title: Thiol pathways in the regulation of tissue factor prothrombotic activity.
abstract: OBJECTIVE
  The transmembrane protein tissue factor (TF), the initiator of the extrinsic coagulation cascade and a risk factor for thrombotic disease, largely resides on the cell surface in an inactive, encrypted conformation. Whereas TF procoagulant activation, or decryption, is closely associated with the exposure of procoagulant phosphatidylserine in the outer leaflet of cell membranes, thiol pathways and protein disulfide isomerase (PDI) play increasingly recognized roles in regulating TF prothrombotic pathways.
  
  
  RESULTS
  TF contains a solvent-exposed allosteric disulfide bond that stabilizes the carboxyl-terminal domain involved in ligand interactions with coagulation factors VIIa and X. PDI is a prime candidate to modify the allosteric disulfide by reduction, S-nitrosylation and glutathionation, implicated as regulators of TF procoagulant activity. In-vivo studies localize PDI to sites of thrombus formation and inhibition of PDI attenuates arterial thrombosis. PDI also contributes to the biogenesis of procoagulant microparticles that are released in the context of TF decryption following ATP-mediated activation of the purinergic P2X7 receptor. Genetic deletion of P2X7 signaling attenuates TF and PDI-dependent thrombosis, identifying a new connection between prothrombotic and proinflammatory pathways.
  
  
  CONCLUSIONS
  Although the precise biochemical events of TF encryption and decryption require further study, PDI and thiol pathways emerge as important regulators of vascular thrombotic diseases.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Research, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D015942:Factor VIIa / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D018740:Genetic Heterogeneity; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D015398:Signal Transduction; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D013925:Thromboplastin; D015942:Factor VIIa; D015951:Factor Xa; D019704:Protein Disulfide-Isomerases