Tissue factor (TF) is a cellular receptor for clotting factor VII/VIIa (FVII/FVIIa). Formation of TF-FVIIa complexes on cell surfaces not only triggers the coagulation cascade but also transduces cell signaling via activation of protease-activated receptors. It is generally believed that only a small fraction of the TF found on cell surfaces is active in coagulation whereas the vast majority is cryptic (non-functional) 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. Both cryptic and coagulant active TF forms can bind FVIIa. It is generally believed that cryptic TF-FVIIa complexes fail to activate factor X as the protein substrate binding site is buried in the encrypted complex and a change in TF-FVIIa complex that exposes the substrate binding site leads to its decryption. 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. Recent studies suggest that cryptic form of TF contains unpaired cysteine thiols at Cys186 and Cys209 in the membrane-proximal domain, whereas the coagulant active form of TF is thought to have an oxidized Cys186-Cys209 disulfide bond. It has been suggested that protein disulfide isomerase (PDI) regulates TF decryption through its oxidoreductase activity by targeting this disulfide bond 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.

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