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Thrombocytosis and essential thrombocythaemia
Written by Dr Claire N Harrison, Consultant Haematologist, St Thomas' Hospital, London and Professor Samuel J Machin, Department of Haematology, University College London Hospital
Medicines
Rarely, some medicines (steroids, vincristine) cause a temporary increase in platelet count. These drugs are sometimes used to treat patients with a low platelet count because of idiopathic thrombocytopenic purpura .
Underactive or absent spleen
The spleen removes platelets from your blood; if it is removed the platelet count usually increases. The increase may remain for a long time, but usually it settles back into the normal range.
In some conditions the spleen is present but either it does not function properly (for example in some patients with Coeliac disease) or it is shrunken (for example in sickle cell disease). The platelet count is sometimes elevated in these conditions.
Examination of blood cells under a microscope may reveal changes that suggest impaired function of the spleen.
Malignancy
Some cancers can cause a high platelet count either by causing damage to tissues, causing blood loss (for example from the bowel) or by erroneously producing a response from the immune system that stimulates the bone marrow to produce platelets.
Rebound from chemotherapy
Some chemotherapy drugs work directly on dividing cells in the body - including the bone marrow where platelets are made. When the body is recovering from the effects of chemotherapy, a temporary overproduction of some cells can occur.
How is RT treated?
The major complications that usually arise in RT relate to the underlying cause of the high platelet count. For this reason, treatment should be directed at the underlying condition.
In rare circumstances, some treatment to protect against inappropriate clot formation might be advised, for example:
Less often, drugs such as aspirin and anticoagulants such as heparin injections may be used.
Thrombocytosis due to a bone marrow disorder
A high platelet count can occur in a number of different bone marrow diseases but most especially in the myeloproliferative diseases, chronic myeloid leukaemia, and the myelodysplastic syndromes.
A high platelet count can occur in any of these conditions, but in each an increase in a particular cell type is more likely. These are:
Chronic myeloid leukaemia
Myelodysplastic syndromes (MDS)
Sometimes it can be difficult to distinguish between a myelodysplastic syndrome and an MPD. You may be classified as having an overlap syndrome.
Essential thrombocythaemia (ET)
When the bone marrow of people with ET is examined, there is an increase in the platelet producing cells, called the megakaryocytes (see Figure 1).
Who is most at risk of ET?
It has been estimated that one person in about every 100,000 to 150,000 will be diagnosed with ET every year.
What problems does this blood disorder cause?
Although the extent of complications varies from 40 to 90 per cent, these differences probably relate to the fact that ET is a rare disorder, so the medical literature is based on relatively small numbers of affected people.
The table below shows some of the clotting and bleeding problems that can occur with ET.
The risk of developing acute leukaemia is increased by some of the drugs used in the treatment of ET. Both acute leukaemia and MF are difficult to treat. The leukaemia is often more resistant to drugs used in its treatment and MF may require regular transfusion as well as removal of the enlarged spleen.
These complications, in particular clotting (thrombotic) episodes, are the major cause of ill health in patients with ET and they also have a significant impact on survival.
What factors influence the complications in ET?
There is an increased risk of bleeding in some ET patients with a platelet count over 1500 million per ml, due to the platelets affecting a protein known as von Willebrand factor, which is important for normal clotting.
Clotting complications
Risk factors for arterial disease (high blood pressure, smoking and diabetes) will influence the chance of a clot affecting the arteries.
There are a number of conditions that make clots in the veins more likely, for example deficiencies of proteins C, S, antithrombin III, Factor V Leiden mutation and antiphospholipid antibodies. It is not known how these affect the development of clots in ET.
What causes this disorder?
JAK2 is a protein that functions as a signal to regulate cell functions. It sends messages in the cell, telling it to grow and make more cells, or else to stop when the body does not need more cells.
Researchers believe that in MPD patients, the mutation in JAK2 enhances messages asking for more cell production. The result is too many blood cells which clog the blood and make it sticky.
The JAK2 mutation (also called the V617F JAK2) is found in about:
The test for the JAK2 mutation is very simple and can be done on a teaspoon of blood; results generally take 1-2 weeks.
It's thought the JAK2 mutation is likely to occur as a result of some damage to the bone marrow, for example as a result of viral infections or background radiation.
Genes
Research has found that affected members of some families have the JAK2 mutation whereas others do not.
In some of these families there is a disruption in the production of a hormone (cytokine) called thrombopoietin, which regulates platelet production.
Hormone disruption
How is ET diagnosed?
Your doctor has to check that the high platelet count is not secondary to another cause or due to one of the other bone marrow disorders that are also associated with thrombocytosis.
Usually a haematologist (blood specialist) will also review the patient, and look for features of one of the other diseases or for a clue to the diagnosis of ET such as an enlarged spleen.
Some of the routine tests that are used as well as blood tests are a chest X-ray, an ultrasound or other scan of the abdomen, and a bone marrow test.
The bone marrow test involves taking a sample from the bones at the back of the pelvis under a local anaesthetic. It is used to exclude the other blood conditions that cause high platelet counts.
Sometimes it is difficult to be certain that the diagnosis is ET and extra tests are done to look for blood loss from the bowel or to check for polycythaemia vera.
What treatment is available?
The benefits of using medicines must be weighed against their side-effects.
Sometimes drugs that work in a similar manner to aspirin are used instead. Examples are dipyridamole and clopidogrel.
Some patients are also treated with warfarin, especially if you have recently had a blood clot in a vein or have had multiple clots.
Most people with ET, with the possible exception of those with increased bleeding risk or a very high platelet count, will be advised to take aspirin or a similar drug.
