Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Steven de Maat, Jenny Björkqvist, Chiara Suffritti, Chantal P. Wiesenekker, Willem Nagtegaal, Arnold Koekman, Sanne van Dooremalen, Gerard Pasterkamp, Philip G. de Groot, Marco Cicardi, Thomas Renné, Coen Maas
BackgroundPatients with angioedema experience unpredictable attacks of tissue swelling in which bradykinin is implicated. Several distinct mutations in Factor XII (FXII) are associated with hereditary angioedema (HAE) in the presence of normal C1 esterase inhibitor activity (FXII-HAE). The underlying disease mechanisms are unclear, which complicates diagnosis and treatment.ObjectiveWe sought to identify the natural trigger for FXII activation, which causes uncontrolled bradykinin production in patients with FXII-HAE.MethodsWe generated recombinant variants of FXII, representing health and disease, and studied their behavior in functional studies. We investigated bradykinin-forming pathways in blood plasma with newly developed nanobody-based analytic methods.ResultsWe here report that FXII-HAE mutations collectively introduce new sites that are sensitive to enzymatic cleavage by plasmin. These FXII mutants rapidly activate after cleavage by plasmin, escape from inhibition through C1 esterase inhibitor, and elicit excessive bradykinin formation. Furthermore, our findings indicate that plasmin modulates disease activity in patients with FXII-HAE. Finally, we show that soluble lysine analogs attenuate this mechanism, explaining their therapeutic value in patients with HAE.ConclusionOur findings indicate a new pathway for bradykinin formation in patients with HAE, in which FXII is cleaved and activated by plasmin. This should lead to the identification of new markers for diagnosis and targets for treatment.

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