Parallel reduction of plasma levels of high and low molecular weight kininogen in patients with cirrhosis

Little is known about the regulation of high-molecular-weight-kininogen (HK ) and low-molecuiar-weight-kininogen (LK) or the relationship of each to th e degree of liver function impairment in patients with cirrhosis. In this s tudy, we evaluated HK and LK quantitatively by a recently described particl e concentration fluorescence immunoassay (PCFIA) and qualitatively by SDS P AGE and immunoblotting analyses in plasma from 33 patients with cirrhosis p resenting various degrees of impairment of liver function. Thirty-three hea lthy subjects served as normal controls. Patients with cirrhosis had signif icantly lower plasma levels of HK (median 49 mu g/ml [range 22-99 mu g/ml]) and LK (58 mu g/ml [15-100 mu g/ml]) than normal subjects (HK 83 mu g/ml [ 65-115 mu g/ml]; LK 80 mu g/ml [45-120 mu g/ml]) (p <0.0001). The plas ma c oncentrations of HK and LK were directly related to plasma levels of cholin esterase (P <0.0001)and albumin (P <0.0001 and P <0.001) and inversely to t he Child-Pugh score (P <0.0001) and to prothrombin time ratio (P <0.0001) ( reflecting the clinical and laboratory abnormalities in liver disease). Sim ilar to normal individuals, in patients with cirrhosis, plasma HK and LK le vels paralleled one another, suggesting that a coordinate regulation of tho se proteins persists in liver disease. SDS PAGE and immunoblotting analyses of kininogens in cirrhotic plasma showed a pattern similar to that observe d in normal controls for LK (a single band at 66 kDa) with some lower molec ular weight forms noted in cirrhotic plasma. A slight increase of cleavage of HK (a major band at 130 kDa and a faint but increased band at 107 kDa) w as evident. The increased cleavage of HK was confirmed by the lower cleaved kininogen index (CKI), as compared to normal controls. These data suggest a defect in hepatic synthesis as well as increased destructive cleavage of both kininogens in plasma from patients with cirrhosis. The decrease of imp ortant regulatory proteins like kininogens may contribute to the imbalance in coagulation and fibrinolytic systems, which frequently occurs in cirrhot ic patients.