What is bone marrow?

Bone marrow is a substance found in the spongy centre of bones and is where blood cells are formed. The bone marrow forms ‘stem cells’ which develop into any of the three types of blood cell – red blood cells, white blood cells and platelets. Normally, the bone marrow controls the number of blood cells formed and released into the blood stream, so the body remains healthy. The number of blood cells is often referred to as a blood count and is often separated into the different types of blood cells.

Red blood cells – about three million red blood cells are produced by the bone marrow every second. They carry a proteincalled ‘haemoglobin’ which carries oxygen to all parts of the body providing energy. The normal level of haemoglobin in a child’s blood varies with age but is around 10 to 12 grams per decilitre (g/dl).

White blood cells – these are larger than red blood cells and have different functions. The two main white blood cells are neutrophils – which fight bacterial infections – and lymphocytes – which help fight viruses and other non-bacterial infections. The normal level of all white blood cells in a child’s blood is about six to 16 x 109/l. The normal level of neutrophils is between 1.5 and 8.5 x 109/l and lymphocytes between two and 9.5 x 109/l. Platelets – these are much smaller than red blood cells and help the blood clot by sticking together. The normal level of platelets is between 150 and 400 x 109/l.

What is aplastic anaemia (AA)?

Aplastic anaemia is a serious condition affecting the blood, where the bone marrow and stem cells do not produce enough blood cells. It is also called bone marrow failure and can happen suddenly (acute) or develop over a period of time (chronic).

What causes AA?

There are two types of AA – acquired and inherited – and the causes of each are different. Acquired: this is the most common type of AA. You develop the condition and are not born with it. Acquired AA is usually ‘idiopathic’, which means we do not know the cause. Inherited: you can inherit a faulty gene, which causes you to develop AA later in life. Inherited AA is rare. There are a number of types, including Fanconi anaemia. If you are born with this faulty gene, you are most likely to develop AA between the ages of 10 and 15.

What causes AA?

Aplastic anaemia can be inherited. It can also develop for unknown reasons – we call this idiopathic aplastic anaemia. In idiopathic aplastic anaemia the immune system sees the body’s bone marrow cells as the ‘enemy’ and starts to attack them. Generally we do not know what triggers this immune reaction but about one in ten patients with aplastic anaemia have had a recent viral infection, often hepatitis. The immune system becomes ‘confused’ and produces antibodies which are targeted at the virus but also damage blood-forming stem cells. Inherited causes of aplastic anaemia are less common; the commonest inherited cause is called Fanconi anaemia.

What are the symptoms of AA?

If your bone marrow does not produce enough blood cells, you may have a number of symptoms.

  • A low number of red blood cells causes anaemia. This leads to low energy levels, headaches, and shortness of breath when you are doing moderate exercise such as going up stairs or light work/activity. You can sometimes have palpitations, where you notice your heartbeats and your heart may feel like it is pounding, fluttering or beating irregularly for a few seconds or minutes. If your anaemia is severe, you may even have chest pain. You usually need regular blood transfusions to increase the number of red cells in your blood and improve your energy levels.
  • A low number of white blood cells – especially neutrophils, which fight bacterial infections – makes you more prone to fevers, bacterial and fungal infections, and sometimes serious infections which means you have to be admitted to hospital.
  • A low number of platelets can make you bruise and bleed more easily. You often need platelet transfusions to help prevent bleeding and bruising. Common signs include: bleeding gums, particularly during or after brushing your teeth, nose bleeds, periods that are heavy or last longer than usual, blood blisters in your mouth, bruised skin, sometimes when you have not knocked yourself, a rash made up of small red spots known as ‘petechiae’ or ‘purpura’, mostly on your legs.

How is it diagnosed?

You will probably have already seen your paediatrician for blood tests to explain his or her symptoms. The results of these tests – particularly the full blood count – may show the bone marrow is not producing enough healthy blood cells. While this test is useful, it cannot prove your child has aplastic anaemia. Sometimes, the symptoms and test results of aplastic anaemia can be confused with leukaemia. At this stage, your child will usually be referred to a paediatric haematologist – a doctor specialising in blood disorders affecting children. The only method of diagnosing aplastic anaemia with certainty, is by examining a sample of bone marrow under a microscope. If your child has aplastic anaemia, the results will show fewer normal cells than usual, whereas in leukaemia there will also be abnormal cancer cells too. Your child’s haematologist may also suggest other tests to rule out other causes of bone marrow failure, and genetic studies to rule out the rarer, inherited form of aplastic anaemia. Once your child has been diagnosed with aplastic anaemia, the severity of his or her condition will be classified as follows:

Very severe
  • Neutrophils less than 0.2 x 109/l
  • Platelets less than 20 x 109/l
  • Bone marrow activity less than 30%
Severe
  • Neutrophils less than 0.5 x 109/l
  • Platelets less than 20 x 109/l
  • Bone marrow activity less than 30%
Non-severe
  • All cases which do not follow the above classification

What treatments are available?

