Cerebrospinal fluid hemolysis precedes secondary brain injury after aneurysmal subarachnoid hemorrhage
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT BACKGROUND After 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. METHODS In 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. RESULTS On 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. CONCLUSION In 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 REGISTRATION ClinicalTrials.gov NCT04998370 . FUNDING CSL Behring; Swiss National Science Foundation; University of Zurich
Source: medRxiv
Authors: Raphael M. Buzzi, Kevin Akeret, Sandra Wymann, Sandra Mena Pérez, Damian Brülhart, Moritz Saxenhofer, Daniel Couto, Jasmin Fischer, Andreas Wassmer, Pavel Tafo, Svenja Ewert, Sara Täschler, Marlies Illi, Jacqueline Adam, Adrien Schmid, Ulrike Held, Florence Vallelian, Michael Hugelshofer, Thomas Gentinetta, Dominik J. Schaer
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212055162