Exploring hemoglobin dynamics and scavenging mechanisms in preterm infants and preterm rabbits with cerebral intraventricular hemorrhage.

Abstract

Intraventricular hemorrhage (IVH) is a leading cause of neurodevelopmental impairment in preterm infants, driven by vascular rupture, intraventricular blood accumulation, and secondary injury. Hemolysis releases extracellular hemoglobin (Hb) into the cerebrospinal fluid (CSF), where it promotes oxidative stress, inflammation, and cytotoxicity. The endogenous Hb-scavenging protein haptoglobin (Hp) may mitigate Hb-mediated injury, but its capacity in the immature brain remains unclear. This study aimed to characterize Hb and Hp dynamics in the CSF of preterm infants with severe IVH and to evaluate the translational utility of a preterm rabbit glycerol-induced IVH model. Fourteen infants with grade III IVH or periventricular hemorrhagic infarction were enrolled in a prospective study. CSF was collected via ventricular access devices and analyzed alongside samples from rabbit pups with induced IVH. Infants showed markedly elevated CSF Hb (mean ± SEM: 133.3 ± 50.1 µmol/L, heme equivalents) and low Hp (0.87 ± 0.15 µg/mL). Similar patterns were observed in IVH-exposed rabbit pups, with elevated Hb and significantly reduced CSF Hp compared to non-IVH controls. These findings indicate a persistent deficit in endogenous Hb clearance following IVH and demonstrate that the rabbit pup model closely reflects the human condition, making it well-suited for preclinical evaluation of Hb-scavenging therapies. The aim of this study was to characterize the dynamics of hemoglobin and haptoglobin in the cerebrospinal fluid of preterm infants with severe IVH and to evaluate the translational validity of a preterm rabbit pup IVH model. By directly comparing hemoglobin and haptoglobin concentrations across species, this study revealed a profound imbalance between hemoglobin burden and scavenging capacity, highlighting a persistent deficit in endogenous clearance. These findings provide a strong rationale for therapeutic strategies targeting hemoglobin clearance in preterm IVH and support the use of the rabbit pup IVH model for translational studies.