Molecular Modeling : Structure-Function-Dynamics relationships  
Aline THOMAS,   
Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia  
Ersayin A., Thomas A., Seyve L., Thielens N., Castellan M., Marlu R., Polack B., Dagher M-C.
Haematologica 2017, 102, e483
New hemophilia treatments aim at releasing the inhibition of tissue factor pathway inhibitor (TFPI) on the extrinsic tenase. Our team has demonstrated that Gladomainless factor Xa (GD-FXa) can restore coagulation in FVIII- or FIX-deficient plasmas and is unable to trigger coagulation per se. In parallel, a catalytically inactive version of GD-FXa, Andexanet alfa, was proposed as antidote to direct oral anticoagulants targeting FXa. Here we show by molecular modeling that GD-FXa and inactive S195A GD-FXa have similar binding properties to TFPI Kunitz 2 domain. The binding parameters between TFPI and inactive S195A GD-FXa, measured using surface plasmon resonance, were similar to those of plasmaderived GD-FXa. As previously found for GD-FXa, inactive GD-FXa was able to restore thrombin generation in FVIII- and FIX-deficient plasmas as well as in plasmas from hemophiliacs. We, therefore, propose to use catalytically inactive GD-FXa in hemophilia.