Contact activation‐induced complex formation between complement factor H and coagulation factor XIIa

Abstract

BackgroundThe 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. ObjectivesThe interaction between FXII and FH was investigated. MethodsUsing 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. ResultsWe 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 Kd 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. ConclusionA 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.