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Thrombophilia is the increased tendency to develop thrombosis (blood clots) in the veins due to a genetic abnormality in the clotting system of the body. In this section of the website, the Lifeblood Medical Director, Dr Beverley Hunt, explains in detail the problem of thrombophilia.
Genetic thrombophilia
The term genetic thrombophilia covers a range of conditions that are inherited by someone at birth. This means that their blood is sticker than normal, which increases the risk of blood clots in the veins. Factor V Leiden and Prothrombin 20210 are the most common thrombophilias among people of European origin. Other genetic thrombophilias include Protein C deficiency, Protein S deficiency, and antithrombin deficiency.
Download our information leaflet on genetic thrombophilia.
Factor V Leiden
Factor V Leiden is by far the most common genetic thrombophilia. In the UK it is present in 1 in 20 individuals of European origin; it is most common in those from the Middle Eastern extraction (present in up to 70% of the population), but rare in people of Afro Caribbean or Asian origin. Factor V Leiden is caused by a change in the gene for Factor V, which helps the blood to clot. To stop a clot spreading a natural blood thinner, known as Protein C, breaks down Factor V.
Download our information leaflet on Factor V Leiden for more information .
Prothrombin 20210
Prothrombin is one of the blood clotting factors. It circulates in the blood and when activated, is converted to thrombin. Thrombin causes fibrinogen, another clotting factor, to convert to fibrin strands, which make up part of a clot. The condition known as Prothrombin 20210 is due to a mutation of the prothrombin gene. Individuals with the condition tend to have slightly stickier blood, due to higher prothrombin levels. Prothrombin 20210 is present in 2 in 100 people of European origin. This means that the risk of having a venous thrombosis is twice that of someone without the condition. Prothrombin 20210 does not increase the risk of arterial thrombosis, so there is no increased risk of heart attacks or strokes.
Download our information leaflet for more information.
Protein C deficiency
Protein C is one of the natural anticoagulants found in the blood. Those who have insufficient Protein C are more likely to have a venous thrombosis. Inheritance of Protein C deficiency Protein C is inherited in an autosomal dominant way. This means that if you have it, there is a 50:50 chance that your children will inherit it. There is an extremely rare chance (less than one in a million) of a child being born with a double dose of Protein C deficiency. This is known as homozygous Protein C deficiency. Babies born with this condition have spontaneous skin thromboses soon after birth and require Protein C concentrates or other anticoagulants to keep them healthy and free from thrombosis.
Download our information leaflet for more information.
Protein S deficiency
Protein S is one of the natural anticoagulants found in the blood. Those who have insufficient Protein S are more likely to have a venous thrombosis.
Download our information leaflet for more information.
Antithrombin deficiency
Antithrombin (previously known as antithrombin III) is one of the natural anticoagulants found in the blood and deficiency affects 1 in 5000 people. People who have insufficient antithrombin are more likely to have a venous thrombosis
Download our information on antithrombin deficiency leaflet for more information.
Acquired thrombophilia
Acquired thrombophilias are tendencies to clot that usually develop in adulthood or older age, and are not inherited.
Antiphospholipid or Hughes' syndrome
Antiphospholipid syndrome (APS) results from the presence of antiphospholipid antibodies in the blood, combined with a previous thrombosis, specific problems during pregnancy, or both. It is also known as Hughes' syndrome, after Dr Graham Hughes, who first described the condition in the British Medical Journal in 1983 (Hughes, GRV. Thrombosis, abortion, cerebral disease and lupus anticoagulant. BMJ 1983; 287: 1088-9).
APS and thrombosis
Unlike the other thrombophilias, which tend to cause venous thrombosis, antiphospholipid antibodies can also lead to arterial thrombosis or thrombosis in small blood vessels. Once someone with APS has had a thrombosis, further thromboses tend to occur in the same area. For example, if an individual has had a stroke, they will tend to have further strokes; if they have had a deep vein thrombosis, they will tend to have further DVT. Antiphospholipid antibodies appear to affect the brain in particular and are a likely cause of strokes in younger people.
APS and pregnancy
Many women with antiphospholipid antibodies do not have any problems during pregnancy. However, some women with antiphospholipid antibodies may have a miscarriage at any point in pregnancy. During the first 12 weeks, the antibodies can inhibit the growth of the early foetal cells. In some pregnant women antiphospholipid antibodies can cause thrombosis in the small and delicate blood vessels of the placenta in the second and third trimesters (14-36 weeks). The placenta is then unable to supply the foetus with enough nutrition, so the foetus may stop growing and may die in extreme cases. Sometimes damage to the placenta prevents the foetus growing to normal size, so the baby is small at birth. This is known as intrauterine growth restriction. In other cases the damaged placenta may lead to pre-eclampsia in the mother. Pre-eclampsia during pregnancy is a potentially dangerous condition, resulting in swelling, leaky kidneys and high blood pressure.
