Antiphospholipid syndrome is sometimes called Hughes' syndrome. It is a disease that affects the blood and makes it more likely to clot than normal - a thrombophilia.
What is antiphospholipid syndrome?
Antiphospholipid syndrome (APS) - also called Hughes' syndrome - makes blood more likely than normal to clot (a thrombophilia). This can lead to unwanted blood clots (called thromboses) forming within blood vessels.
APS can cause disability, serious illness and even death in a pregnant woman or her unborn baby if untreated. Unfortunately, it is a disease that is often under-recognised and under-diagnosed. This is probably because it can cause so many different problems, many of which have other, more common causes. Early diagnosis is important to try to prevent serious complications.
People with APS are often referred to and managed by a specialist. This is usually a blood specialist (a haematologist) or a specialist in bone, joint and soft tissue disorders and certain autoimmune diseases (a rheumatologist).
Pregnant women with APS are at high risk of complications. If you are pregnant and have APS, you may need to have some of your antenatal care under the supervision of a doctor who specialises in pregnancy and childbirth (a consultant obstetrician).
What is a thrombosis?
Medically speaking, a blood clot in a blood vessel is called a thrombus. The process of a thrombus forming is called thrombosis. A thrombus blocking a blood vessel (such as an artery or a vein) causes a thrombosis. An embolism occurs when the thrombus dislodges from where it formed and travels in the blood. It becomes stuck in a narrower blood vessel, elsewhere in the body. The thrombus is then called an embolus. An unwanted blood clot can cause various problems in the body, depending on where the clot forms. The main problems that may occur are:
- A blood clot in an artery (arterial thrombosis) - causing diseases such as stroke and transient ischaemic attack (often called TIA, or mini-stroke).
- A blood clot in a vein (venous thrombosis) - causing diseases such as deep vein thrombosis (DVT) in a leg and pulmonary embolus (PE) in a lung.
- A blood clot in the placenta - causing problems in pregnancy such as repeated miscarriage, stillbirth, pre-eclampsia, premature delivery and growth restriction. This is also known as obstetric APS.
What causes antiphospholipid syndrome?
The exact cause is unknown; however, APS seems to be related to the presence of antiphospholipid antibodies in the blood.
Normally, the immune system makes proteins called antibodies that are helpful and do jobs such as fighting infection. In APS, unhelpful antibodies are formed as well and these attack a normal substance called phospholipid (which is why the antibodies are called antiphospholipid).
APS is called an autoimmune condition - when the body's normal defences begin to work against itself. The presence of the antiphospholipid antibodies causes the increased tendency of the blood to clot - they can trigger the coagulation cascade. The coagulation cascade is a chain reaction of events or chemical reactions that occur in the blood, leading to the formation of a blood clot. The antibodies can also cause inflammation which further increases the likelihood of the blood to clot.
In most people a certain event, such as pregnancy or an infection, provides a trigger for this chain of events in APS. Pregnancy itself (even without APS) makes a blood clot more likely to develop.
What are the typical problems in antiphospholipid syndrome?
APS can cause many different problems affecting many different parts of the body. The main problems are:
- Blood clots in veins (venous thromboses). Veins are blood vessels that bring blood back to the heart. They carry deoxygenated blood (blood without much oxygen left in it). After reaching the heart, the blood is sent to the lungs to get more oxygen. Venous means anything relating to the veins.
- Blood clots in arteries (arterial thromboses). Arteries are blood vessels that take blood away from the heart. They carry blood containing oxygen (oxygenated blood) around the body. Arterial means anything relating to the arteries.
- Blood clots in the placenta (thromboses in the placenta).
A blood clot in a vein can lead to diseases such as a DVT and PE. In one study, a DVT was the first sign of APS in over 6 in 20 people and a PE was the first sign in about 3 in 20 people. If you have APS and have a venous thrombosis, you have a high chance of having another one at some point in the future.
A blood clot in an artery can lead to diseases such as a stroke, TIA and high blood pressure (hypertension). About 13 in 100 people with APS first present with a stroke and, in 7 out of 100 people, the first sign of APS is a TIA. Arterial thrombosis can occur in any artery in the body. If a thrombosis occurred in an artery in the leg, you could develop problems such as gangrene in the toes, or leg ulcers. If you have APS and have an arterial thrombosis, you have a high chance of having another one at some point in the future.
