The contact activation system (CAS) is a plasma serine protease cascade, which involves surface-induced interactions among factor XII (FXII or Hageman factor), prekallikrein (PK), and kininogen (high molecular weight kininogen, HMWK) in response to various stimuli such as tissue injury, toxic compounds, or microbial infection. Activated components of CAS coordinate inflammatory signaling pathways, complement activation, coagulation and fibrinolysis (reviewed by Renne T et al., 2012; Maas C & Renne T., 2018; Schmaier AH 2016; Long AT et al., 2016; Shamanaev A, Litvak M et al., 2023; Motta G et al., 2023).
Abnormal activation of FXII is implicated in the pathogenesis of various diseases including hereditary angioedema (HAE) and Alzheimer’s disease (AD), though the mechanisms and consequences differ.
In HAE, uncontrolled activation of FXII-dependent kallikrein-kinin system (KKS) and excessive release of bradykinin from HMWK is usually associated with defective function of SERPING1 (C1-INH), a major regulator of the contact system (Suffritti C et al. 2014). More rarely, HAE occurs in individuals with normal SERPING1 activity, and has been linked to mutations in other proteins, including FXII (Cichon S et al. 2006; Magerl M et al. 2017; Zuraw BL & Christiansen SC 2016; Ivanov I et al. 2019). The proinflammatory byradykinin causes vasodilation and increased vascular permeability at the level of the post capillary venule, resulting in angioedema (Bossi F et al. 2009; Kaplan AP 2010; Suffritti C et al. 2014).
In AD patients, aggregated amyloid beta (Aβ) peptides provide a negatively charged surface that facilitates the binding and activation of factor XII (FXII) (Joseph K et al., 1999; Bergamaschini L et al., 2001; Zamolodchikov D et al., 2015). Enhanced FXII activation and downstream effects on the kallikrein-kinin system contribute to vascular dysfunction, prothrombotic state, neuroinflammation, and cognitive decline associated with AD pathology (Zamolodchikov D et al., 2015, 2016; Chen ZL et al., 2023; reviewed by Kaplan AP et al., 2024). Both PK and FXIIa are recognized as upstream triggers of the coagulation system. However, the clinical significance of these factors in thrombosis and hemorrhage is not fully understood. Blockade of the contact activation system (CAS) results in prolonged coagulation times in the activated partial thromboplastin time (aPTT) assay. Nevertheless, the absence of thrombotic or hemostatic abnormalities in individuals with genetic deficiencies of PK or FXII suggests that the CAS plays a minimal role in physiological coagulation (Müller F et al., 2011). However, it may contribute to thrombus formation under pathological conditions (Zamolodchikov D et al., 2016).
Genetic variants are named following Human Genome Variation Society (HGVS) nomenclature with sequence numbering starting from the first methionine of the protein as +1 (Goodeve AC et al.2011).
