Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage

Bart J van Dijk, Joost C M Meijers, Anne T Kloek, Veronique L Knaup, Gabriel J E Rinkel, B Paul Morgan, Marije J van der Kamp, Koji Osuka, Eleonora Aronica, Ynte M Ruigrok, Diederik van de Beek, Matthijs Brouwer, Marcela Pekna, Elly M Hol, Mervyn D I Vergouwen

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Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3-10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.

Original languageEnglish
Pages (from-to)678-688
Number of pages11
JournalTranslational Stroke Research
Issue number4
Early online date6 Dec 2019
Publication statusPublished - Aug 2020


  • Aneurysmal subarachnoid hemorrhage
  • Brain injury
  • Complement system


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