Activated factor FXII (FXIIa) promotes fibrin clot formation by converting FXI to FXIa (Cheng Q et al., 2010), while plasma kallikrein directly binds and activates FIX (Kearney KJ et al., 2021), thereby facilitating crosstalk between coagulation and inflammation. Despite this, both FXII and plasma kallikrein are non-essential for normal hemostatic pathway, as individuals deficient in FXII or prekallikrein do not exhibit bleeding disorders (Kokoye Y et al., 2016). At the same time, studies using animal disease models suggest that these factors may contribute to thrombotic events under pathological conditions (Revenko AS et al., 2011; Matafonov A et al., 2014; reviewed by Schmaier A, 2016). Deficiencies of FXII, prekallikrein (PK), high molecular weight kininogen (HK), and the bradykinin B2 receptor are associated with prolonged thrombin generation times in murine models of arterial and venous thrombosis (Pauer HU et al., 2004, Stavrou EV et al., 2015, Merkulov S et al., 2008, Shariat-Madar Z et al., 2006; Fang C et al., 2013). Alternatively, FXI null mice exhibit a bleeding phenotype, whereas prolylcarboxypeptidase- and C1 inhibitor-deficient mice display a prothrombotic phenotype (Gailani D et al., Adams GA et al., 2011; Grover S et al., 2023). Large population studies indicate that FXII deficiency protects against venous thrombosis, whereas C1 inhibitor deficiency is associated with increased thrombotic risk (Haj AK et al., 2025; Rodriguez Espada A et al., 2026).