Factor XII (F12) is a serum glycoprotein that initiates blood coagulation through a multi-step cascade. The protein functions as a zymogen that undergoes activation by plasma kallikrein to form alpha-factor XIIa, which subsequently activates factor XI in the intrinsic coagulation pathway 123. Beyond hemostasis, F12 participates in fibrinolysis, bradykinin generation, and innate immunity 4. Recent evidence demonstrates that F12-driven coagulation enhances host defense by promoting fibrin deposition that traps bacteria and restricts infection; F12-deficient mice showed increased susceptibility to Streptococcus pneumoniae and Staphylococcus aureus infections with impaired bacterial containment 4. F12 deficiency presents clinically in two forms: complete deficiency causing prolonged activated partial thromboplastin time, and mutations in F12 associated with hereditary angioedema type III (HAE), characterized by recurrent angioedema unresponsive to antihistamines 567. F12 mutations account for approximately 25% of hereditary angioedema cases with normal C1 inhibitor 7. Pathogenic variants include missense mutations, deletions, insertions, and nonsense variants affecting protein structure and serine protease activity 89. Clinically, heterozygous F12 loss-of-function variants confer protection against venous thromboembolism without increasing bleeding risk, supporting F12 as a viable therapeutic anticoagulation target 10.