title: Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations.
abstract: Patients 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.
  
  
  
  We sought to identify the natural trigger for FXII activation, which causes uncontrolled bradykinin production in patients with FXII-HAE.
  
  
  
  We 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.
  
  
  
  We 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.
  
  
  
  Our 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.
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: de Maat
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Solna, Sweden; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Björkqvist
authors.affiliation: Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, and Luigi Sacco Hospital Milan, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Suffritti
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Chantal P
authors.initials: CP
authors.lastname: Wiesenekker
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Nagtegaal
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Arnold
authors.initials: A
authors.lastname: Koekman
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: van Dooremalen
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.affiliation: Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, and Luigi Sacco Hospital Milan, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cicardi
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Solna, Sweden; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: cmaas4@umcutrecht.nl.
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
mesh_terms: D015119:Aminocaproic Acid / Q000494:pharmacology; D054179:Angioedemas, Hereditary / Q000378:metabolism*; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism*; D050718:Complement C1 Inhibitor Protein / Q000378:metabolism; D005174:Factor XII / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011247:Pregnancy
chemical_list: D000933:Antifibrinolytic Agents; D050718:Complement C1 Inhibitor Protein; D005174:Factor XII; D005341:Fibrinolysin; D001920:Bradykinin; D015119:Aminocaproic Acid
keywords: Angioedema; C1 esterase inhibitor; Factor XII; bradykinin; kininogen; plasma kallikrein; plasmin