Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways

Abstract

An asymptomatic woman (Ms. Williams) was found to have a severe abnormality in the surface-activated intrinsic coagulation, fibrinolytic, and kinin-generating pathways. Assays for known coagulation factors were nromal while Fletcher factor (pre-kallikrein) was 45%, insufficient to account for the observed markedly prolonged partial thromboplastin time. Plasminogen proactivator was present at 20% of normal levels and addition of highly purified plasminogen proactivator containing 10% plasminogen activator partially corrected the coagulation and fibrinolytic abnormalities but not the kinin-generating defect. This effect was due to its plasminogen activator content. In addition, Williams trait plasma failed to convert prekallilrein to lakkilrein or release kinin upon incubation with kaolin. Kininogen antigen was undetectable. When normal plasma was fractionated to identify the factor that corrects all the abnormalities in Williams trait plasma, the Williams factor was identified as a form of kininogen by its behavior on ion exchange chromatography, gel filtration, disc gel electrophoresis, and elution from an anti-low molecular weight kininogen immunoadsorbent. High molecular weight kininogen as well as a subfraction of low molecular weight kininogen, possessed this corrective activity while the bulk of low molecular weight kininogen functioned only as a kallikrein substrate. Kininogen therefore is a critical factor required for the functioning of Hageman factor-dependent coagulation and fibrinolysis and for the activation of prekallikrein.