Coagulation factor XIa (FXIa) and coagulation factor XIIa (FXIIa) (FXIa and FXIIa)

Coagulation factors XIa (FXIa) and XIIa (FXIIa) are serine proteases that play central roles in the intrinsic or contact activation pathway of the coagulation cascade (Gailani & Renné, 2007; PubMed: 17650147). FXIa is generated from its zymogen FXI by FXIIa or thrombin and serves to amplify thrombin generation by activating factor IX (UniProt P03951). FXIIa is the activated form of factor XII, which initiates the cascade upon contact with artificial or biological polyanionic surfaces and also links coagulation to the inflammatory kallikrein-kinin system (UniProt P00748). These factors have emerged as high-interest therapeutic targets because clinical and preclinical data suggest that their inhibition can prevent thrombosis with a significantly lower risk of bleeding compared to conventional anticoagulants (Al-Horani & Afosah, 2018; PubMed: 30103531). This 'uncoupling' of thrombosis from hemostasis makes FXIa and FXIIa inhibitors, such as milvexian and garadacimab, attractive candidates for treating conditions like venous thromboembolism and stroke prevention in atrial fibrillation (Hsu et al., 2021; PubMed: 34462457). Furthermore, FXIIa inhibition is specifically relevant in preventing contact-induced thrombosis on medical devices and managing hereditary angioedema (Fredenburgh et al., 2017; PubMed: 28838935). Overall, these targets represent a paradigm shift in anticoagulation therapy by focusing on the intrinsic pathway to improve the safety profile of antithrombotic drugs.

Other names

Plasma thromboplastin antecedent (FXI)Hageman factor (FXII)Contact activation factorsIntrinsic pathway factors

Inhibition of the intrinsic pathway of coagulation to prevent pathological thrombus formation while preserving the extrinsic pathway for physiological hemostasis.