The summer is over and the conference season is nearly upon us. This years Annual Sickle Cell & Thalassaemia Conference, organised by Guy’s & St Thomas’ Hospital, in early October looks set to provide lots of material for the blog. Before we get there though I thought it might be interesting to look at sickle cell trait, the carrier state for sickle cell. This is normally considered to be a benign and completely harmless condition but evidence is accumulating that this may not be the whole story.
If you inherit two copies of the sickle cell mutation, one from each of your parents, you have sickle cell disease, with all the problems and complications we know about. However, if you inherit only one copy of the sickle cell mutation, from either your mum or dad, and a normal haemoglobin gene from the your other parent, then you have sickle cell trait; your blood looks normal down the microscope, you are not anaemic and you do not get painful crises, the classic problem in sickle cell disease.
When you have sickle cell trait, in every one of your red cells, there will be a mixture of Hb A, or normal haemoglobin, and somewhere between 25-45% of Hb S or sickle haemoglobin. This compares with the situation in sickle cell disease where usually >90% of the haemoglobin will be Hb S and there is no Hb A. The smaller quantity of Hb S present in sickle cell trait red cells appears to be insufficient to cause a problem, which is why sickle cell carriers are fit and well. The sickle mutation is said to be recessive, in other words it only causes a problem if you have two copies of the abnormal gene, one from both parents. As we will see later, recent information indicates that this sweeping statement is no longer completely true.
But there is more to this story – let’s begin with the positives. Under certain circumstances, being a carrier for sickle cell can also be a positive advantage. This is because the mutation provides a major degree of protection against malaria. As a result, carrier rates for sickle cell have reached very high levels in populations regularly exposed to this devastating disease.
Malaria is one of the great scourges of mankind. It is caused by a small parasite which lives inside red blood cells and which it is transmitted from person to person by the bite of female Anopheles mosquitos. The female needs a blood meal before she can lay her eggs and whilst she is feeding malaria parasites are injected into the victim’s bloodstream.
There are several different types of malaria but the most serious is caused by Plasmodium falciparum. The tiny malaria parasites, which in this high powered photograph are coloured blue and red, live inside red blood cells feeding on haemoglobin. When the parasites are mature the red cells rupture, releasing many new parasites into the bloodstream which then go on to infect another generation of red cells.
Statistics from a WHO report in 2013 illustrate the impact of the infection. Ninety-seven countries around the world are affected by malaria with a total of 3.4 billion people at risk of the disease. In 2012 there were about 207 million infections with 627,000 deaths; 80% of the infections and 90% of the deaths occurred in Africa.
It is likely that cases of human malaria increased dramatically about 5,000 -10,000 years ago when, with the advent of organised agriculture, large areas of tropical rainforest were cleared of vegetation. This created ideal breeding grounds for the Anopheles mosquito, which lays her eggs in pools of stagnant water. With this threat to survival any genetic adaptation, which helped to protect people against the deadly effects of malaria, would have been strongly selected for. Over time many different, protective genetic variants, affecting the human red cell and haemoglobin, became established in human populations exposed to the disease. One of these protective variations is the sickle cell mutation.
Although being a carrier for sickle cell doesn’t stop you from getting malaria, it does greatly decrease the risk of dying from falciparum malaria, particularly in young children. Sickle cell trait children are 50-90% less likely to develop severe malarial disease compared to their Hb AA friends.
The graph shows that, at the most vulnerable age, between 2 and 5 years, sickle cell trait children have many fewer malaria parasites in their blood. As a result they have fewer complications and lower mortality rates. Sickle cell carrier children are more likely to survive childhood and go on to have children of their own ensuring that the sickle cell mutation is maintained at high levels in the population. In many parts of tropical Africa 20-30%, or more, of the population are carriers for sickle cell.
How does the sickle cell mutation protect against severe malaria? Well the story is complicated and not well understood. Firstly, malaria parasites appear to be able to cause even sickle trait red cells to sickle, despite their low content of Hb S. The sickled red cells and their contained parasites are then removed from the circulation and destroyed by the spleen. Secondly, infected sickle trait red cells stick less readily to the inner lining of blood vessels, one of the ways in which they begin to cause problems and thirdly, sickle carrier children acquire higher levels of immunity to malaria than their Hb AA contemporaries. Finally, it is possible that malaria parasites find sickle haemoglobin less easy to digest and use as a food source than normal haemoglobin.
