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What is thrombocytopenia?

Thrombocytopenia is the term for a reduced platelet (thrombocyte) count. It occurs when platelets are lost from the circulation faster than they can be replaced from the bone marrow where they are made.

Thrombocytopenia may either result from a failure of platelet production and/or an increased rate of removal from blood.

What are platelets?

Platelets are tiny cells which circulate in the blood and whose function is to take part in the clotting process. (see Figure 1) Inside each platelet are many granules, containing compounds that enhance the ability of platelets to stick to each other and also to the surface of a damaged blood vessel wall.

The platelet count in the circulating blood is normally between 150 and 400 million per millilitre of blood (x109/L). Newborn babies have a slightly lower level, but are normally within the adult range by three months of age.

Many factors can influence an individual’s platelet count including exercise and racial origin. The average life span of a platelet in the blood is approximately 10 days.

What do platelets do?

Platelets are essential in the formation of blood clots to prevent haemorrhage – bleeding from a ruptured blood vessel.

An adequate number of normally functioning platelets is also needed to prevent leakage of red blood cells from apparently uninjured vessels.

In the event of a haemorrhage, muscles in the vessel wall contract and reduce blood flow. The platelets then stick to each other (aggregation) and hold on to the vessel wall (this is called primary haemostasis). The coagulation factors are then ‘activated’ resulting in normally liquid blood becoming an insoluble clot or glue.

What are the risks of a low platelet count?

The main effect of a reduced platelet count is an increased risk of bleeding, but this rarely occurs until there are less than 80-100 million platelets per ml (x109/L).

There is not a close relationship between the number of platelets and the severity of bleeding, but there is an increasing risk of haemorrhage if platelet numbers fall or if platelet function is impaired (for example by aspirin, which reduces the ’stickiness’ of the platelets).

There is a particularly high risk of spontaneous bleeding once the platelet count drops below 10 million per ml. The bleeding is usually seen on the skin in the form of tiny pin-prick haemorrhages (purpura), or bruises (ecchymoses) following minor trauma.

Bleeding from the nose and the gums is also quite common. More serious haemorrhage can occur at the back of the eye (retina), sometimes threatening sight. But the most serious complication, which is potentially fatal, is spontaneous bleeding inside the head (intracranial) or from the lining of the gut (gastrointestinal).

What causes a low platelet count?

The different causes of a low platelet count are described below.

Artefactual thrombocytopenia

Some people have platelets that stick together due to the presence of proteins in the blood (antibodies) that bind to the platelets. These antibodies, which are formed by the immune system of the body also bind to a chemical in blood that is tested in test tubes, giving a falsely low platelet count. So it can be helpful to repeat the sample in different tubes with different chemicals. The platelet count can also be reduced if the blood sample is difficult to take and the blood clots - thus using up some of the platelets.

Congenital thrombocytopenia

Several rare inherited diseases cause low platelet counts. The severity of the thrombocytopenia varies with the condition and also the individual patient. In some of these conditions, eg May Hegglin anomaly, bleeding does not often occur, whereas in other inherited diseases, eg Bernard Soulier syndrome, the platelets function less well and lifelong bleeding symptoms can occur.

Impaired platelet production

Platelets, as with the rest of the blood cells, are produced within the bone marrow and the cells from which platelets originate are called megakaryocytes. If there is a problem in the bone marrow, for example because of a build-up of abnormal cells due to some other reason, then the number of megakaryocytes will be reduced, thus lowering the number of platelets that can be produced.

Examples of abnormal cells accumulating in the bone marrow include acute leukaemia where leukaemic cells, or ‘blasts’, are seen, and other abnormal cancer cells such as lymphoma, or more rarely cancers developing in another part of the body (such as the breast or prostate gland) which have spread (metastasised) to the bone marrow.

Alternatively the platelet production process may be abnormal and so although the number of precursors may be normal, adequate numbers of platelets are not produced. Impaired platelet production can also be due to the toxic side effects of drugs such as chemotherapy (anti-cancer) agents, alcohol, or viral infections, such as HIV, or due to an abnormality of the bone marrow called myelodysplasia.

Sometimes platelet production may be impaired due to an abnormality of the bone marrow cells which are not involved in blood production, but make up the structural parts of the marrow (called the ’stroma’).

An example of this is the inherited condition called marble bone disease, or osteopetrosis, where increased bone formation occurs at the expense of bone marrow.

A similar but not inherited condition called myelofibrosis is characterised by massively increased fibrous tissue, which impairs platelet production as well as the production of other blood cells.

Increased platelet destruction

Platelet numbers fall if they are removed from the circulation more rapidly than they are produced. Platelets are removed for several reasons. They may be coated with an antibody, or are clumped together and then removed, or they may not be removed but are used up by a condition in which the blood clotting process is inappropriately ’switched on’ called disseminated intravascular coagulation (DIC).

DIC can happen in several different conditions, including severe infections such as meningitis, as a complication of pregnancy or labour (eg high blood pressure and pre-eclampsia), in some cancers (specifically types of acute myeloid leukaemia and prostate cancer) and in some rare blood disorders such as thrombotic thrombocytopenic purpura or the haemolytic uraemic syndrome (sometimes due to food poisoning outbreaks).

