Coagulation factor XII Fibronectin type I–Epidermal growth factor-like domain interface (FXII FnI-EGF interface)

The EGF–fibronectin interface refers to a specific structural region within the heavy chain of Coagulation Factor XII (FXII), specifically the junction between the Fibronectin type I (FnI) and the second Epidermal Growth Factor-like (EGF2) domains. This interface is critical for maintaining Factor XII in a 'closed' zymogen conformation in the blood, preventing spontaneous autoactivation. Upon contact with negatively charged surfaces or specific biological triggers, conformational changes at this interface allow Factor XII to transition to an 'open' state, facilitating its conversion into the active protease FXIIa. FXIIa then initiates the intrinsic coagulation cascade and the proinflammatory kallikrein-kinin system, leading to the generation of bradykinin. Therapeutic targeting of Factor XII, particularly with monoclonal antibodies like garadacimab, aims to inhibit these pathways to treat conditions such as hereditary angioedema and prevent pathological thrombosis without increasing bleeding risk.