High-molecular-weight kininogen (HMWK) (HMWK)

High-molecular-weight kininogen (HMWK) is a multifunctional plasma glycoprotein synthesized primarily by hepatocytes, circulating at ~70-120 kDa due to extensive glycosylation, and encoded by the KNG1 gene on chromosome 3q26. It serves as a non-enzymatic cofactor in the contact activation (intrinsic) pathway of coagulation, facilitating the binding and activation of prekallikrein, factor XII, and factor XI on negatively charged surfaces to promote thrombin generation. HMWK is also the precursor for bradykinin, a potent vasodilator released by kallikrein cleavage within its domain 4, which increases vascular permeability and contributes to inflammation. The protein features six domains: domains 1-3 (heavy chain) bind calcium and inhibit cysteine proteases like calpain and papain; domain 4 generates bradykinin; and domains 5-6 (light chain) enable heparin/cell binding, antiangiogenic effects, and interactions critical for coagulation. In disease, HMWK plays a key role in endotoxemia by binding lipopolysaccharide (LPS) via domain 5, maintaining circulating LPS levels, disaggregating it, and amplifying cytokine production (TNF, IL-1β, IL-6), leading to organ damage and mortality—HK-deficient models are protected. Cleavage to the two-chain HKa form exposes binding sites, enhancing these proinflammatory effects, while therapeutic blockade of domain 5 reduces LPS persistence and inflammation. Dysregulated bradykinin generation links HMWK to hereditary angioedema. No approved drugs directly target HMWK, but preclinical strategies like anti-domain 5 antibodies highlight its potential in sepsis.

Other names

HKkininogenhigh molecular weight kininogenalpha 2-thiol proteinase inhibitor

Blockade of HMWK-LPS binding (reduces circulating LPS levels and inflammation); Inhibition of domain 5 (anti-D5 mAb reduces LPS-induced mortality); Cleavage to HKa form enhances LPS disaggregation and cytokine amplification