Authors: Hackeng, Tilman M., Seré, Kristin M., Tans, Guido, Rosing, Jan
Format: Article
Language:English
Subjects:
Antibodies
Anticoagulants
Biochemistry
Biological Sciences
Biology
Blood
Blood plasma
Coagulation
Factor VIIa - antagonists & inhibitors
Factor VIIa - metabolism
Factor Xa - metabolism
Factor Xa Inhibitors
Humans
Inhibitor drugs
Kinetics
Lipoproteins - genetics
Lipoproteins - metabolism
Phospholipids
Physiological regulation
Plasma interactions
Protein S - pharmacology
Proteins
Signal transduction
Signal Transduction - drug effects
Thrombin - biosynthesis
Thromboplastin - antagonists & inhibitors
Thromboplastin - metabolism
Tissues
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Summary:Tissue factor (TF) plays an important role in hemostasis, inflammation, angiogenesis, and the pathophysiology of atherosclerosis and cancer. In this article we uncover a mechanism in which protein S, which is well known as the cofactor of activated protein C, specifically inhibits TF activity by promoting the interaction between full-length TF pathway inhibitor (TFPI) and factor Xa (FXa). The stimulatory effect of protein S on FXa inhibition by TFPI is caused by a 10-fold reduction of the Ki of the FXa/TFPI complex, which decreased from 4.4 nM in the absence of protein S to 0.5 nM in the presence of protein S. This decrease in Ki not only results in an acceleration of the feedback inhibition of the TF-mediated coagulation pathway, but it also brings the TFPI concentration necessary for effective FXa inhibition well within range of the concentration of TFPI in plasma. This mechanism changes the concept of regulation of TF-induced thrombin formation in plasma and demonstrates that protein S and TFPI act in concert in the inhibition of TF activity. Our data suggest that protein S deficiency not only increases the risk of thrombosis by impairing the protein C system but also by reducing the ability of TFPI to down-regulate the extrinsic coagulation pathway.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0504240103