Tissue factor: mechanisms of decryption

L. Vijaya Mohan Rao¹, Hema Kothari¹, Usha R. Pendurthi¹

1Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Tissue factor expression on cell surfaces: Evidence for cryptic tissue factor

4. Cryptic tissue factor - the definition matters

5. Differences in cryptic and procoagulant TF in their abilities to bind FVIIa and TFPI

6. Models of tissue factor encryption/decryption

6.1. Phospholipid asymmetry: Exposure of phosphatidylserine

6.2. Tissue factor self-association: Dimers vs. monomers

6.3. Protein disulfide isomerase: Disulfide bond switching

6.4. Protein disulfide isomerase: Regulation of TF activity by modulation of lipid environment

6.5. Protein disulfide isomerase: Regulation of TF activity by chaperone function

6.6. Caveolae, lipid rafts and cholesterol: Modulation of tissue factor procoagulant activity

7. Cryptic TF and TF-FVIIa signaling

8. TF encryption and FVII activation

9. Conclusions

10. Acknowledgements

11. References

1. ABSTRACT

It is generally believed that only a small fraction of the tissue factor (TF) found on cell surfaces is active whereas the vast majority is cryptic in coagulation. It is unclear how cryptic TF differs from the coagulant active TF or potential mechanisms involved in transformation of cryptic TF to the coagulant active form. Exposure of phosphatidylserine (PS) in response to various chemical or pathophysiological stimuli has been considered as the most potent inducer of TF decryption. In addition to PS, TF self-association and association with specialized membrane domains may also play a role in TF decryption. It has been suggested recently that protein disulfide isomerase regulates TF decryption through its oxidoreductase activity by targeting Cys186-Cys209 disulfide bond in TF extracellular domain or regulating the PS equilibrium at the plasma membrane. However, this hypothesis requires further validation to become an accepted mechanism. In this article, we critically review literature on TF encryption/decryption with specific emphasis on recently published data and provide our perspective on this subject.