The aim of treatment for aplastic anaemia is two fold – supportive management to correct your child’s initial symptoms and treatment of the bone marrow failure.

Supportive management

When your child is diagnosed with aplastic anaemia, the first treatment is to correct his or her blood count. This may involve blood transfusions of platelets and red blood cells. All blood is screened to reduce the risk of reactions. If your child develops a temperature or becomes unwell especially if they are neutropenic, this will need to be treated immediately with antibiotics. While this treatment should improve your child’s symptoms, it will not treat the underlying condition.

Treatment options

Until recently, children and adults with idiopathic aplastic anaemia have been treated in a similar manner. Children are, however, very different to adults. They are more likely to have an inherited form of aplastic anaemia. They also do better than adults with stronger treatment options such as bone marrow transplantation. The best treatment for idiopathic aplastic anaemia remains a bone marrow transplant from a brother or sister who is a tissue match. A quarter of children will be able to have a matched sibling bone marrow transplant. For those children who do not have a matched sibling, we have in the past given them immunosuppressive treatment with a medicine called ATG and ciclosporin. This is a relatively safe treatment, but only works in six out of ten children at best. However, even when it works, it is not perfect; many children relapse after successful ATG treatment, or develop further bone marrow problems later. Even when blood counts do respond following ATG, they often tend to be low. In the four out of ten children in whom ATG has had no benefit, we have then historically recommended a bone marrow transplant from a closely matched unrelated volunteer donor. We call this type of transplant a matched unrelated donor (MUD) transplant. Results from this type of transplant have now become so good that they are similar to the results seen with transplants from matched siblings. Currently nine out of ten children, who have not responded to ATG, are cured with matched unrelated donor transplants. Due to the excellent results now seen with matched unrelated donor transplants in childhood idiopathic aplastic anaemia, many paediatric haematologists are offering unrelated donor transplants upfront, rather than waiting to see if children respond to ATG. Not all children will have a matched unrelated donor and so for them treatment with ATG will continue to be the best option. Parents will need to discuss with their clinician which option would be best for their child. More information about each follows:

Bone marrow transplantation

This replaces your child’s defective bone marrow with a healthy one. As with blood transfusions and organ transplantation, the donated bone marrow has to be a good match for your child’s body, to reduce the risk of it being rejected. When your child is diagnosed, we will take blood samples from your other children and yourselves, to see whether you or your children are a good match. During the bone marrow transplant your child will need to have chemotherapy to damp down their immune system. This will prevent your child’s body rejecting the donated bone marrow. The bone marrow itself is given like a blood transfusion. It takes a few weeks for the bone marrow to engraft or take root, and during that time your child will need to stay in hospital, as they will be at risk of infection.

Immunosuppressive therapy

The aim of this treatment is to reduce the number of lymphocytes circulating in the bloodstream using medicines called antithymocyte globulin (ATG) and ciclosporin, which stimulate the bone marrow to restart blood cell production. The ATG is given intravenously through the central venous access device over a period of five days. There is a chance your child could have an allergic reaction to ATG which originates from horse serum (part of the blood), but this usually occurs during the first few days of treatment. Over the next few weeks, a problem called serum sickness can occur, which can cause high temperatures, rashes and swollen, painful joints. This is uncomfortable but can be treated successfully with steroids. The ciclosporin is given by mouth. The main side effect of ciclosporin is extra hair growth on the body, which may be quite obvious on the face. This will stop when the ciclosporin is stopped. It can take a while for the blood counts to recover using this treatment, sometimes taking many months. During this time, your child will continue to be at risk from infection and bleeding, and so may still need transfusions of platelets and red blood cells. Other drugs are often given alongside ATG and ciclosporin. The main drug used is prednisolone, a steroid which helps deal with any side effects from ALG. These drugs can cause your child’s appetite to increase, which may show as weight gain on the face. The steroids are usually given in short burst of treatment, to minimise the side effects.

What is the outlook for children with aplastic anaemia?

Your child will need to have regular check-ups for a few years after treatment has finished, as some children can relapse and develop aplastic anaemia again. These check-ups will usually involve blood tests to check their full blood count. However, theywill also be checked for any long-term side effects of both aplastic anaemia and the treatments used.