title: High Presence of Extracellular Hemoglobin in the Periventricular White Matter Following Preterm Intraventricular Hemorrhage.
abstract: Severe cerebral intraventricular hemorrhage (IVH) in preterm infants continues to be a major clinical problem, occurring in about 15-20% of very preterm infants. In contrast to other brain lesions the incidence of IVH has not been reduced over the last decade, but actually slightly increased. Currently over 50% of surviving infants develop post-hemorrhagic ventricular dilatation and about 35% develop severe neurological impairment, mainly cerebral palsy and intellectual disability. To date there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. It is known that blood rapidly accumulates within the ventricles following IVH and this leads to disruption of normal anatomy and increased local pressure. However, the molecular mechanisms causing brain injury following IVH are incompletely understood. We propose that extracellular hemoglobin is central in the pathophysiology of periventricular white matter damage following IVH. Using a preterm rabbit pup model of IVH the distribution of extracellular hemoglobin was characterized at 72 h following hemorrhage. Evaluation of histology, histochemistry, hemoglobin immunolabeling and scanning electron microscopy revealed presence of extensive amounts of extracellular hemoglobin, i.e., not retained within erythrocytes, in the periventricular white matter, widely distributed throughout the brain. Furthermore, double immunolabeling together with the migration and differentiation markers polysialic acid neural cell adhesion molecule (PSA-NCAM) demonstrates that a significant proportion of the extracellular hemoglobin is distributed in areas of the periventricular white matter with high extracellular plasticity. In conclusion, these findings support that extracellular hemoglobin may contribute to the pathophysiological processes that cause irreversible damage to the immature brain following IVH.
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Ley
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Romantsik
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Suvi
authors.initials: S
authors.lastname: Vallius
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Kristbjörg
authors.initials: K
authors.lastname: Sveinsdóttir
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Snjolaug
authors.initials: S
authors.lastname: Sveinsdóttir
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Agyemang
authors.affiliation: Department of Clinical Sciences Lund, Infection Medicine, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Baumgarten
authors.affiliation: Department of Clinical Sciences Lund, Infection Medicine, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: ImaGene-iT AB Lund, Sweden.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Lutay
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bruschettini
authors.affiliation: ImaGene-iT AB Lund, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Holmqvist
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Gram
keywords: hemoglobin; imaging; immature brain; intraventricular hemorrhage; periventricular white matter; peroxidase activity; plasticity