Proposed mechanism of TF activation by ATG. TF is maintained in a predominantly noncoagulant (cryptic) state by possible mechanisms of tonic inhibition by cholesterol-rich lipid rafts, homo- or hetero-dimerization, association with PDI, and/or sequestration of PS to the inner membrane leaflet (left). We propose that ATG binds to surface-located PDI in close proximity of the cryptic pools of TF and activates complement through the classical pathway. Formation of the initial membrane insertion complex C5b-7 is critical for TF activation and PS exposure (right), but full MAC assembly leading to lytic PS externalization is not required. PDI-dependent thiol-disulfide exchange reactions occur following C5 conversion through engagement of complement regulatory proteins,35 resulting in depletion of membrane reductive equivalents (ie, thioredoxin-1) with consecutive PDI and TF oxidation.38 Rearrangements of the cell membrane by C5b-7 insertion may lead to PS exposure in raft domains and thus facilitate dissociation of TF from regulatory proteins and/or TF oxidation.