The best way of predicting how well a pregnancy will progress is by looking at what has happened before. If a woman with antiphospholipid antibodies has previously had a normal pregnancy, then it is likely that she will do so again. One area requiring further research is to find a way of predicting whether women with antiphospholipid syndrome who are planning their first pregnancy will have any problems, and if so, what sort of problems are likely.
Other problems related to APS
A number of other symptoms may be seen in individuals with APS. These include: - Blotchy skin (livedo reticularis)
About 10% of individuals with APS have a type of skin blotchiness, known as livedo reticularis. This may be in the form of purplish vein colouration on the thighs, arms and sometimes the trunk. It is useful in making a diagnosis in some cases. - Thrombocytopenia
In a small percentage of people with antiphospholipid antibodies, the blood platelet numbers are reduced below the normal range. This is known as thrombocytopenia. The decrease in platelet count does not usually cause any problems, other than a tendency to bruise easily. It is very rare for platelet counts to fall to dangerously low levels. - Systemic lupus erythematosus
Some individuals with APS may also have systemic lupus erythematosus, or lupus. Lupus affects many thousands of people, particularly women. It is a disorder of the immune system, causing an overproduction of antibodies. This results in a complex illness that includes fatigue, rashes, joint pains and in some cases, potentially life-threatening kidney and brain disease. Evidence suggests that very few individuals with APS go on to develop more generalised lupus. People with APS who do not have lupus outnumber those with the disease. When APS alone is present it is known as primary APS. When it occurs with systemic lupus erythematosus it is known as secondary APS.
Tests for antiphospholipid antibodies
Tests for antiphospholipid antibodies are usually carried out as part of a thrombophilia screen. These include two main tests: anticardiolipin antibodies and the confusingly named lupus anticoagulant. The lupus anticoagulant is a double misnomer, as it is neither a test for lupus, nor is it a test for an anticoagulant. There are major differences between the two tests and some people may show a positive result for one, but not the other. Therefore both tests must be performed, to ensure a diagnosis is made. Based on the test results, an individual's anticardiolipin levels are generally expressed as low, medium or high. However this level is not necessarily an accurate indicator of risk, as some individuals with high anticardiolipin levels never suffer any medical problems, while others with low or medium levels have many thromboses.
Treatment of APS
As for other thrombophilias, treatment for APS involves giving anticoagulant drugs to prevent the antibodies from causing further thrombosis. The three drugs commonly used are aspirin, warfarin and low molecular weight heparin.
Aspirin is given in small doses, such as 75-100mg daily (one quarter aspirin or 'baby aspirin'). It has long been established that aspirin thins the blood by reducing the function of platelets. In cases of recurrent miscarriage, for example, giving aspirin alone has dramatically improved success rates.
If someone has already had a thrombosis, then aspirin is not strong enough to prevent a recurrence. In this case warfarin is usually given. Warfarin (coumadin) is an anticoagulant drug, used worldwide as a blood-thinning agent. For example, most people with a deep vein thrombosis in the leg are given warfarin for six months.
For those with APS, it is usually recommended that warfarin treatment is indefinite and that the blood thinness level is kept higher than for most other conditions. The INR (international normalised ratio) measure of blood thinness for people with APS is kept at 3-4 when they have had a stroke or arterial problem, whereas for patients with other thrombotic risks it tends to be kept at 2-3.
Heparin is usually given to people with APS before and after surgery and during pregnancy. This is because its anticoagulant effects, unlike those of warfarin, can be easily reversed. Also heparin can be used safely throughout pregnancy, whereas warfarin can affect the developing foetus, especially if taken during the first 12 weeks.
Rare thrombotic conditions
Paroxysmal nocturnal haemoglobinuria
Paroxysmal nocturnal haemoglobinuria is an extremely rare condition, and is due to a bone marrow disorder. It can result in a number of problems, including venous thrombosis. In this condition the red cells are prone to break down in the blood (known as haemolysis). The bone marrow then fails, leading to anaemia, low white cell counts (increasing the risk of infection) and low platelet counts. Up to 39% of individuals with this condition have venous thromboses. These thromboses are often unusual, as they may occur in the abdomen – usually in the liver veins – and in the veins draining the brain.
Antithrombin deficiency
Antithrombin (previously known as antithrombin III) is one of the natural anticoagulants found in the blood and deficiency affects 1 in 5000 people. People who have insufficient antithrombin are more likely to have a venous thrombosis
Download our information on antithrombin deficiency leaflet for more information.
Hyperhomocysteinaemia
Homocysteine is an amino acid that, if present at a high level within the blood, is associated with an increased risk of arterial thrombosis, including heart attacks and strokes. This condition is known as hyperhomocysteinaemia. It is believed that high blood levels of homocysteine have a toxic effect, by damaging the lining of the blood vessels (known as the endothelium).