Whatever the exact mechanism it is vitally important to remember that being a carrier for sickle cell does not give you any protection against acquiring malaria in the first place and all individuals, those with normal blood, sickle cell trait or sickle cell disease MUST take proper anti-malaria precautions when they visit malarial areas.
- Avoid mosquito bites – use a mosquito repellant spray, wear shirts with long sleeves and long trousers, sleep under an impregnated mosquito net.
- Kill any malaria parasites – take anti-malaria tablets; check with your GP or hospital doctor for the right tablets to take for the part of the world you are visiting.
So much for the health benefits of sickle cell trait. What about the downsides we alluded to at the beginning? Well, there are more than 300 million people around the world with sickle cell trait and for most of them, most of the time, it is a harmless disorder. But there is increasing evidence that sometimes sickle cell trait may cause it’s own problems.
We have all been made aware recently that sudden, tragic deaths sometimes occur in fit young men when they exercise at a very high intensity.
Such deaths, although rare, are made more likely by high temperatures, dehydration and poor physical fitness. Studies by the American military have recently confirmed that being a carrier for sickle cell is also a risk factor for sudden, exercise related death, and a similar association has been found in top class US athletes; those with sickle cell trait are 37 times more likely to die during exercise than athletes with normal blood. The latter realisation prompted the USA to pass legislation requiring testing for sickle cell in all premier division athletes. Why the carrier state for sickle cell and vigorous exercise should interact in this deadly way is unclear. It is tempting to speculate that the combination of sickle cell trait and severe dehydration, together with the other metabolic effects of extreme exercise, are sufficient to provoke widespread sickling and an overwhelming vaso-occlusive crisis, although this remains unproven. In the meantime, when exercising the advice is the same to everybody – keep well hydrated, access a cool, shaded environment if it is hot and only build up exercise levels gradually.
Although sudden death during exercise is the most dramatic association of sickle cell trait, the carrier state also seems to predispose to two much more common conditions – chronic kidney disease and blood clots in the veins (deep vein thrombosis or DVT and pulmonary embolism or PE).
The clots seem to begin in the little pockets, or valves, which help the blood in the veins of the legs to flow in the right direction, towards the heart and against gravity. It is possible that the oxygen level in these valve pockets is quiet low and may even be low enough to provoke the red cells to sickle in someone with sickle cell trait. It is presumed that these clumps of sickled red cells can then, in some way, stimulate the formation of a true blood clot. If the clots in the legs break free they can travel through the circulation and lodge in the lungs, a condition known as pulmonary embolus. There are many risk factors which increase the chance of having a DVT or PE. These include, prolonged sitting or bed rest, pregnancy, the oral contraceptive pill and hormone replacement therapy (HRT), obesity and smoking, heart failure and cancer, among many others. Sickle cell trait is yet another one to join this list which, when taken together, all add up to define a persons DVT/PE risk profile.
The benefits of having sickle cell trait, namely the protection it offers against the lethal effects of malaria infection, are very clear and dramatic. On the other hand the problems it can cause are much less significant and the vast majority of individuals with sickle cell trait remain well and do not suffer any consequences as a result of their inheritance. Interestingly, it is likely that all the problems associated with sickle cell trait are, in the end, all down to red cell sickling. Fortunately, because of the small amounts of sickle haemoglobin present in sickle trait red cells, this sickling only occurs under extreme or unusual circumstances.
Can someone with sickle cell trait ever have a painful sickle cell crisis? Well the answer is no, under normal circumstances but, if conditions are extreme enough, it is possible that they might. Travelling to extreme environments, say climbing to high altitudes in the Himalaya, where oxygen levels are very low, or travelling to the polar regions where it is very cold, may be sufficient to provoke a painful crisis in someone with sickle cell trait. More prosaically, every now and again patients with sickle cell trait, who have surgery, may wake up from the anaesthetic with symptoms of widespread bone pain indistinguishable from a classic sickle cell crisis. This is usually because they were inadvertently exposed to low levels of oxygen during the operation. One reason why it remains customary to check the sickle cell status of all “at risk” patients before surgery.
Negative health implications of sickle cell trait in high income countries: from the football field to the laboratory. Key NS, Connes P and Derebail VK. British Journal of Haematology, volume 170, pages 5-14