Developing haptoglobin as a novel intracranial therapeutic

There are several types of intracranial haemorrhage, depending on where in the brain the haemorrhage occurs. In subarachnoid haemorrhage, there is bleeding in the subarachnoid space, over the surface of the brain. Up to one third of patients die instantly with this type of bleed, and most survivors have neurological and/or cognitive deficits. The underlying mechanisms are a subject of intense study. When the blood clot on the surface of the brain breaks down, the red blood cells release haemoglobin, the red pigment in blood. Haemoglobin is toxic and damages nerve cells when outside red blood cells, since it is a potent oxidizing agent. We have found that there is significant iron deposition in the brain, as demonstrated by histochemistry and quantitative susceptibility-weighted magnetic resonance imaging, up to six months after subarachnoid haemorrhage, suggesting that haemoglobin had penetrated the cortex. The amount of iron (and therefore haemoglobin penetration) was in turn related to cognitive dysfunction.

Luckily the body has developed a system to clear haemoglobin when it is released from red blood cells, which is based on haptoglobin, a protein in blood which binds haemoglobin and neutralizes its toxicity. However we found that the brain has very little of this protein. Since patients with subarachnoid haemorrhage and large blood clots have an external ventricular drain as part of their clinical care, this protein can be delivered to the brain via this drain, if one proves it can really help. In this project, we collaborate with our industrial partner, Bio Products Laboratory Limited, in order to test whether haptoglobin can still bind to haemoglobin in human cerebrospinal fluid after subarachnoid haemorrhage and to establish the therapeutic window for such treatment. We also study haptoglobin genotype and how this is related to clinical outcome after subarachnoid haemorrhage in humans.