21 August 2019

Scientists have reported a potential mechanism explaining a connection between anaemia, blood transfusions and the development of necrotising enterocolitis (NEC) in premature babies.

A team led by Dr Akhil Maheshwari from Johns Hopkins University in Baltimore, USA, set out to investigate the conditions necessary for the development of NEC, a condition that can lead to sepsis and death.

They developed an animal model using infant mice to accurately represent the disease process. The animals were made anaemic, then at a week old they were injected with bacteria originally isolated from a premature baby with NEC.

The pups were then transfused with blood from infant mice of a different strain, to mimic an allogenic blood donation. The team analysed the mice’s blood using an advanced analysis system that only requires a tiny volume of blood.

Dr Maheshwari reports: “Only the severely anaemic pups who received blood transfusions showed intestinal damage that resembled human necrotising enterocolitis. The next step was to see if we could find a mechanism for why this occurred.”

Interestingly, an invasion of macrophages into the intestine was only seen in anaemic pups, and not in non-anaemic controls. The presence of macrophages was required for the triggering of NEC-like symptoms by transfusions.

Further blood tests showed clear differences in the blood of animals with NEC and without. One difference was that levels of haptoglobin, a protein that removes free haemoglobin from the blood, were extremely low in anaemic animals.

This prevents the free haemoglobin, generated from the degradation of blood before it is transfused, from being properly removed. Instead, the free haemoglobin attaches to a protein receptor on the intestinal wall where bacteria normally bind. The researchers propose that this triggers the release of inflammatory proteins and ultimately NEC.

Giving haptoglobin to the anaemic mice before transfusion blocked macrophage activation and prevented NEC.

The team hopes that these findings, published in the journal Nature Communications, can be used to develop blood biomarkers to identify which infants are most at risk. They also call for a re-evaluation of current guidelines for blood transfusions in premature infants.

Source: MohanKumar K., Namachivayam, K., Song, T., Jake Cha, B., Slate, A., Hendrickson, J.E., Pan, H., Wickline, S.A., Oh, J.Y., Patel, R.P., He, L., Torres. B.A., Maheshwari, A. (2019) “A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions”, Nature Communications, available at doi: 10.1038/s41467-019-11199-5


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