Plasma FXI, encoded by the F11 gene, circulates as an inactive homodimeric zymogen, with its subunits stabilized by disulfide bonds (Wu W et al., 2008; Mohammed BM et al., 2018). Unlike other vitamin K-dependent clotting factors, FXI lacks the gamma-carboxyglutamic acid (Gla) domain, a calcium-binding domain essential for a binding to phospholipid membranes. Instead, FXI associates with cell surfaces through receptor-mediated interactions. On the cell surface, FXI is converted to activated factor XI (FXIa) through proteolytic cleavage at Arg387-Ile388 within its protease domain. In the body, this reaction occurs primarily on the surfaces of activated platelets via interactions between FXI and platelet receptors, including glycoprotein Ib (GPIb:IX:V) complex, glycoprotein IV (CD36), and apolipoprotein E receptor 2 (ApoER2) (Greengard JS et al. 1986; Baird TR and Walsh PN 2002; 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 shield FXIa from inactivation by platelet-derived inhibitors (Reitsma SE et al., 2021). Studies showed that while FXI and FXIa can interact with endothelial cell (EC) surface via high molecular weight kininogen (HMWK) or directly in its absence, these interactions do not significantly contribute to thrombin generation (Shariat-Madar Z et al., 2001; Mahdi F et al., 2003; Puy C et al., 2024, reviewed by Pathak M et al., 2018; Lira AL et al., 2024). Additionally, FXI can also 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).