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Contact activation‐induced complex formation between complement factor H and coagulation factor XIIa
Author(s) -
Thangaraj Sai Sindhu,
Christiansen Stig Hill,
Graversen Jonas Heilskov,
Sidelmann Johannes Jakobsen,
Hansen Søren Werner Karlskov,
Bygum Anette,
Gram Jørgen Brodersen,
Palarasah Yaseelan
Publication year - 2020
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14742
Subject(s) - factor xii , chemistry , hereditary angioedema , c1 inhibitor , complement system , coagulation , prekallikrein , kallikrein , bradykinin , biophysics , receptor , biochemistry , immunology , angioedema , medicine , enzyme , immune system , biology
Background The complement and coagulation systems share an evolutionary origin with many components showing structural homology. Certain components, including complement factor H (FH) and coagulation factor XII (FXII), have separately been shown to have auxiliary activities across the two systems. Objectives The interaction between FXII and FH was investigated. Methods Using enzyme‐linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) complex formation between different FXII forms and FH was investigated. The presence of α‐FXIIa:FH complexes upon contact activation in plasma was evaluated by ELISA and immunoprecipitation. Results We identified and characterized a direct interaction between the components and demonstrated that among different forms of FXII, only the activated α‐FXIIa formed complexes with FH, with an apparent binding strength K d of 34 ± 9 nmol/L. The complex formation involved the kringle domain of the heavy chain of FXII. C1‐inhibitor induced inhibition of α‐FXIIa did not alter the binding of α‐FXIIa toward FH. We further demonstrated the presence of α‐FXIIa:FH complexes in normal human plasma upon contact activation, indicating formation of α‐FXIIa:FH complexes as a consequence of α‐FXIIa generation. Complex formation between α‐FXIIa and FH was also assessed in hereditary angioedema (HAE) patients with C1‐inhibitor deficiency as well as rheumatoid arthritis (RA) patients with high levels of anti‐cyclic citrullinated peptide (anti‐CCP) upon contact activation. We observed elevated levels of α‐FXIIa:FH complexes in HAE patients, and equal levels of complexes in RA patients and healthy individuals upon contact activation. Conclusion A direct interaction between α‐FXIIa and FH is demonstrated. Our findings represent a new crosstalk between these systems, potentially important in the onset and pathology of inflammatory vascular diseases.