Aplastic anaemia

Written by Professor TJ Hamblin, consultant haematologist

What can your doctor do?
Whenever pancytopenia is suspected on the basis of the symptoms described above, your doctor should request a full blood count.

If the blood count shows reduced numbers of red cells, white cells and platelets he should request an urgent referral to a haematologist. The haematologist should see you within 48 hours.

What else could it be?
The most important distinction that the haematologist must make is between aplastic anaemia and acute leukaemia, which can show very similar blood pictures. For this reason a bone marrow sample is essential. The doctor will take samples both of the fluid of the bone marrow (an aspirate) and of the more solid bone marrow structure (a trephine biopsy). For most cases the diagnosis is easily made.

In acute leukaemia the marrow is full of abnormal cells but in aplastic anaemia it is empty and comprises mainly fat spaces.

Other possible diagnoses will also be sorted out by the bone marrow. Myelodysplastic syndrome is one in which there is faulty blood cell production by abnormal bone marrow cells rather than by the lack of precursor cells. It also causes pancytopenia but the bone marrow is full of cells that are recognisably abnormal.

Some cases of megaloblastic anaemia (including pernicious anaemia) also have pancytopenia, but again the bone marrow is characteristically full of cells. The doctor will also measure blood levels of vitamin B12 and folic acid to exclude this possibility.

Any condition that infiltrates the bone marrow can also cause pancytopenia, but these should be diagnosable by the bone marrow investigation. Likely conditions include lymphoma, myeloma and secondary cancer.

Occasionally some of these conditions may present with empty bone marrows just like aplastic anaemia. Experts can sometimes distinguish small numbers of leukaemic cells or myelodysplastic cells and are therefore able to make the diagnosis of hypoplastic (underdeveloped) acute leukaemia or hypoplastic myelodysplastic syndrome. Sometimes these conditions supervene after treatment of the aplastic anaemia, and the assumption is that they have been there all along.

An important supplementary diagnosis is paroxysmal nocturnal haemoglobinuria (PNH). In this condition the red cells lack a special molecule on their surface that is used to anchor many other types of protein to the membrane of the red cell - known as the phosphatidylinositol glycan (GPI) anchor. As a consequence, the red cells are very susceptible to destruction (haemolysis). It has been known for a long time that the two conditions can occur together. PNH has been described as occurring in between 15 and 52 per cent of people with aplastic anaemia at diagnosis. The diagnosis of PNH is important because it can lead to problems with thrombosis (blood clots) and difficulties with blood transfusion.

What can you do yourself?
It is important that you take charge of your illness:

try to find out all you can about aplastic anaemia and the various treatment options.

don't be afraid to ask questions of your doctor and other patients.

you could encourage your friends and family to become blood and bone marrow donors.

join a support group and read about ways to cope.

check with your doctor about what things to avoid like salads and soft cheeses, which carry some infection risk.

your doctor will also give you advice about how to recognise the first signs of infection.

you should take your temperature regularly.

it is dangerous to live too far from a hospital capable of giving the right sort of supportive care.

before trying complementary therapies, always consult your doctor.

What can your doctor do?
The first thing your doctor will do is ask about the various drugs and toxins that could have caused the disease, and make sure that they are avoided in future.

He will then take blood samples to tissue type you and your close relatives in case a bone marrow transplant is needed. Severe and very severe aplastic anaemia are life-threatening conditions that need to be taken very seriously. Leaving the disease untreated is not an option.

Supportive care
Patients with mild aplastic anaemia will only require supportive care and often very little of that. Sometimes all that is needed is to remove the noxious agent and wait to see if spontaneous recovery will occur.

Even if you are going to receive a bone marrow transplant or immunosuppressive therapy you will need short-term treatment to protect you from the consequences of pancytopenia.

Infections are the major hazard. This is especially so if you need an indwelling (Hickman-like) intravenous line. These are catheters that are inserted in to the main veins within the chest and can be left in place for a long time in order to give chemotherapy drugs repeatedly. In general prophylactic or 'just in case' antibiotics are not favoured and your best protection is vigilance. A fever of 38oC lasting more than two hours requires antibiotics in hospital. Your doctors may change the antibiotics depending on the results of the bacterial investigations or response to treatment.

Platelet transfusions are given to lessen the risk of bleeding. It is now usual practice to restrict these to patients who are actually bleeding or those whose platelet count falls to below 10 x 109/L. Platelet transfusions should be screened to ensure they are free of contamination with cytomegalovirus (CMV) as this virus can interfere with immunity. They should also be depleted of white blood cells and, if being used after bone marrow transplantation or immunosuppression they should also be exposed to X-ray sterilisation.

