Gene therapy-based prophylaxis to rescue the “prima ballerina”

The activation of factor VII (FVII) represents a key step for the initiation of blood coagulation, amplified by the activation of several serine proteases in the cascade (1). The physiological activity of activated FVII (FVIIa), and thus blood clotting, is triggered when plasma comes into contact with wound-exposed tissue factor (TF) thus forming the TF-FVIIa complex (2), which requires phospholipid membranes because TF is an integral membrane glycoprotein and FVIIa binds to membrane surfaces via its vitamin K-dependent domain (3,4). The TF-FVIIa pathway, defined as the “prima ballerina” of the whole coagulation process (5), includes the activation of factor IX (FIX) and factor X (FX) by limited proteolysis, ultimately leading to fibrin deposition and clot formation. Alterations of the TF-FVIIa pathway, increasing or decreasing its function, play multiple roles in human diseases (Figure 1).