Cerebrospinal fluid hemolysis precedes secondary brain injury after aneurysmal subarachnoid hemorrhage
- 1Division of Internal Medicine, Universitatsspital and University of Zurich, Zurich, Switzerland
Abstract
BACKGROUNDAfter aneurysmal subarachnoid hemorrhage (aSAH), erythrocyte lysis within cerebrospinal fluid (CSF) releases cell-free hemoglobin, a potential driver of secondary brain injury (SBI). Whether hemolysis precedes SBI and how its temporal associations compare with those of inflammation and neuroglial injury remain unclear.
METHODSIn this biomarker profiling study of the prospective multicenter HeMoVal cohort, 259 patients with aSAH requiring external ventricular drainage contributed 2,411 serial CSF samples over days 1-14 after hemorrhage. We quantified 22 analytes using spectrophotometry, immunoassay, and mass spectrometry; 19 were assigned to five prespecified disease pathway composites. Day- and site-adjusted generalized estimating equations estimated associations with same-day SBI and future first SBI (angiographic vasospasm, delayed cerebral ischemia, or delayed ischemic neurological deficit); a day-wise landmark analysis assessed robustness.
RESULTSOn the day of sampling, SBI was associated with four pathways, with the largest estimates for inflammation and neuroglial injury. Within the prespecified +72-hour horizon, only hemolysis (OR 1.40 per SD; 95% CI, 1.17-1.68) and the erythrophagocyte response (OR 1.28; 1.07-1.54) had FDR-significant forward associations with first SBI. Hemolysis had the largest forward estimate at every horizon; landmark analysis was concordant (pooled OR 1.86; 95% bootstrap CI, 1.37-2.65). The protective scavenger proteins haptoglobin and hemopexin declined to fitted plateaus of 2.4% and 12.5% of day-1 concentrations, versus [~]36% for plasma-protein references.
CONCLUSIONIn a scavenger-depleted CSF compartment, hemolysis and the erythrophagocyte response were associated with subsequent SBI. These findings identify hemolysis as a candidate upstream process and support testing sustained CSF hemoglobin scavenging to prevent SBI.
TRIAL REGISTRATIONClinicalTrials.gov NCT04998370.
FUNDINGCSL Behring; Swiss National Science Foundation; University of Zurich
Related
- Do Early Prognostic Measures Differentiate Mechanisms of ICU Death in Aneurysmal Subarachnoid Hemorrhage? An Analysis of Fatal Outcomes
- Non-aneurysmal perimesencephalic subarachnoid hemorrhage in a middle-aged female possibly triggered by Valsalva-like event and uncontrolled hypertension: a case report
- Interventional Rescue Therapy for Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: 10-Year Experience
- Reverse Takotsubo Cardiomyopathy Complicated by Neurogenic Pulmonary Edema in Aneurysmal Subarachnoid Hemorrhage: A Case Report.
- Explainable machine learning–based prediction of postoperative pulmonary infection after aneurysmal subarachnoid hemorrhage clipping and exploratory analysis of enteral nutrition timing: a dual-cohort retrospective study
BibTeX
@misc{buzzi2026cerebrospinal,
title = {{Cerebrospinal fluid hemolysis precedes secondary brain injury after aneurysmal subarachnoid hemorrhage}},
author = {R. M. Buzzi and K. Akeret and S. Wymann and S. M. Perez and D. Brulhart and M. Saxenhofer and D. Couto and J. Fischer and A. Wassmer and P. Tafo and S. Ewert and S. Taschler and M. Illi and J. Adam and A. Schmid and U. Held and F. Vallelian and M. Hugelshofer and T. Gentinetta and D. J. Schaer},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.26362434},
url = {https://www.medrxiv.org/content/10.64898/2026.09.08.26362434v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cerebrospinal fluid hemolysis precedes secondary brain injury after aneurysmal subarachnoid hemorrhage
AU - R. M. Buzzi
AU - K. Akeret
AU - S. Wymann
AU - S. M. Perez
AU - D. Brulhart
AU - M. Saxenhofer
AU - D. Couto
AU - J. Fischer
AU - A. Wassmer
AU - P. Tafo
AU - S. Ewert
AU - S. Taschler
AU - M. Illi
AU - J. Adam
AU - A. Schmid
AU - U. Held
AU - F. Vallelian
AU - M. Hugelshofer
AU - T. Gentinetta
AU - D. J. Schaer
PY - 2026
DA - 2026/09/08
PB - medRxiv
DO - 10.64898/2026.09.08.26362434
UR - https://www.medrxiv.org/content/10.64898/2026.09.08.26362434v1
AB - BACKGROUNDAfter aneurysmal subarachnoid hemorrhage (aSAH), erythrocyte lysis within cerebrospinal fluid (CSF) releases cell-free hemoglobin, a potential driver of secondary brain injury (SBI). Whether hemolysis precedes SBI and how its temporal associations compare with those of inflammation and neuroglial injury remain unclear. METHODSIn this biomarker profiling study of the prospective multicenter HeMoVal cohort, 259 patients with aSAH requiring external ventricular drainage contributed 2,411 serial CSF samples over days 1-14 after hemorrhage. We quantified 22 analytes using spectrophotometry, immunoassay, and mass spectrometry; 19 were assigned to five prespecified disease pathway composites. Day- and site-adjusted generalized estimating equations estimated associations with same-day SBI and future first SBI (angiographic vasospasm, delayed cerebral ischemia, or delayed ischemic neurological deficit); a day-wise landmark analysis assessed robustness. RESULTSOn the day of sampling, SBI was associated with four pathways, with the largest estimates for inflammation and neuroglial injury. Within the prespecified +72-hour horizon, only hemolysis (OR 1.40 per SD; 95% CI, 1.17-1.68) and the erythrophagocyte response (OR 1.28; 1.07-1.54) had FDR-significant forward associations with first SBI. Hemolysis had the largest forward estimate at every horizon; landmark analysis was concordant (pooled OR 1.86; 95% bootstrap CI, 1.37-2.65). The protective scavenger proteins haptoglobin and hemopexin declined to fitted plateaus of 2.4% and 12.5% of day-1 concentrations, versus [~]36% for plasma-protein references. CONCLUSIONIn a scavenger-depleted CSF compartment, hemolysis and the erythrophagocyte response were associated with subsequent SBI. These findings identify hemolysis as a candidate upstream process and support testing sustained CSF hemoglobin scavenging to prevent SBI. TRIAL REGISTRATIONClinicalTrials.gov NCT04998370. FUNDINGCSL Behring; Swiss National Science Foundation; University of Zurich
ER -