In contrast with the vast body of research conducted on the association between hyperhomocysteinaemia and arterial thrombosis, little research has been carried out to establish the risk of venous thrombosis for individuals with this condition. However, existing research indicates a very small but significant association between elevated homocysteine levels and a minor risk of venous thrombosis.
It is likely that on their own, raised levels of homocysteine are too minor a risk factor to cause any problems. However, this risk increases when it is combined with another risk factor, such as Factor V Leiden. Considerable interest has focused on a mutation in the gene for one of the proteins that breaks down homocysteine. This gene is known as methylenetetrahydrofolate reductase, or MTHFR.
If an individual has two MTHFR genes with what is known as the C677T variant, they are described as homozygotes for MTHFRC677T. This includes between 5 and 20 per cent of the population. People who are homozygotes for MTHFRC677T have a reduced ability to metabolise homocysteine, especially if they are deficient in folic acid.
Treatment of hyperhomocysteineaemia
Treatment includes eating more green vegetables, giving supplements of folic acid, a vitamin present in green vegetables. Clinical studies show that folic acid lowers homocysteine levels by as much as 40 per cent. Vitamins B12 and B6 also have a minor effect in reducing homocysteine levels. Clinical studies also show that by reducing plasma homocysteine levels, there is an improvement in the function of the endothelium (lining of the blood vessels). It is not yet known whether in the long term, folic acid supplementation will reduce the risk of heart attacks and strokes and this question is being addressed through ongoing clinical trials.
Myeloproliferative disorders
Myeloproliferative disorders (MPD) include blood disorders such as polycythaemia vera, idiopathic myelofibrosis, chronic myeloid leukaemia and essential or primary thrombocythaemia (ET). Both polycythaemia vera and essential thrombocythaemia can lead to thrombosis.
Polycythaemia vera
Polycythaemia vera is due to a sustained elevation in the blood's red cell count. There may also be an elevated platelet count and white cell count. Individuals with this condition have an increased risk of both venous thrombosis and arterial thrombosis, unless excess numbers of cells are reduced by the use of venesection, when up to a half a litre of blood is taken away, or with certain cytotoxic drugs. These drugs control the disease by reducing the number of cells made in the bone marrow.
Essential or primary thrombocythaemia
Essential or primary thrombocythaemia (ET) results from a sustained elevation in the blood platelet count. Arterial or venous thrombosis is one of the most common complications of ET. Thrombosis may occur anywhere in the body, but the majority tends to affect large arteries. Individuals with ET are therefore at particular risk of strokes and heart attacks. Small blood vessels may also be affected. People with this condition may have headaches and thrombosis in the fingers. This is often associated with painful, red toes or fingers, known as erythromelalgia. Venous thrombosis is less common in people with ET. However thromboses may occur in unusual places, such as the abdomen.
Between 50 and 80% of individuals with ET show symptoms of thrombosis. While symptoms appear to be more common in those with high blood platelet counts, there is no clear correlation between the degree of thrombocythaemia and the risk of thrombosis. Treatment of ET aims to reduce the risk of thrombosis by giving aspirin and other antiplatelet drugs, such as clopidogrel, and by reducing the platelet count with certain cytotoxic drugs. To find out more, click here
Thrombotic Thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura, or TTP, is a very rare disorder, which affects around three people in one million. The name describes the effects caused in a person and TTP is life threatening without treatment but it can be controlled, and in the majority of cases can be curable.
What is TTP?
The name describes the effects – so what are they? Thrombotic – Small clumps (thrombi) of platelets that block or partially block small blood vessels (capillaries). Thrombocytopenic – The clinical term for a low platelet count of less than 100 billion cells per litre of blood. A normal platelet count is between 150 and 400 billion cells per litre. Purpura – Little pin prick spots due to bruising caused by a low platelet count, which can occur spontaneously.
What causes these effects?
The exact cause of TTP has not been fully worked out. What is known is that the formation of platelet clumps is linked with a shortage of a protein called von Willebrand Factor cleaving protease. Von Willebrand Factor (vWF) is necessary for blood clotting and is made up of lots of small units that are linked to form a long string. The vWF cleaving protease breaks up this long string into smaller, usable pieces. In TTP vWF cleaving protease is missing, leading to the long strings of vWF remaining. These bind to platelets causing them to clump.
When this happens they can become ‘stuck’ to blood vessel walls leading to blocking or partial blocking of the blood flow. The main blood vessels affected are in the brain but it can also occur in the kidney, heart, lungs and the gut. The blockages then cause two things to happen:
- Firstly, the blockage prevents blood getting to the affected areas – so blockages in the brain lead to symptoms such as headaches, blurred vision, confusion, weakness seizures, and in extreme cases can cause unconsciousness.
- Secondly, as the red blood cells try to pass the blockage some are broken up (haemolyse) and so the numbers of red cells fall leading to anaemia. Because red blood cells carry oxygen in your body, a lack of them leads to feeling tired, light-headed or short of breath.
Download our information leaflet to find out more.
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