Hereditary angioedema: a current state-of-the-art review. III: mechanisms of hereditary angioedema

Objective: To review the available evidence on the pathophysiologic mechanism of episodes of edema in hereditary angioedema (HAE). Data Sources: MEDLINE and PubMed were searched using the following keywords: hereditary angioedema, C1 inhibitor, complement system, contact system, and bradykinin. Study Selection: Studies were selected based on their relevance to the pathophysiologic features of HAE. Results: Early studies from the 1970s and 1980s disagreed as to whether the symptoms in HAE were mediated via complement or contact system activation. Studies have demonstrated that, in vitro, in C1 inhibitor (C1-INH)-deficient plasma, only contact system activation results in generation of a vascular permeability enhancing factor. Furthermore, individuals who express a variant C1-INH that is a normal inhibitor of contact system proteases but is deficient in the ability to inactivate complement system proteases do not develop angioedema. The blood of patients with HAE, during attacks, contains elevated levels of cleaved high-molecular-weight kininogen and bradykinin. Last, C1-INH-deficient mice develop increased vascular permeability that is mediated via contact system activation. Conclusions: Hereditary angioedema attacks are mediated by bradykinin generated via contact system activation. The specific factors that trigger attacks remain unclear.