Medicines that reduce the number of platelets in your blood
Hydroxycarbamide has relatively few side-effects including some darkening of skin pigment, mouth and leg ulcers and rarely stomach and bowel disturbance. It can damage DNA and may affect fertility, so shouldn't be used by pregnant women or those trying to conceive.
There have been concerns that this medicine may increase the risk of ET transforming into acute leukaemia. Though yet to be proven, the chance of this occurring is likely to be in less than 5 per cent of patients over a period of 10 years.
Melphalan, busulfan and radioactive phosphorus (32P): these drugs belong to a group medicines called alkylating agents and used to be the main treatment for ET. They reduce cell count by binding to DNA and damaging it, preventing complete separation of the two DNA strands at cell division. This means these medicines can permanently damage fertility and the bone marrow.
They increase the risk of ET turning into a form of acute leukaemia, probably in about 5-10 per cent of patients over 10 years.
Busulfan and 32P are still used to treat ET when other drugs don't work, cause unacceptable side-effects or if you can't take the hydroxycarbamide tablets.
Interferon-alpha: this is a naturally occurring protein that inhibits the growth of bone marrow cells. It has to be given by injection, usually three times a week.
Interferon-alpha is used in some patients with ET, particularly in young people who want to preserve their fertility. It is the only drug used to treat ET that can be safely given to pregnant women.
It has many side-effects, including flu-like symptoms, hair loss, depression, liver and thyroid abnormalities: a high proportion of patients who are prescribed this drug will not be able to continue using it.
Anagrelide: this drug specifically lowers the platelet count. It appears to work by reducing the size of the platelet-producing cells within the bone marrow (the megakaryocytes).
Anagrelide should not affect fertility or increase the risk of developing acute leukaemia. It cannot be taken in pregnancy because it will cross the placenta and transfer to the baby's blood.
Side-effects include headache, palpitations (forceful heart beats) and fluid retention. It must be used with caution in those with heart disease.
An international study by the Medical Research Council investigated the benefit of treatment with aspirin and either hydroxycarbamide or anagrelide in patients at high risk of clotting. It found hydroxycarbamide with aspirin was better at preventing clots in arteries, bleeding and progression to myelofibrosis.
Anagrelide was better at preventing clots in veins, but these clots are far less common in ET. As a result, anagrelide is licensed for use in patients where initial drug treatment has failed or is not tolerated.
Blood filtering: a sophisticated blood-filtering technique called plateletpheresis is used very rarely and only in acute life-threatening situations. This involves taking the patient's blood into a special machine, removing some of the platelets and returning the blood. It achieves a rapid, but temporary, control of the platelet count.
Pregnancy and ET
ET is not an absolute barrier to pregnancy, but pregnancy itself is associated with an increased risk of clotting, which is likely to be magnified by your already high risk.
ET appears to make miscarriage more likely and cause foetal growth problems later in pregnancy (intrauterine growth retardation). It's thought these complications occur because the blood flow to the placenta is compromised either by clot or drifts of platelets.
Although the platelet count normally reduces somewhat during pregnancy, most haematologists would consider the use of interferon, particularly if the platelet count is greater than 1000 million per ml with a history of thrombosis, or if you were already having treatment.
Many pregnant women will also be given aspirin and some will receive the anticoagulant drug heparin to minimise the risk of clotting.
What is the outlook for people with ET?
In the absence of severe complications, you can probably expect a near normal lifespan. If acute leukaemia or myelofibrosis develop, the outlook is less good and survival more limited.
Further information
Chronic myeloid leukaemia used to be grouped with the MPDs. It is now classified independently because its course is very different, and it has a distinct biology.
This is a group of conditions in which the bone marrow does not function properly and doesn't make enough blood cells. Usually the platelet count is low, but in certain subtypes of this disease it may be higher.
The blood disorder that is characterised by a high platelet count is primary thrombocytosis (PT), also called essential thrombocythaemia (ET).
ET is usually diagnosed in people aged 60 and above, but it appears to be on the increase in people under 40 years of age - particularly in women. This may be a result of more sophisticated blood cell counters in the past 30 years that can automatically count platelets and make the diagnosis more often.
Some people with ET can suffer from bleeding or clotting due to their disease, but others have no symptoms at all.
Less commonly, ET can cause acute myeloid leukaemia or a condition known as myelofibrosis (MF) where fibrous tissues scar and stiffen the bone marrow leading to reduced cell production and an enlarged spleen.
Complication
Minor events due to clotting
Headache
Major events due to clotting
Deep vein thrombosis (blood clot in deep veins of the leg)
Haemmorrhagic events
Nosebleeds
The biggest risk factors for clotting events are:
Until recently, the cause of ET was a mystery. Now there have been several breakthroughs.
While unusual, ET can be hereditary; this is known as familial thrombocytosis.
In the Summer of 2006 a further mutation was identified in a receptor for thrombopoietin in about 1 in 20 ET patients. This is also thought to be responsible for the disease.
There is no simple test to decide if a person has ET. A test for the JAK2 mutation can be done, but even if it is negative you may still have a bone marrow disease.
Medicines can help to limit the risk of bleeding and clotting complications in ET by:
Hydroxycarbamide: previously known as hydroxyurea, this drug works by interfering with the cell's metabolism. It is a common treatment for ET and usually needs to be taken daily. Your blood count will be monitored at least every two to three months.
Many of the drug treatments are toxic to sperm and foetus. If you want to start a family, talk to your haematologist about whether it's possible to change medication.
Your outlook depends on whether ET causes clotting or bleeding disorders that affect your quality of life. There is some disagreement as to whether people with ET have any worse prognosis than healthy individuals of the same age.
For more help and information about essential thrombocythaemia, contact the patient support group MPD-Support.
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