Antibodies that cause platelet removal can be due to infections such as HIV, or to the presence of drugs - eg the anti-malaria drug quinine. Sometimes antibodies causing thrombocytopenia arise in a patient with a specific disease in which abnormal production of other antibodies may occur. These include so-called autoimmune disorders such as rheumatoid arthritis or systemic lupus erythematosis, or the blood disease chronic lymphocytic leukaemia. But the antibodies can also occur in someone who is completely well - known as idiopathic or unknown cause.

Abnormal distribution of platelets

Thrombocytopenia may be due to a build up of platelets outside the normal blood ‘pool’, eg in a patient with a very large spleen.

Dilution of platelets

When a patient is massively transfused with a large volume of red blood cells, which do not contain platelets, the platelet count can fall because of dilution of normal blood factors.

These different causes of thrombocytopenia are not mutually exclusive and more than one may be responsible for an abnormal platelet count. For example, platelet production may be impaired in a baby deprived of oxygen at birth, but these babies are also susceptible to infections that might cause worsening of thrombocytopenia due to DIC.

A summary of the causes of thrombocytopenia is provided below.

Artefactual (false) thrombocytopenia

• Clot in the sample.

• Platelets clumped.

Congenital thrombocytopenia

• Rare inherited disorders (eg May Hegglin Anomaly or Bernard Soulier syndrome).

Defective platelet production

• Bone marrow aplasia (failure).

• Metabolic disorders (shortage of vitamin B12 or folic acid, kidney failure, alcohol).

• Abnormal platelet precursors (viral infections, inherited abnormalities).

• Abnormal bone marrow (preleukaemia).

• Bone marrow infiltration (leukaemia, lymphoma, myeloma, marble bone disease).

Loss of platelets from the circulation

• Massive or exchange transfusion (dilution).

• Enlarged spleen (abnormal distribution).

Diminished platelet survival

• Immune mediated (antibodies due to drugs, blood transfusion, another autoimmune disease, or idiopathic [ITP]).

• Other mechanisms (malaria, glandular fever, AIDS, drugs).

• Disseminated intravascular coagulation (DIC).

• Thrombotic thrombocytopenic purpura.

• Leaking artificial heart valves.

How is thrombocytopenia diagnosed?

Investigation usually starts with asking the person for their history of symptoms, signs of bleeding or bruising, other medical problems, recent infections, medications (prescribed and bought over the counter). In the haematology laboratory the scientist and the doctor perform a full blood count and examine the blood film (see Figure 1) under a microscope as well as the sample in the test tube. A repeat full blood count sample is usually requested to confirm the result and see if it is a persisting abnormality.

Depending upon both the severity of the platelet lack and the likely cause, the person is likely to be referred to a haematologist at the hospital. If the platelet count is very low the person may need to be seen on the same day, and have a bone marrow test performed. A bone marrow test is usually done under local anaesthetic - the samples are usually taken from the back of the pelvis. This test helps the haematologist to decide if platelets are being produced normally and whether the rest of the bone marrow appears normal. Further tests, such as genetic tests, can also be done on a bone marrow sample.

What treatment is available?

The choice of treatment depends upon the severity of thrombocytopenia, its cause and the presence or absence of haemorrhage.

Treatment of acute bleeding

If life-threatening bleeding (eg into the head or bowel) occurs then urgent treatment with platelet concentrates provided by the blood transfusion service is required (see Figure 2). However, in the condition known as thrombotic thrombocytopenia purpura the use of platelet concentrates is in fact particularly hazardous. The usefulness of platelet concentrates is monitored both by measuring the platelet count and also by assessing any continuing haemorrhage. The management of acute bleeding in a patient also involves treatment of the underlying cause of the low platelets.

Treatment of the underlying cause

When there is no major haemorrhage the treatment is aimed at the cause of the low platelet count. If a drug is thought to be the cause then it is stopped (providing this is safe) and the platelet count monitored. If an infection is suspected then treatment for that infection, eg with antibiotics, could be started. For some infections, especially viral ones such as glandular fever (caused by Epstein Barr virus), there is no specific treatment and close observation may be necessary.

When an infection results in thrombocytopenia by causing DIC then treatment tackles not only the underlying infection but also the DIC using blood components to replace the clotting factors and platelets that are consumed during the DIC process.

If platelet production fails due to the presence of abnormal or malignant cells, eg leukaemia, then treatment is directed at those abnormal cells – such as chemo- or radiotherapy. This can temporarily damage the bone marrow and worsen the thrombocytopenia. In this situation platelet transfusions are given before bleeding occurs if the platelet count becomes very low. This is continued until the platelet count reaches a safer level or the bone marrow recovers its ability to maintain a safe platelet count.

Specific types of thrombocytopenia include:

• idiopathic thrombocytopenic purpura (ITP)

• thrombotic thrombocytopenic purpura (TTP)

• haemolytic uraemic syndrome.