Title: Studies of the Mechanisms of Bradykinin Generation in Hereditary Angioedema Plasma
Abstract: Factor XII-dependent bradykinin formation is thought to be responsible for the swelling associated with the various forms of C1 inhibitor deficiency while complement activation is augmented during attacks of swelling. We wished to further elucidate those interactions of the kinin-forming cascade that lead to complement activation during attacks of swelling and to determine whether fibrinolysis is augmented as well. Spontaneous activation of normal plasma and plasma of patients with Hereditary Angioedema (HAE) was compared by prolonged incubation in 96 well plates (polystyrene) as well as by activation with kaolin. We assayed for activated factor XII, prekallikrein, high molecular weight kininogen cleavage, C4a formation, and plasmin-α2-antiplasmin complex formation. HAE plasma demonstrates augmented factor XII activation, production of factor XII fragment (XIIf), prekallikrein activation and HK cleavage when compared to normal plasma. As a result, bradykinin formation is markedly increased. Production of factor XIIf, demonstrated for the first time in whole plasma, may be responsible for C1 activation based on C4a production. There is also increased baseline levels of C4a and plasmin-α2 antiplasmin complexes in HAE plasma which increase further upon activation with kaolin. All parameters indicative of activation of the bradykinin-forming cascade are activated in HAE plasma vs normal plasma. The factor XII-dependent fibrinolytic cascade is also activated. Complement activation during attacks of swelling are likely a result of HFf activation of C1r. Therapy with C1 inhibitor (purified) should prevent activation of all factor XII-dependent pathways including bradykinin formation, increased fibrinolytic activity, and activation of the classical complement pathway.
Publication Year: 2008
Publication Date: 2008-02-01
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 1
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