Thromboses in the placenta
Tiny blood clots in the blood vessels within the placenta can lead to complications in pregnancy. This is called obstetric APS. The most common problem is recurrent miscarriage. This is more than three consecutive miscarriages. It is important to note that blood clots in the placenta can have other causes, unrelated to APS (such as non-APS pre-eclampsia).
Obstetric APS is also associated with:
- Growth restriction - also known as intrauterine growth restriction (IUGR).
- Stillbirth. This occurs when the baby has died in the womb after 24 weeks of pregnancy.
- Pre-eclampsia. This is a disease of pregnancy, which is associated with high blood pressure, swelling (oedema) and protein in the urine (proteinuria).
- Premature birth. This means delivery of the baby before 37 weeks of pregnancy.
Symptoms can occur in virtually any organ of the body.
- Kidney (renal) problems. A blood clot can occur in a blood vessel within a kidney. This can affect the kidney function and may lead to chronic kidney disease (CKD). See separate leaflet called Chronic Kidney Disease for more details.
- Heart (cardiac) problems. This includes problems with the valves in the heart which can also increase the risk of stroke. An inflammation of the lining of the heart (endocarditis) can occur because of blood clots forming on the heart valves. Heart attack (myocardial infarction, or MI) due to a blood clot in one of the blood vessels that supply the heart muscle itself (the coronary arteries) can occur in APS. About 3 people in 100 with APS have an MI as their first sign of the disease. See separate leaflet called Heart Attack (Myocardial Infarction) for more details.
- Brain (cerebral) involvement. As well as stroke and TIA, APS is associated with other problems in the brain. These include migraine, seizures, memory loss and abnormal movement disorders.
- Skin problems. A lace-like, purple mottled rash called livedo reticularis can occur - usually on the legs. It is caused by swelling of medium-sized veins in the skin. This can also have a totally innocent explanation and is common during winter in young women without APS.
- Other blood problems. For example, a low level of platelets, which can cause easy bruising and a type of anaemia called haemolytic anaemia.
- Avascular necrosis of the bone (also called osteonecrosis). Bones are a living part of the body and need a blood supply. The blood supply brings oxygen and other nutrients to the bone cells. Interruption of this blood supply (by a blood clot, for example) can lead to death of the bone - called avascular necrosis. It can lead to pain and arthritis.
- Eye problems such as a blood clot in a retinal artery or vein. This can lead to permanent sight problems.
- Budd-Chiari syndrome. This is a rare condition where a blood clot occurs in a vein in the liver. It can cause an enlarged liver, yellowing of the skin and of the whites of the eyes (jaundice) and tummy (abdominal) swelling due to fluid.
- Infertility. Antiphospholipid antibodies are associated with infertility. Testing for them is becoming more routine in investigations to find the cause of infertility.
- Catastrophic APS. This is a rare but very severe form of APS. About half of people who have it may die. This is because widespread blood clots affect the oxygen supply to the body's main organs. These start to shut down, which is called organ failure. Usually the brain, kidneys, lungs and skin are affected.
Types of antiphospholipid syndrome
APS is divided into two types - primary and secondary:
- Primary APS. More than half of people with APS have primary APS. This is APS on its own, and not associated with any other disease.
- Secondary APS. This is APS that is associated with another disease, such as a rheumatic disease that affects either the bones, joints or soft tissues. An example is systemic lupus erythematosus (SLE, or lupus). SLE seems to be the disease most commonly associated with APS. Many of the rheumatic diseases (including SLE) that are associated with APS are autoimmune diseases. This means that the immune system (which normally protects the body from infections) mistakenly attacks itself. This can cause symptoms and may damage the affected parts of the body.
Primary and secondary APS are still commonly used terms. However, most people now say 'APS with or without associated rheumatic disease'.
Who develops antiphospholipid syndrome?
It is not known exactly how many people have APS. It is probably undiagnosed in many people, where it does not cause any problems. It is estimated that 1 person in 200 develops APS at some stage.
