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

Ståhl, Anne-lie LU ; Vaziri Sani, Fariba LU ; Heinen, Stefan; Kristoffersson, Ann-Charlotte LU ; Gydell, Karl-Henrik; Raafat, Reem; Gutierrez, Alberto; Beringer, Ortraud; Zipfel, Peter F and Karpman, Diana LU (2008) In Blood 111. p.5307-5315
Abstract
Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations at 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) 15-20. Four FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, E1198Stop) in aHUS patients, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding to normal washed platelets compared to normal FH, detected by flow cytometry. Washed platelets taken from the four aHUS patients during remission exhibited C3 and C9 deposition, as well as CD40-ligand (CD40L) expression indicating platelet activation. Combining patient... (More)
Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations at 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) 15-20. Four FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, E1198Stop) in aHUS patients, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding to normal washed platelets compared to normal FH, detected by flow cytometry. Washed platelets taken from the four aHUS patients 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 pre-incubated 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
111
pages
5307 - 5315
publisher
American Society of Hematology
external identifiers
  • pmid:18268093
  • wos:000256336500012
  • scopus:45949108983
ISSN
1528-0020
DOI
10.1182/blood-2007-08-106153
language
English
LU publication?
yes
id
e5ed796c-3237-4fdd-a7b4-178dfa6dc5b9 (old id 1042062)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18268093?dopt=Abstract
date added to LUP
2008-03-06 15:59:31
date last changed
2017-10-01 04:58:27
@article{e5ed796c-3237-4fdd-a7b4-178dfa6dc5b9,
  abstract     = {Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations at 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) 15-20. Four FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, E1198Stop) in aHUS patients, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding to normal washed platelets compared to normal FH, detected by flow cytometry. Washed platelets taken from the four aHUS patients 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 pre-incubated 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.},
  author       = {Ståhl, Anne-lie and Vaziri Sani, Fariba and Heinen, Stefan and Kristoffersson, Ann-Charlotte and Gydell, Karl-Henrik and Raafat, Reem and Gutierrez, Alberto and Beringer, Ortraud and Zipfel, Peter F and Karpman, Diana},
  issn         = {1528-0020},
  language     = {eng},
  pages        = {5307--5315},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation.},
  url          = {http://dx.doi.org/10.1182/blood-2007-08-106153},
  volume       = {111},
  year         = {2008},
}