Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma

Background: Factor XII-dependent bradykinin formation is thought to be responsible for the swelling associated with the various forms of Cl inhibitor deficiency, and complement activation is augmented during attacks of swelling. Objectives: To further elucidate the interactions of the kinin-forming cascade that lead to complement activation during attacks of swelling and to determine whether fibrinolysis is augmented as well. Methods: We compared spontaneous and kaolin-induced activation of normal plasma with the plasma of patients with hereditary angioedema. Results: Hereditary angioedema plasma demonstrated augmented factor XII activation, production of factor XIIf, prekallikrein activation, and high-molecular-weight kininogen cleavage, and, as a result, bradykinin formation was markedly increased. Baseline levels of C4a and plasmin-alpha(2) antiplasmin complexes increased, and, on activation with kaolin, levels increased further. Conclusions: All parameters indicative of activation of the bradykinin-forming cascade are activated in hereditary angioedema plasma vs normal plasma. Production of factor XIIf. demonstrated for the first time in whole plasma, may be responsible for C1 activation based on C4a production. The factor XII-dependent fibrinolytic cascade is also activated.