Kininogens

Kininogens are a group of plasma proteins that serve as precursors to kinins in the kallikrein–kinin system. The two main forms are high‑molecular‑weight kininogen (HMWK) and low‑molecular‑weight kininogen (LMWK). They are synthesized primarily by the liver and circulate in blood plasma, where they participate in coagulation and inflammatory pathways and interact with components of the contact activation system.

In the activation of the contact pathway, factor XII (Hageman factor) autoactivates to XIIa and then activates prekallikrein to kallikrein. Kallikrein cleaves kininogens to release kinins, notably bradykinin and kallidin (lys‑bradykinin). Bradykinin acts on B2 receptors to promote vasodilation, increased vascular permeability, and pain. HMWK also serves as a cofactor for prekallikrein activation and for forming the contact complex on negatively charged surfaces, while LMWK primarily acts as a substrate for kallikrein.

Genetics and structure: In humans, the KNG1 gene encodes high‑molecular‑weight kininogen. Low‑molecular‑weight kininogen arises by proteolytic processing of HMWK and is also associated with the same gene. HMWK is a roughly 62–64 kDa protein consisting of a heavy chain with coagulation‑related domains and a light chain with kringle domains, linked by a disulfide bond.

Clinical relevance: Alterations in kininogen levels or function can influence bradykinin generation and thereby affect inflammation and coagulation through the contact pathway. Deficiencies of kininogens are rare and may present with a prolonged activated partial thromboplastin time and variable bleeding tendencies. In conditions such as hereditary angioedema, dysregulation of bradykinin production is central, with kininogens providing the substrate for its formation.