Cerebrospinal Fluid Hemopexin As a Candidate Biomarker for Secondary Sepsis and In-Hospital Outcome after Spontaneous Intracerebral Hemorrhage: an Exploratory Translational Proteomics Study

Secondary sepsis is a frequent and clinically important complication after spontaneous intracerebral hemorrhage (ICH), but biomarkers linking hemorrhage-related heme stress to subsequent systemic complications remain poorly defined. We investigated cerebrospinal fluid hemopexin (CSF-HPX) as a candidate biomarker associated with hemorrhage burden, secondary sepsis, and in-hospital outcome after ICH. We integrated a 2-hit exploratory animal proteomics model with a retrospective clinical CSF cohort. In rats, autologous blood-induced ICH was followed 6 h later by cecal ligation and puncture (CLP), and soluble brain proteins collected at 24 h were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ)-based liquid chromatography–tandem mass spectrometry (LC–MS/MS). In the clinical cohort, archived CSF samples obtained through routine external ventricular drainage within 24 h after surgery were analyzed in adults with first-ever spontaneous ICH (n = 41). HPX and vitamin D-binding protein(GC/VDBP) were quantified by enzyme-linked immunosorbent assay (ELISA). Secondary sepsis was identified using an operationalized Sepsis-3 framework after excluding infection or sepsis at admission. In the animal model, ICH + CLP was associated with worse early survival than ICH alone (log-rank χ2 = 12.25, p = 0.0005), and HPX was identified as a candidate protein linked to the combined hemorrhage–sepsis condition. In the clinical cohort, CSF-HPX was positively associated with hematoma volume and was higher in patients who subsequently developed secondary sepsis than in those who did not (558.17 [279.48–773.39] ng/mL vs. 305.99 [218.77–354.24] ng/mL, p = 0.006). This association remained significant after adjustment (adjusted odds ratio (OR) 1.016, 95