Haemoglobin scavenging in intracranial bleeding: biology and clinical implications

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. Free haemoglobin released from red blood cells after intracranial bleeding can lead to neurotoxicity and exacerbate injury. In this Review, the authors consider the biology behind haemoglobin toxicity and the clinical potential of targeting haemoglobin scavenging systems to aid recovery. Key points Extracellular haemoglobin induces cell death, mainly via oxidation and inflammation. Mechanisms in the brain that can mitigate haemoglobin toxicity and enable its clearance are easily overwhelmed by extensive haemolysis after intracranial haemorrhage. Variation in genes related to haemoglobin binding and metabolism influence outcomes after subarachnoid haemorrhage or intracerebral haemorrhage. Treatments that mitigate haemoglobin toxicity and increase clearance might have clinical benefits for patients with intracranial bleeding. Research priorities include prospective genetic association studies and an improved basic scientific understanding of the mechanism of haemoglobin toxicity and its clearance from the brain.