Tissue factor pathway inhibitor beta (TFPIβ), an alternatively spliced form of TFPI, is expressed on the surface of endothelial cells (Girard TJ et al., 2012). TFPIβ comprises an N-terminal acidic region, two Kunitz-type protease inhibitory domains (K1 and K2), and a basic C-terminus. A glycosylphosphatidylinositol (GPI) anchor at the C-terminus attaches TFPIβ to the outer leaflet of the cell membrane (Zhang J et al., 2003; Piro O & Broze GJ Jr., 2005). During the initiation phase of coagulation, TFPIβ limits the activity of factor VIIa (FVIIa) and factor Xa (FXa) within the heterotetrameric TFPIβ:FXa:TF:FVIIa complex at the endothelial surface (reviewed by Broze GJ, Jr & Girard TJ 2012; Maroney SA et al., 2013; Wood JP et al., 2014; Mast AE & Ruf W 2022; Ahnström J et al., 2024). In this complex, the K2 domain of TFPIβ initially binds and inhibits FXa through the formation of an encounter complex, which is subsequently stabilized via structural isomerization. Next, the K1 domain of TFPIβ binds to FVIIa inhibiting activity of the TF:FVIIa complex. Inhibition of TF:FVIIa requires the prior formation of the TFPI:FXa complex (Baugh RJ et al., 1998; Peraramelli S et al., 2013, 2014; reviewed by Broze GJ, Jr & Girard TJ 2012; Ahnström J et al., 2024).
Anti-TFPI drugs, concizumab and marstacimab, target the K2 domain of TFPI, preventing its interaction with FXa, thereby restoring thrombin generation (Hilden I et al., 2012; reviewed by Petersen LC 2012).
