Brief Report THROMBOSIS AND HEMOSTASIS In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia

• The negative impact on thrombin generation of zymogen FVII competing with rFVIIa for TF is counteracted by FVII (auto)activation. • Correction of hemophilia A occurs in a rFVIIa concentration range where detectable effects of FVII competition are minimal or absent. Successful competition of activated factor VII (FVIIa) with zymogen factor VII (FVII) for tissue factor (TF) and loadingof the platelet surfacewithFVIIa areplausibledriving forces behind the pharmacological effect of recombinant FVIIa (rFVIIa) in hemophilia patients. Thrombin generation measurements in platelet-rich hemophilia A plasma revealed competition for TF, which potentially could reduce the effective (r)FVIIa:TF complex concentration and thereby attenuate factor Xa production. However, (auto)activation of FVII apparently counteracted the negative effect of zymogen binding; a small impact was observed at endogenous concentrations of FVII and FVIIa but was virtually absent at pharmacological amounts of rFVIIa. Moreover, corrections of the propagation phase in hemophilia A required rFVIIa concentrations above the rangewhere a physiological level of FVII was capable to downregulate thrombin generation. These data strongly suggest that rFVIIa acts independently of TF in hemophilia therapy and that FVII displacement by rFVIIa is a negligible mechanistic component. (Blood. 2014;124(20):3172-3174)