Background: The plasma kallikrein-kinin system (KKS) is comprised of the zymogens prekallikrein and factor XII (fXII) and the cofactor high-molecular-weight kininogen (HK). Kallikrein, the active form of prekallikrein, cleaves HK, releasing bradykinin. In the disorder hereditary angioedema (HAE), episodes of soft tissue swelling are triggered by excessive bradykinin production. The most common cause is deficiency of C1-inhibitor, the major regulator of kallikrein. However, mutations in other proteins appear to cause HAE, including a Lys311 to glutamate substitution in the fibrinolytic protease zymogen plasminogen (Plg).

Aims: Determine how Plg-311Glu contributes to excessive bradykinin production in HAE.

Methods: Wild type Plg (Plg-WT) and Plg-311Glu, and their activated plasmin (Plm) forms, were tested in plasma and purified protein systems for their effects on bradykinin generation.

Results: Adding tPA (to activate Plg) to normal plasma supplemented with Plg-311Glu resulted in substantially greater bradykinin production (measured by ELISA) than in plasma supplemented with Plg-WT. Similar results were obtained in plasmas lacking prekallikrein or fXII, and in normal plasma treated with kallikrein or fXIIa inhibitors. In purified systems, tPA converted Plg-WT and Plg-311Glu to Plm at similar rates. FXII and prekallikrein were activated by Plm-WT and Plm-311Glu comparably. Plm-311Glu released bradykinin from HK at a rate at least 10-fold faster than Plm-WT in a reaction that appeared stoichiometric. Mass spectroscopic analysis revealed the peptide released from HK by Plm-311Glu has a mass identical to bradykinin. Interestingly, Plg residue 311 is glutamate in most mammalian species, but this does not cause an HAE-like condition. We noted that while Plm-311Glu releases bradykinin from human HK, it does not from mouse HK.

Conclusions: The Lys311Glu substitution converts human plasmin into an efficient kininogenase that can bypass the KKS to generate bradykinin by direct cleavage of HK. Specific features of human HK appear to make it susceptible to cleavage by Plm-311Glu.

« Back to ISTH 2021 Congress

ISTH Congress Abstracts - https://abstracts.isth.org/abstract/a-mechanism-for-hereditary-angioedema-caused-by-a-plasminogen-lys311glu-substitution/