High molecular weight kininogen (HMWK) is a 72kDa highly glycosylated protein with an important role in the assembly of the plasma kallikrein-kinin system and in the blood coagulation process. It is encoded by the KNG1 gene, which generates both HMWK and low molecular weight kininogen (LMWK) via alternative splicing. Both HMWK and LMWK share a heavy chain consisting of protein domains 1, 2 and 3 and differ in their light chain. HMWK contains a 56kDa light chain consisting of domain 5 and 6H, whereas LMWK contains a 4kDa light chain consisting of domain 5L. Heavy and light chains of HMWK and LMWK are linked via domain 4 which contains the bradykinin nonapeptide.

HMWK is mainly secreted by the liver and helps position optimally prekallikrein and factor XI next to factor XII. Positioning of prekallikrein in contact with factor XII results in activation and cleavage of factor XII into factor XIIa. This leads to a positive feedback mechanisms of contact activation and cleavage of HMWK with the release of bradykinin. Active bradykinin affects smooth muscle contraction, induces hypotension, natriuresis, diuresis, decreases blood glucose level, mediates inflammation by releasing prostaglandins, increases vascular permeability and stimulates nociceptors. Furthermore, HMWK also inhibits the thrombin- and plasmin-induced aggregation of thrombocytes.

HMWK deficiency is an autosomal recessive coagulation defect known as Fitzgerald trait, Flaujeac trait, Fujiwara trait, Reid trait or Williams’s trait. Patients with low levels of HMWK exhibit abnormal surface-mediated activation of fibrinolysis noted by prolonged partial thromboplastin time (PTT), normal prothrombin time (PT) and normal thrombin time typically found during a preoperative screening workup in asymptomatic individuals. A SNPs in KNG1 gene (rs710446) has been significantly associated with shortened activated partial thromboplastin time (aPTT) increasing the risk of venous thrombosis.