Red cell transfusions should also carry the same provisos, and are given for anaemia severe enough to be causing symptoms. Patient who require long-term red cell support from repeated transfusions are at risk from building up excess iron within the body and may require iron-removing treatment (chelation therapy) with desferrioxamine.

Bone marrow transplantation from a sibling
For patients aged 50 or less with severe or very severe aplastic anaemia who have an HL-A compatible sibling (ie a 'close match' in tissue type), bone marrow transplantation is the treatment of choice.

This means that stem cells will be harvested from your brother or sister. This can either be done in the operating theatre under a general anaesthetic or, increasingly these days, in the day-ward using a cell separator.

Under general anaesthetic, bone marrow is sucked out of the hipbones on either side through a hollow needle. About 4 per cent of the marrow is extracted in this way.

Using the cell separator, the donor's arm veins are connected via plastic tubes to a large machine that works something like a spin dryer. The process separates the stem cells (which are retained) from the rest of the blood (which is returned to the donor). About 10 litres of blood are processed on each occasion. In either case the stem cells are transfused into the recipient just like a bag of blood. Before this happens the patient must receive conditioning treatment to allow the donor cells to 'take'.

For aplastic anaemia 'non-ablative' conditioning is used. This comprises large doses of cyclophosphamide and avoids radiotherapy. This preserves fertility, and reduces the risk of lung disease and secondary malignancy, but increases the risk of rejection. Graft rejection is prevented by ciclosporin therapy.

Immunosuppressive therapy
In patients over the age of 50 and those without an HL-A compatible sibling, immunosuppression is the treatment of choice. The best regimen is a combination of anti-thymocyte globulin (ATG) and ciclosporin. ATG is an antibody which acts against T-lymphocyes - another type of white cell which is probably involved in the immune attack of the bone marrow. There are data to suggest that patients failing to respond to ATG have a 43 per cent chance of responding to a second course.

Patients treated by immunosuppression have a much higher risk than those treated by bone marrow transplantation of developing another disorder of the bone marrow, such as PNH, acute leukaemia or myelodysplastic syndrome (these are known as 'clonal' marrow disorders). Factors that increase the risk of these complications are:

age at diagnosis

multiple courses of immunosuppression

previous removal of the spleen

the addition of androgens (male sex hormones, which have been used in some previous treatment regimes).

Bone marrow transplantation and immunosuppression compared
The survival rate for 168 patients transplanted at Seattle between 1978 and 1991 was 69 per cent at 15 years. The 15-year survival rate for 227 patients treated by immunosuppression was only 38 per cent. The difference in mortality is attributable to the development of clonal marrow disorders, but the group treated by immunosuppression was older. Recent papers have suggested that the outcome for bone marrow transplantation is still improving with 90 per cent success rates for children and young adults.

Treatment failures Bone marrow transplant from a matched volunteer donor or a partially matched family donor carries a greater risk of graft failure or severe graft-versus-host disease. The risk is most acceptable in patients aged less than 20 and should be offered to such patients who fail the first round of immunosuppressive therapy and to patients under 40 who fail a second round. For older patients, further courses of ATG are an option, together with androgens, cytokines (small proteins released by cells which influence the behaviour of other cells) and experimental therapies.

Living with aplastic anaemia
Patients will need to steel themselves, at least initially, to a life dependent on the local haematology service. While it is possible to continue working or schooling, there are certain restrictions. Bodily contact sports must be avoided and a close watch must be kept for infection. Transfusions will be a regular interruption. Some infections proceed very rapidly and need instant remedies, hence the need for close contact with the haematology service.

All of the therapies carry side effects. ATG may cause a fever and often leads to 'serum sickness'. During this phase there may be rashes and joint pains.

Ciclosporin can also cause problems with unusual hair growth and gum swelling. In higher doses it can cause high blood pressure and kidney failure.

For these reason blood levels have to be regularly monitored. The major complication of bone marrow transplantation is graft-versus-host disease. This shows itself as a rash, diarrhoea or liver abnormalities.

Support for patients
The Aplastic Anaemia Support Group, 16 Sidney Road, Borstal, Rochester ME1 3HF. Tel: 0870 487 0099. Email: aplasticanaemia@hotmail.com .

The Leukaemia Research Fund (LRF) publishes a useful booklet and supports research into aplastic anaemia. Leukaemia Research Fund, 43 Great Ormond Street, London WC1N 3JJ. Tel: 020 7405 0101. Fax: 020 7242 1488. Email: info@lrf.org.uk.

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