Artikel
Cerebrospinal fluid haemoglobin drives subarachnoid haemorrhage-related secondary brain injury
Hämoglobin im Liquor als Driver für sekundären Hirnschaden nach aneurysmatischer Subarachnoidalblutung
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Autoren
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Kevin Akeret
- Universitätsspital Zürich, Department of Neurosurgery, Zürich, Schweiz
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Raphael Buzzi
- Universitätsspital Zürich, Division of Internal Medicine, Zürich, Schweiz
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Christian A. Schär
- Universitätsspital Zürich, Department of Anesthesiology, Zürich, Schweiz
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Bart R. Thomson
- Universitätsspital Zürich, Department of Neurosurgery, Zürich, Schweiz
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Florence Vallelian
- Universitätsspital Zürich, Division of Internal Medicine, Zürich, Schweiz
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Sophie Wang
- Universitätsspital Zürich, Department of Neurosurgery, Zürich, Schweiz
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Jan Willms
- Universitätsspital Zürich, Neurointensive Care Unit, Zürich, Schweiz
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Martina Sebök
- Universitätsspital Zürich, Department of Neurosurgery, Zürich, Schweiz
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Ulrike Held
- Universitätsspital Zürich, Epidemiology, Biostatistics and Prevention Institute, Zürich, Schweiz
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Jeremy W. Deuel
- Universitätsspital Zürich, Division of Internal Medicine, Zürich, Schweiz
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Rok Humar
- Universitätsspital Zürich, Division of Internal Medicine, Zürich, Schweiz
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Luca Regli
- Universitätsspital Zürich, Department of Neurosurgery, Zürich, Schweiz
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Emanuela Keller
- Universitätsspital Zürich, Department of Neurosurgery, Zürich, Schweiz; Universitätsspital Zürich, Neurointensive Care Unit, Zürich, Schweiz
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Michael Hugelshofer
- Universitätsspital Zürich, Department of Neurosurgery, Zürich, Schweiz
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Dominik Schär
- Universitätsspital Zürich, Division of Internal Medicine, Zürich, Schweiz
| Veröffentlicht: | 4. Juni 2021 |
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Gliederung
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Objective: Secondary brain injury (SBI) is an important driver of mortality and morbidity in patients with aneurysmal subarachnoid hemorrhage (aSAH). The lag time between aneurysm rupture and aSAH-related SBI (SAH-SBI) provides a potential window of opportunity for therapeutic interventions; however, diagnostic biomarkers and novel drug targets represent an unmet need. Prior experimental evidence has suggested that cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) is an upstream pathophysiological driver of SAH-SBI that promotes vascular and neuronal toxicity. The aim of our study was to investigate the clinical and pathophysiological association between CSF-Hb and SAH-SBI.
Methods: We prospectively enrolled 47 consecutive patients with aSAH and collected daily CSF samples and clinical data between days 1 and 14 after aneurysm rupture.
Results: Using a generalized additive model, we found very strong evidence for a positive association between CSF-Hb and SAH-SBI. The diagnostic accuracy of CSF-Hb for SAH-SBI markedly exceeded that of other biomarkers as well as radiological and clinical scores (area under the curve: 0.89 [0.85-0.92]). LC-MS/MS analysis of the temporal changes in the levels of 757 CSF proteins demonstrated that erythrolysis accompanied by an adaptive macrophage response are the two dominant biological processes occurring in the CSF space after aSAH. To further investigate the pathophysiological association between CSF-Hb and SAH-SBI, we explored the vasoconstrictive and lipid peroxidation activities of Hb ex vivo within the CSF-Hb concentration range defined by our patient cohort. These experiments revealed critical inflection points overlapping CSF-Hb concentration thresholds in patients with SAH-SBI. Selective Hb depletion and in-solution neutralization by the hemoglobin-scavenger haptoglobin or the heme-scavenger hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb in patient CSF.
Conclusion: Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.
