LAUSR

Patients with hereditary angioedema (HAE) experience episodes of bradykinin-induced swelling of skin and mucosal membranes. The most common cause is reduced plasma activity of C1-inhibitor, the main regulator of the proteases plasma kallikrein (PKa) and factor XIIa (FXIIa). Recently, HAE patients were described with a Lys311 to glutamic acid substitution in plasminogen (Plg), the zymogen of the protease plasmin (Plm). Adding tissue plasminogen activator to plasma containing Plg-Glu311 results in greater bradykinin generation than in plasma containing wild type plasminogen (Plg-Lys311). Similar results were obtained in plasmas lacking prekallikrein or factor XII (the zymogens of PKa and FXIIa), and in normal plasma treated with a PKa inhibitor, indicating Plg-Glu311 induces bradykinin generation independently of PKa and FXIIa. Plm-Glu311 cleaves high-molecular-weight and low-molecular-weight kininogens (HK and LK, respectively), releasing bradykinin more efficiently than Plm-Lys311. Based on the plasma concentration of HK and LK, the latter may be the source of most bradykinin generated by Plm-Glu311. The lysine analog e-aminocaproic acid blocks plasmin-catalyzed bradykinin generation. The Glu311 substitution introduces a lysine-binding site into the plasminogen kringle 3 domain, perhaps altering binding to kininogens. Plasminogen residue 311 is glutamic acid in most mammals. Glu311 in HAE patients, therefore, represents reversion to the ancestral condition. Substantial BK generation occurs during Plm-Glu311 cleavage of human HK, but not mouse HK. Furthermore, mouse plasmin, which has Glu311, did not liberate bradykinin from human kininogens more rapidly than human Plg-Lys311. This indicates Glu311 is pathogenic in the context of human plasmin when human kininogens are the substrates.