Bradykinin (BK)-induced swelling of the skin and mucosal membranes occurs in patients with hereditary angioedema (HAE). The most prevalent reason is decreased C1 inhibitor plasma activity, which is the major regulator of the proteases plasma kallikrein (PKA) and factor XIIa (FXIIa). Patients with HAE were recently characterized as having plasminogen (Plg), the zymogen of the protease plasmin, with a Lys311 to glutamic acid substitution (Plm). When tissue plasminogen activator is added to plasma carrying Plg-Glu311 versus plasma having wild-type Plg (Plg-Lys311), more BK is produced. Similar findings were observed in plasma lacking prekallikrein or FXII (PKA and FXIIa zymogens) and in normal plasma treated with a PKA inhibitor, demonstrating that Plg-Glu311 causes BK production independently of PKA and FXII. Plm-Glu311 cleaves high and low molecular weight kininogens (HK and LK, respectively) more effectively than Plm-Lys311. Based on plasma HK and LK concentrations, the latter might be the source of the majority of the BK produced by Plm-Glu311. Plm-catalyzed BK production is inhibited by the lysine analog -aminocaproic acid.
The Glu311 alteration adds a lysine-binding site to the Plg kringle 3 domain, which might affect kininogen binding. In most mammals, Plg residue 311 corresponds to glutamic acid. As a result, Glu311 in HAE patients signified a return to the original state. Significant BK was produced during the Plm-Glu311 cleavage of human HK but not mouse HK. Furthermore, mouse Palm, which contains Glu311, did not release BK from human kininogens faster than human Plg-Lys311. When human kininogens are the substrates, Glu311 is harmful in the setting of human Plm.
