Picomolar Sensitivity Analysis of Multiple Bradykinin-Related Peptides in the Blood Plasma of Patients With Hereditary Angioedema in Remission: A Pilot Study.

Background: Hereditary angioedema (HAE) is a rare autosomal dominant disease; the most well understood forms concern the haplodeficiency of C1 esterase inhibitor (C1INH) and a gain of function mutation of factor XII (FXII). The acute forms of these conditions are mediated by an excessive bradykinin (BK) formation by plasma kallikrein.
Methods: A validated LC-MS/MS platform of picomolar sensitivity developed for the analysis of eleven bradykinin-related peptides was applied to the plasma of HAE-C1INH and HAE-FXII sampled during remission.
Results: In HAE-C1INH plasma, the concentrations of the relatively stable BK _1-5 fragment (mean ± S.E.M.: 12.0 ± 4.2 pmol/L), of BK _2-9 (0.7 ± 0.2 pmol/L) and of the sums of BK and its tested fragments (18.0 ± 6.4 pmol/L) are significantly greater than those recorded in the plasma of healthy volunteers (1.9 ± 0.6, 0.03 ± 0.03 and 4.3 ± 0.8 pmol/L, respectively), consistent with the previous evidence of permanent plasma kallikrein activity in this disease. Kinin levels in the plasma of HAE-FXII patients did not differ from controls, suggesting that triggering factors for contact system activation are not active during remission.
Conclusion: BK _1-5 , BK _2-9 and the sum of BK and its fragments determined by the sensitive LC-MS/MS technique are proposed as potential biomarkers of HAE-C1INH in remission while this was not applicable to HAE-FXII patients.
Competing Interests: FM served as a consultant for Pharvaris B.V. and received research funds from Shire/Takeda and Pharvaris B.V., outside the submitted work. G-ER has been a member of advisory boards (Baxalta, Bayer, Biogen Idec, CSL Berhing, Novo Nordisk, Octapharma, Pfizer) and received funding from Bayer, CSL Behring and Pfizer (unrelated to the submitted work). JH has been a speaker/teacher for CLS Behring, Novartis, and Shire; he has been a member of advisory committees (CLS Behring, Shire, and Novartis) and a clinical investigator for Merck (ALK), Stallergene, Boehringer-Ingelheim, GlaxoSmithKline (GSK), Novartis, Sanofi, AstraZeneca, CLS Behring, Shire, Roche, and Griffols (unrelated to the submitted work). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Marceau, Rivard, Hébert, Gauthier, Bachelard, Gangnus and Burckhardt.)