KLKB1 encodes plasma prekallikrein, a serine protease that plays a central role in the contact activation system of blood coagulation. The protein participates in surface-dependent activation of coagulation, forming a reciprocal activation loop with coagulation factor XII (F12) when binding to negatively charged surfaces 1. KLKB1 releases bradykinin from high molecular weight kininogen, making it a key regulator of the kallikrein-kinin system that controls vascular permeability and inflammation 2. The gene arose through duplication of the ancestral coagulation factor XI gene, establishing its unique evolutionary relationship within the coagulation cascade 1. Clinically, KLKB1 deficiency causes prekallikrein deficiency, while its overactivity contributes to hereditary angioedema pathogenesis through excessive bradykinin production 23. KLKB1 has emerged as a promising therapeutic target, with CRISPR-based gene editing therapies (NTLA-2002) showing 75-77% reduction in angioedema attacks by knocking out KLKB1 in hepatocytes 2. The protein also shows associations with cardiovascular disease risk through its role in HDL-mediated cholesterol efflux capacity 4 and has been identified as a potential drug target in stroke genetics studies 5.