Challenges for intraventricular hemorrhage research and emerging therapeutic targets

Abstract

Intraventricular hemorrhage (IVH) affects both premature infants and adults. In both demographics, it has high mortality and morbidity. There is no FDA approved therapy that improves neurological outcome in either population highlighting the need for additional focus on therapeutic targets and treatments emerging from preclinical studies. Areas covered: IVH induces both initial injury linked to the physical effects of the blood (mass effect) and secondary injury linked to the brain response to the hemorrhage. Preclinical studies have identified multiple secondary injury mechanisms following IVH, and particularly the role of blood components (e.g. hemoglobin, iron, thrombin). This review, with an emphasis on pre-clinical IVH research, highlights therapeutic targets and treatments that may be of use in prevention, acute care, or repair of damage. Expert opinion: An IVH is a potentially devastating event. Progress has been made in elucidating injury mechanisms, but this has still to translate to the clinic. Some pathways involved in injury also have beneficial effects (coagulation cascade/inflammation). A greater understanding of the downstream pathways involved in those pathways may allow therapeutic development. Iron chelation (deferoxamine) is in clinical trial for intracerebral hemorrhage and preclinical data suggest it may be a potential treatment for IVH.

Keywords: Intraventricular hemorrhage; post-hemorrhagic hydrocephalus; preclinical models; prevention; therapeutic targets; treatments.

Figure 1.

Schematic showing effects of IVH related to erythrocyte lysis and hemoglobin release within the ventricular system. IVH causes ependymal damage and this may facilitate the penetration of hemoglobin from CSF into brain parenchyma. Hemoglobin may then be taken up into microglia/ macrophages via the CD163 receptor, particularly when hemoglobin is complexed to haptoglobin. Alternately, heme released from hemoglobin may be taken up by microglial cells via the CD91 receptor. Inside microglia, hemoglobin/heme is degraded by heme oxygenase-1 (HO-1) to iron, carbon monoxide and biliverdin. HO-1 is inducible and it is markedly upregulated after cerebral hemorrhage. In microglia, iron produced by HO-1 can be chelated by ferritin reducing iron-mediated damage. Recent evidence indicates that neurons can also express CD163 and hemoglobin uptake into those cells may be more toxic due to a lack of ferritin. Neurons express a constitutive form of heme oxygenase, HO-2. Hemoglobin in CSF can also cause damage to the choroid plexus and this may impact CSF homeostasis, result in infiltration of leukocytes and potentially contribute to hydrocephalus, an understudied area.

Figure 2.

After vessel rupture, prothrombin and fibrinogen enter the brain and there is activation of the coagulation cascade and the final cleavage of fibrinogen to fibrin by thrombin. The main role of the coagulation cascade is to stop bleeding (hemostasis). However, thrombin and fibrinogen have other actions within brain, some of which may contribute to injury after IVH. Thrombin can activate microglia, induce astrogliosis and cause BBB disruption. In addition, thrombin has neuronal effects. These can be beneficial at low concentrations but harmful at high concentrations. Some of the effects of thrombin are via protease activated receptor-1 (PAR-1). Fibrinogen also causes microglial activation, via the CD11b/CD8 (Mac-1) receptor. While there is mounting evidence of the role of the coagulation cascade in hemorrhagic brain injury, targeting that cascade therapeutically is complicated by the essential role of that cascade in hemostasis. Targeting downstream mediators of injury may be an approach.