A team of French sickle cell doctors, from the Robert-Debre Hospital in the Sorbonne, Paris, have been studying a group of 375 babies identified at birth with sickle cell disease. Following them up carefully, recording what happens to them and noting the results of all the tests they have had done. “Cohort” studies such as this are a very powerful way of looking at how often various complications occur and what makes some individuals more at risk of these complications than others.
The team were particularly interested in strokes, which are a frequent and devastating event in children with sickle cell. What were the risk factors for having a stroke? And were there are any interventions which could protect the children most at risk? A lot is known about strokes in sickle cell and major improvements in care followed the publication of the STOP trials and the TWITCH trial (see a blog on “The TWITCH trial ….. posted on 18/02/16 for more information) but despite these efforts some children still suffer this life changing complication.
In the French cohort, by the age of 14 years, 26% of the children had developed evidence of cerebral macrovasculopathy detected by transcranial Doppler ultrasound (TCD). In plain English, by their early teens just over a quarter of the children had abnormal blood vessels in the brain predisposing them to a stroke. Despite the immediate implementation of a regular blood transfusion programme followed by hydroxycarbamide therapy after two years a small number of the children still went on to have a serious stroke.
The team found three factors which increased the risk of developing abnormal brain blood vessels and one protective factor. As you might guess the protective factor was a high foetal haemoglobin (Hb F) level. A high Hb F is a key variable protecting individuals with sickle cell from painful crises, the acute chest syndrome, stroke and early death. This study demonstrates that it also protects the blood vessels in the brain.
The three factors increasing the risk of damage to the brain’s blood vessels were:
Upper airway obstruction – this is usually indicated by either snoring at night or by episodes of suspended breathing whilst asleep (sleep apnoea) and is commonly found in children with enlarged tonsils or adenoids. It can be effectively treated either by nasal steroid sprays or surgical removal. It was already known that intermittent obstruction to the upper airways while asleep caused low levels of oxygen in the blood (nocturnal hypoxaemia) and that this was associated with an increased risk of large or small strokes and seizures or fits. This study demonstrated that the low oxygen levels directly damage the blood vessels in the brain causing the cerebral macrovasculopathy which is in turn the precursor of a stroke.
Lower airway obstruction – this presented with wheezing and chronic cough together with evidence on lung function testing (spirometry) of narrowing of the airways in the lungs. These are all features of asthma. The previous blog (Asthma and sickle cell disease – posted 20/06/16) discussed how asthma is associated with frequent painful crises and the acute chest syndrome. This study also documents that a diagnosis of asthma also has an effect on the blood vessels in the brain. Like all patients with asthma the symptoms in patients with sickle cell can be controlled with inhaled drugs, steroids or bronchodilators, which help to relax and increase the diameter of the airways.
High reticulocyte count – reticulocytes or “retics” are the very young red blood cells which have just been released from the bone marrow. Everyone with sickle cell breaks their red cells down faster than normal, which is why it is called sickle cell anaemia. But the rate of breakdown or haemolysis varies from person to person. The higher the reticulocyte count the faster the rate of haemolysis and a fast rate of haemolysis, as this study documents, will damage the blood vessels in the brain resulting in cerebral macrovasculopathy and an increased risk of stroke.
As the authors themselves comment, treatment with hydroxycarbamide not only increases the Hb F level but also reduces the rate of haemolysis and the reticulocyte count. Hydroxycarbamide therefore has a double protective effect in children at risk of stroke. Emphasising once again the potential usefulness of this drug in people with sickle cell. One of the other interesting treatment implications of this careful study is that you don’t have to have a “miracle cure” to have a major effect on the well being of patients with sickle cell. Simple treatments, which have been used for a long time and are known to be safe, targeted at those at high risk, can also have a very significant impact.
Clinical and haematological risk factors for cerebral macrovasculopathy in a sickle cell disease newborn cohort: a prospective study. Julie Sommet, Corinne Alberti, Nathalie Couque, Suzanne Verlhac, Zinedine Haouari, Damir Mohamed, Martine Francßois, Florence Missud, Laurent Holvoet, Monique Elmaleh, Ghislaine Ithier, Andre´Denjean, Jacques Elion, Andre Baruchel and Malika Benkerrou. British Journal of Haematology (March 2016), volume 172, pages 966-977.