title: High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency.
abstract: BACKGROUND
  The inherited deficiency of C1-inhibitor (C1-INH), which can be quantitative (type I) or qualitative (type II), is characterized by recurrent attacks of oedema, and it is known as hereditary angioedema due to C1-INH deficiency (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.
authors.affiliation: Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Ospedale Luigi Sacco, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Suffritti
authors.forename: A
authors.initials: A
authors.lastname: Zanichelli
authors.forename: L
authors.initials: L
authors.lastname: Maggioni
authors.forename: E
authors.initials: E
authors.lastname: Bonanni
authors.forename: M
authors.initials: M
authors.lastname: Cugno
authors.forename: M
authors.initials: M
authors.lastname: Cicardi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D054179:Angioedemas, Hereditary / Q000175:diagnosis* / Q000378:metabolism* / Q000517:prevention & control; D001920:Bradykinin / Q000378:metabolism*; D016022:Case-Control Studies; D018890:Chemoprevention; D002648:Child; D050718:Complement C1 Inhibitor Protein / Q000235:genetics / Q000378:metabolism; D015922:Complement C1q / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059748:Proteolysis; D012720:Severity of Illness Index; D013256:Steroids / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D050718:Complement C1 Inhibitor Protein; D003181:Complement C4; D019679:Kininogen, High-Molecular-Weight; D013256:Steroids; D015922:Complement C1q; D001920:Bradykinin
keywords: C1-inhibitor deficiency; angioedema; biomarkers; disease severity; high-molecular-weight kininogen; kallikrein