Plasma prekallikrein (KLKB1) (KLKB1)

Plasma prekallikrein is a 619-amino acid glycoprotein zymogen synthesized in the liver and secreted into the blood, where it circulates as a complex with high-molecular-weight kininogen (HMWK) (UniProt: P03952). It is a key component of the contact activation system (CAS), also known as the intrinsic pathway of coagulation, alongside Factor XII and HMWK (StatPearls: Physiology, Coagulation Pathways). Upon activation by Factor XIIa, prekallikrein is converted into the active serine protease plasma kallikrein, which then cleaves HMWK to release bradykinin, a potent mediator of inflammation and vascular permeability (PMID: 30139471). This pathway is a major therapeutic target for Hereditary Angioedema (HAE), a condition characterized by recurrent episodes of severe swelling due to uncontrolled bradykinin production (PMID: 30139471). Modern pharmacological interventions include monoclonal antibodies like lanadelumab and small molecules like berotralstat that inhibit the active enzyme, as well as antisense oligonucleotides like donidalorsen that reduce the production of the prekallikrein zymogen itself (DrugBank: DB13867; ClinicalTrials.gov: NCT04030598). Beyond HAE, the contact activation system is increasingly studied for its role in thrombosis and diabetic complications without significantly impairing primary hemostasis (PMID: 28637778).

Other names

Fletcher factorPlasma kallikrein B1PKPrekallikreinContact activation system

Inhibition of plasma kallikrein enzymatic activity or reduction of prekallikrein protein synthesis to prevent the cleavage of high-molecular-weight kininogen and subsequent release of bradykinin.