Factor XII is a serine protease encoded by the F12 gene. It is predominantly synthesized in the liver and is secreted as an inactive zymogen, FXII (20-615) (Cool DE et al., 1985; Heinz S & Braspenning J, 2015). Little FXII exists in the kidney; however, renal proximal tubular cells can produce FXII during inflammation (Elwakiel A et al., 2024). Endothelial cells do not constitutively express factor XII antigen (Merkulova AA et al., 2023). Neutrophils can produce and secrete FXII when activated (Stavrou EX et al., 2018). In the blood, FXII circulates in its zymogen or "closed" conformation, which resists activation due to interactions between its fibronectin type 2 (FN2), kringle (KNG), and catalytic domains. Surface binding induces a conformational change to an "open" form, unmasking the catalytic domain and enabling proteolytic auto-activation or plasma kallikrein-mediated cleavage of FXII (Samuel M et al., 1992; de Maat S et al., 2019; Clark CC et al., 2020; Shamanaev A, Ivanov I et al., 2022; Shamanaev A, Ma Y et al., 2025; reviewed by Shamanaev A, Litvak M, Gailani D, 2022). Natural variants affecting FXII structure, such as the FXII W287R variant, may result in abnormal FXII-driven contact activation (Hofman ZLM et al., 2020; Scheffel J et al., 2020).

Artificial surface binding sites have been identified within the non catalytic heavy chain of FXII, particularly in the FN2 domain (Citarella F et al., 2000), first epidermal growth factor like (EGF1) (Shamanaev A, Litvak M, Ivanov I et al., 2023; Shamanaev A, Litvak M, Cheng Q et al., 2023), FN1 and EGF2 domains (Beringer DX & Kroon-Batenburg LMJ 2013), KNG domain (Ravon DM et al.,1995), and the proline rich region (PRR) (Heestermans M et al., 2021). However, the importance of each of these domains? in FXII surface binding and activation require further clarification (Clark CC et al., 2020; Shamanaev A, Litvak M, Cheng Q et al., 2023).

FXII also binds to cell surface receptors in a Zn²?-dependent manner (Mahdi F et al., 2002). Receptors implicated in this process include putative receptor(s) on endothelial cells, such as complement C1q-binding protein (C1QBP, also known as globular C1q receptor or gC1qR), cytokeratin 1 (CK1, encoded by the KRT1 gene), and the urokinase plasminogen activator receptor (uPAR, encoded by the PLAUR gene) (Madhi F et al, 2002; Kaira BG et al. 2020). The cell surface binding sites of FXII have been identified and largely correspond to regions within the FXII heavy chain that mediate binding to artificial, negatively charged surfaces. FXII binds to endothelium in a specific, saturable, and reversible manner. Peptides derived from the FN2 region block FXII binding to endothelial cells (Madhi F et al, 2002). FXII binds gC1qR (C1QBP) at a different region than high-molecular-weight kininogen (HK), allowing formation of a trimolecular complex (Kaira BG et al. 2020). Additional cell surface binding regions (reviewed by Silbak S & Schmaier AH, 2024) include the EGF1 domain (Shamanaev AH et al., 2022) and the proline-rich region (Heestermans M et al., 2021) that are also artificial surface binding sites as well. Of note, two additional peptides on FXII?s kringle region block FXII binding to cells (Elwakiel A et al, 2024). Collectively, these findings suggest that multiple (at least five) regions on FXII participate in cell surface interactions.

Binding of FXII to endothelial cells alone does not result in activation. FXII can remain bound to cultured endothelial cells for up to 2 hours without being activated (Merkulova AA et al. 2023). However, upon exposure to HK and prekallikrein (PK) on endothelial surfaces, FXII is rapidly converted to FXIIa.

Activation of FXII also occurs upon binding of FXII to the cell membrane-associated particles such as polyphosphate chains in activated platelets (Verhoef JJ et al., 2017) and phosphatidylserine in the apoptotic T-lymphoblast cells (Yang A et al., 2017).