FXI, when bound to the cell surface, is converted to activated factor XI (FXIa) through a proteolytic cleavage at Arg387-Ile388 within its protease domain. In the body, this reaction occurs on the surfaces of activated platelets via interactions of FXI with platelet receptors such as GPIb (GPIb:V:IX), glycoprotein IV (CD36), and apolipoprotein E receptor 2 (ApoER2) (Baglia FA et al., 2004a, b; White-Adams TC et al., 2009; Emsley J et al., 2010; Kossmann S et al., 2017; Mohammed BM et al., 2018; Reitsma SE et al., 2021). Binding to the platelet surface appears to protect FXIa from platelet-derived inhibitors (Reitsma SE et al., 2021). Alternatively, FXI can be activated upon binding to negatively charged surfaces, such as polyphosphate secreted from the dense granules of activated platelets (Choi SH et al., 2011; Geng Y et al., 2013). Activation of FXI can be catalyzed by factor XIIa, initiating fibrin clot formation. However, the efficient activation of larger quantities of FXI, needed to propagate the blood clotting process, appears to be mediated by thrombin (FIIa) (Gailani D and Broze GJ 1993; Naito K and Fujikawa K 1991; von dem Borne PA et al., 1995; Oliver JA et al. 1999; Monroe DM et al. 2002; Kravtsov DV et al., 2009; Matafonov A et al., 2011). Additionally, FXIa can be generated via autoactivation (Wu W et al., 2008).

Cleavage of FXI induces a conformational change that exposes the factor IX interaction site in the A3 domain of FXIa, enabling it to activate FIX (Gailani D et al., 2014; reviewed by Lira AL et al., 2024). Once activated, FXIa converts factor IX to FIXa, which subsequently activates FX, amplifying thrombin generation in a positive feedback loop.