High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin mediated angioedema due to hereditary c1-inhibitor deficiency

BACKGROUND: The inherited deficiency of C1-inhibitor (C1-INH), which can be quantitative (type I) or qualitative (type II), is characterised by recurrent attacks of edema and it is known as hereditary angioedema due to C1-INH deficincy (HAE-C1-INH). The frequency of symptoms varies widely among patients and in the same patient during life. OBJECTIVE: To identify laboratory markers of disease severity in HAE-C1-INH patients. METHODS: We studied 162 patients with differently severe HAE-C1-INH during remission, 31 HAE-C1-INH patients during attacks and 81 normal controls, evaluating complement parameters, spontaneous plasma kallikrein activity, the capacity of plasma to inhibit exogenous kallikrein activity and cleavage of high-molecular-weight kininogen (HK). Sixty-five HAE-C1-INH patients were screened for mutations in the C1-INH gene. RESULTS: As expected, plasma C1-INH levels and activity and C4 levels were low in the HAE-C1-INH patients. Spontaneous plasma kallikrein activity in patients in remission was higher than in controls (P=0.001), and increased during acute attacks (P=0.01), whereas the capacity of inhibiting kallikrein activity was lower in patients in remission than in controls (P=0.001) and further reduced during attacks (P=0.001). HAE-C1-INH patients in remission had higher levels of cleaved HK than controls (P=0.001), and these further increased during acute attacks (P=0.001). Cleaved HK levels were higher in highly symptomatic HAE-C1-INH patients than in those with less frequent attacks (P=0.001). Thirty-five different mutations in the C1-INH gene were equally distributed in patients with different attack frequencies. CONCLUSIONS: Measuring plasma levels of cleaved HK may be a sensitive mean of assessing disease severity in HAE-C1-INH patients.