APS mainly first develops in younger women, before the menopause. For every two men with APS, there are seven women affected. The average age at which the disease first develops is 34 years. It develops after the age of 50 in just over 1 in 10 people with APS. APS rarely affects children.
Fortunately, less than 1 in 100 people with APS develop catastrophic APS. Most people who develop catastrophic APS have not had a previous blood clot either. This means that, usually, the first sign of catastrophic APS is widespread blood clots.
SLE affects between 1 and 20 people in every 200,000 people. Of these, about 3 in 10 develop secondary APS. Antiphospholipid antibodies are found in many other rheumatological conditions such as Sjögren's syndrome, rheumatoid arthritis and psoriatic arthritis.
How is antiphospholipid syndrome diagnosed?
APS is diagnosed on the basis of blood tests and on a history of one or more blood clots or problems in pregnancy.
Blood tests for APS
The blood tests for APS involve detecting antiphospholipid antibodies. Blood testing in APS or suspected APS is a complicated process. Antiphospholipid antibodies are found in between 1 and 5 people in every 100 people without APS. So, a single positive test for any or all of the antiphospholipid antibodies does not mean you have APS. This is why it is important that only certain people should be tested (see section below).
There are three antiphospholipid antibodies:
- Lupus anticoagulant.
- Anticardiolipin antibodies.
- Anti-beta glycoprotein I antibodies.
Lupus anticoagulant and anticardiolipin antibodies are the main ones. People with positive tests for all three antibodies have a high risk of developing a blood clot and/or pregnancy-related problems.
If you have a positive blood test for any of the antiphospholipid antibodies, it will need to be repeated after 6-8 weeks. This is because many people have these antibodies in their blood for a short period of time, without any harm being caused (called transient positivity). Transient positivity can occur in healthy people, harmlessly, after infections or some medications.
It is also possible that a first positive test has been a false positive. False positive tests are common (up to 1 in 4) in tests for antiphospholipid antibodies. This is because different laboratories have different techniques for measurement and different thresholds for a positive result.
Persistent positive blood tests in the absence of APS are rare. So, if you test positive on a second, later occasion, the chances are that the test is correct (but this doesn't necessarily mean you have APS).
Antiphospholipid antibodies are more likely to be found in your blood the older you are and if you take certain medications. They are also more likely if you have cancer, other long-term (chronic) diseases or infections. In these cases, the tests tend to be only weakly positive and they are not associated with an increased risk of blood clot or pregnancy problems.
So, two positive tests, at least 6-8 weeks apart, are needed for diagnosing APS. However, some people have the antibodies and no problems. So, to diagnose APS you need a combination of a positive blood test for one of the antibodies AND one of the clinical criteria.
Clinical criteria for APS
APS is a complicated condition. There is no single blood test to diagnose it. In addition to the blood tests for antiphospholipid antibodies, you need to have had either:
- A blood clot. This can be arterial or venous, in any organ of the body. It is important that this has been proved - for example, with a scan.
- A pregnancy-related problem. This includes either:
- Repeated miscarriage. Three or more miscarriages before 10 weeks of pregnancy. Other causes of miscarriage (such as chromosomal abnormalities) have to be excluded.
- Miscarriage after 10 weeks of pregnancy or stillbirth after 24 weeks of pregnancy. Again, other causes have to be excluded.
- Premature birth before 34 weeks of pregnancy, due to eclampsia or severe pre-eclampsia. Eclampsia is a seizure in pregnancy caused by pre-eclampsia. Pre-eclampsia is a pregnancy-related problem with high blood pressure, protein in the urine and swollen legs.
Other tests in APS
Other tests may be needed in APS, although not necessarily to diagnose the condition. Other tests are usually needed to investigate the medical problems caused by APS.
Doppler ultrasound scans are usually needed to diagnose DVTs. Special lung scans called computerised tomographic pulmonary angiography (CTPA) scans or isotope scans (also called a ventilation/perfusion scan or V/Q scan) and chest X-rays may all be used in the diagnosis of PE. Strokes are usually confirmed with a computerised tomography (CT) scan or a magnetic resonance imaging (MRI) scan of the brain. Heart attacks are usually diagnosed with blood tests and a heart tracing (electrocardiogram, or ECG). The type of test used depends of the type of problem suspected.
