Working hypothesis for the mechanism of action of Ixolaris.

Initially, the (second) Kunitz domain of Ixolaris binds to exosite of FXa,45-47 or to an FX putative “pro-exosite” (not shown), leading to the formation of a stable Ixolaris/FXa complex. Then, the scaffold using presumably a similar docking mechanism as the natural substrate, FX (not shown)37 or the product FXa,38 interacts with the exosite formed by FVIIa and TF.39,40 This interaction allows the (first) Kunitz domain of Ixolaris/FXa to dock into the active site of FVIIa/TF, with subsequent assembling of a tightly bound quaternary inhibitory complex composed of FVIIa/TF/Ixolaris/FXa. The scaffold Gla-domain may participate in complex formation mediating Ixolaris/FXa interaction with FVIIa/TF,37-40 and with the membrane.50