The different proposed models to explain rFVIIa dosing in hemophilia. (A) In the TF-dependent model, high doses of rFVIIa (yellow) compete with endogenous FVII (brown) for binding to their cofactor TF (green) on a phospholipid membrane. The rFVIIa in the TF-rFVIIa complex can then rapidly cleave circulating FX (pink) to its active form (FXa, red), as well as any endogenous FVII complexed with TF (not shown), further enhancing FXa generation. (B) In the TF-independent model, generation of FXa by rFVIIa is essentially by direct FX activation on a phospholipid membrane in the absence of TF. The contribution of the TF-rFVIIa complex is minor (not shown). (C) In the report by Feng et al, the authors generate a chimeric mouse FVIIa molecule that has the Gla and first epidermal growth factor domains from mouse FIX (cyan). As a result, in contrast to wild-type mFVIIa, the chimeric molecule has lost its TF-dependent activity (far right) and can only generate FXa by direct FX activation on a phospholipid membrane. Feng et al report that, when administered in hemophilic mice, both wild-type mFVIIa and the chimeric mFVIIa exhibit similar hemostatic capacity, suggestive of a TF-independent action.