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

Ståhl, Anne-LieLund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Pediatrisk nefrologi,Forskargrupper vid Lunds universitet,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Pediatric Nephrology,Lund University Research Groups (author)

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.

Vaziri Sani, FaribaLund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Celiac Disease and Diabetes Unit,Lund University Research Groups(Swepub:lu)fa3255va (author)
Heinen, Stefan (author)
Kristoffersson, Ann-CharlotteLund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)pedi-ack (author)
Gydell, Karl-Henrik (author)
Raafat, Reem (author)
Gutierrez, Alberto (author)
Beringer, Ortraud (author)
Zipfel, Peter F (author)
Karpman, DianaLund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Pediatrisk nefrologi,Forskargrupper vid Lunds universitet,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Pediatric Nephrology,Lund University Research Groups(Swepub:lu)pedi-dka (author)
Pediatrik, LundSektion V (creator_code:org_t)

By the author/editor: Ståhl, Anne-Lie; Vaziri Sani, Far ...; Heinen, Stefan; Kristoffersson, ...; Gydell, Karl-Hen ...; Raafat, Reem; show more...; Gutierrez, Alber ...; Beringer, Ortrau ...; Zipfel, Peter F; Karpman, Diana; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

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