Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation.

摘要

Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations in the C-terminal of factor H (FH). FH binds to platelets via the C-terminal as previously shown using a construct consisting of short consensus repeats (SCRs) 15 to 20. A total of 4 FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, and E1198Stop) in patients with aHUS, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding to normal washed platelets compared with normal FH, detected by flow cytometry. Washed platelets taken from the 4 patients with aHUS during remission exhibited C3 and C9 deposition, as well as CD40-ligand (CD40L) expression indicating platelet activation. Combining patient serum/plasma with normal washed platelets led to C3 and C9 deposition, CD40L and CD62P expression, aggregate formation, and generation of tissue factor-expressing microparticles. Complement deposition and platelet activation were reduced when normal FH was preincubated with platelets and were minimal when using normal serum. The purified FH-E1198Stop mutant added to FH-deficient plasma (complemented with C3) allowed considerable C3 deposition on washed platelets, in comparison to normal FH. In summary, mutated FH enables complement activation on the surface of platelets and their activation, which may contribute to the development of thrombocytopenia in aHUS.