Haemoglobin scavenging in intracranial bleeding: biology and clinical implications

Abstract

Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.

Haptoglobin genotype and aneurysmal subarachnoid hemorrhage

“…The HP2 allele codes for an α 2 subunit that contains an extra cysteine residue compared to α 1 and is therefore able to make multiple disulfide bonds, resulting in several polymers of increasing size in HP2-1 heterozygotes and HP2-2 homozygotes. 10 Whether there is a functional difference between the proteins expressed by different HP genotypes is controversial and very much depends on which characteristic of Hp one considers. It is well established that Hp expression is influenced by genotype: HP1-1 > HP1-2 > HP2-2.…”

“…4 Some studies have suggested that haptoglobin (HP) genotype may also influence outcome, [5][6][7][8][9] but results are conflicting. 10 A recent meta-analysis found that the HP2 allele was associated with a worse short-term but not long-term outcome. 11 This meta-analysis had limitations, including small study sizes, heterogeneity in outcome classification, and inability to control for covariates.…”

“…The main potential mechanism of the HP effect is through the function of its protein (Hp) as a scavenger of extracellular hemoglobin (Hb). 10 Because the Hp-Hb scavenging system is active in the CNS after aSAH, 12 there is a strong biological rationale to hypothesize that HP genetic variation influences aSAH outcome. We therefore conducted an individual patient-level data (IPLD) analysis of all identified published and unpublished studies to investigate the relationship between HP genotype and outcome after aSAH.…”

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

“…By understanding the relationship between ER stress in either activation of inhibition of other prominent factors of ICH including microglial activation [5,9], ROS production [6], proinflammatory cytokine release [11], and heme and iron release [13,14]; we will have a greater knowledge on the molecular mechanism involved in ICH induced secondary brain injury. In a traumatic brain injury (TBI) model, increased PERK phosphorylation resulted in the excessive release of interferon (IFN)-β through stimulator of interferon gene (STING) signaling pathway.…”

Surgically Treated Intracerebral Haemorrhage : Pathophysiology and Clinical Aspects

“…There are several naturally occurring protective pathways in the brain, guarding against the oxidative stress caused by blood toxicity, but these pathways get exhausted by ICH. Examples of such pathways include astrocytic release of haptoglobin (79)(80)(81)(82)(83) and haemopexin which scavenge haem and facilitate subsequent macrophage phagocytosis of these haem-scavenger complexes (79, 82).…”