Prekallikrein Activation and High-Molecular-Weight Kininogen Consumption in Hereditary Angioedema

Patients with hereditary angioedema lack C1̄ inhibitor, a plasma α 2 -glycoprotein that inhibits both the proteolytic action of C1̄, the activated first component of the complement system, and the activity of components of the contact phase of coagulation: kallikrein, factor XI a , and factor XII a . Such patients have been shown to have low levels of C4 and C2, the natural substrates for C1̄, but the levels were not correlated with the presence of symptoms. We studied three patients with angioedema for evidence of activation of the contact system and found that during a symptomatic period they had decreased levels of prekallikrein, a substrate for the activated forms of factor XII, and reductions in high-molecular-weight kininogen, a substrate for plasma kalli-krein. These observations suggest that zymogens of the contact system are activated during attacks of hereditary angioedema and that some of the clinical manifestations may be mediated through products of this pathway, such as kinins. (N Engl J Med 1983; 308:1050–4.) Hereditary angioedema is characterized by recurrent attacks of mucocutaneous swellings and abdominal pain. 1 , 2 Death may result from airway obstruction. 1 , 2 A biochemical abnormality was recognized in hereditary angioedema when patients with this condition were shown to lack an inhibitor for plasma kallikrein. 3 The missing inhibitor was subsequently identified as C1̄ inhibitor, a plasma α 2 -glycoprotein that inhibits the proteolytic and esterolytic activities of C1̄, the activated first component of the complement system. 4 Additional studies 5 6 7 revealed that C1̄ inhibitor was an inhibitor not only for the C1̄r and C1̄s subunits of C1̄ and plasma kallikrein and plasmin, but also for coagulation . . .