Who should be tested for antiphospholipid syndrome?
Blood testing for APS is not straightforward. In fact, the blood tests are complicated and can be quite confusing. This is why it is important that:
- The correct people should be tested.
- The tests should be requested and interpreted by a specialist, usually by a specialist in blood disorders (a haematologist).
Testing in people with SLE
If you are diagnosed with SLE, testing for antiphospholipid antibodies is usually recommended as part of the initial investigations. This is because it is common for APS to co-exist with SLE. If you have SLE and do not initially test positive for antiphospholipid antibodies, it may be appropriate to test you again in the future. Follow-up testing is likely to be advised if you develop new risk factors for developing a blood clot. It can also influence treatment decisions - such as if you become pregnant or need to have surgery.
Testing in pregnancy
Although pregnant women have many routine blood tests, it is not advised to test all pregnant women for antiphospholipid antibodies. Not only are the results affected by being pregnant, the results may cause confusion and may not change what is advised. For example, if you have had a blood clot in the past and are pregnant, you might (in certain situations) be advised to use aspirin or heparin anyway, whether or not you have APS.
It is recommended to test women only after three or more miscarriages. This is because it is not really known whether antiphospholipid antibodies definitely cause early miscarriage. Early miscarriage itself is very common and has many causes - the most common reason being an abnormality in the fetal chromosomes (a genetic problem).
Testing in people who have had a blood clot
It is not recommended to test everyone who has a blood clot for antiphospholipid antibodies. This is because most people with problems related to having a blood clot do not have APS.
Your doctor may, however, be more suspicious of APS if you have a problem such as a stroke at a relatively young age. It is estimated that 1 in 5 of people who have a stroke before the age of 40 years have APS.
What is the treatment for antiphospholipid syndrome?
Treatment can be thought of in four areas:
- Treatment to prevent blood clots.
- Treatment of a blood clot.
- Treatment of catastrophic APS (if this rare problem develops).
- Other general points.
Treatments to prevent blood clots
Once you have been diagnosed with APS, the main aim of treatment is to prevent you from developing a further blood clot or pregnancy-related complication. Therefore, one or more of the following treatments may be advised: warfarin; heparin; dabigatran; apixaban; rivaroxaban; aspirin; clopidogrel; dipyridamole; compression stockings.
The exact treatment(s) used, the dose and the length of treatment can all vary, depending on various factors such as:
- If you have already had a blood clot (and if so, whether it was arterial or venous).
- Whether you have obstetric APS (and whether you have had either repeated miscarriage, a stillbirth, pre-eclampsia or a growth-restricted baby).
- Whether you are pregnant.
- Whether you have SLE or another rheumatological disease as well as APS.
Note: the following is an overview of treatment but your doctor will decide upon the best course of action for you for your particular circumstances. This information is therefore a guide:
Anticoagulant medication. Anticoagulation is often called 'thinning' of the blood. However, it does not actually thin the blood. It alters certain chemicals in the blood to stop clots forming so easily. It doesn't dissolve a blood clot. Anticoagulation prevents an existing blood clot (such as one causing a PE or DVT) from getting larger and prevents any new ones from forming. The body's own healing mechanisms can then get to work to break up the blood clot.
Anticoagulation can be used to treat an existing blood clot or to prevent further blood clots forming in the future.
Anticoagulation medication comes in two forms: injections and tablets (or syrup for those who cannot swallow tablets). The injectable form is heparin; the tablets or syrup are warfarin, dabigatran, apixaban or rivaroxaban.
Antiplatelet medicines. Clopidogrel, dipyridamole and aspirin are antiplatelet medicines. They stop platelets in the blood sticking together (which usually helps to form a blood clot, as part of the mechanism of blood clotting). These medicines are not, strictly, anticoagulants.
Compression stockings. These are also known as elastic compression hosiery. They can be used after a DVT in the leg, to prevent complications and to prevent further blood clots forming. Special compression stockings, called thromboembolic deterrent (TED) stockings, are often worn when you are in bed in hospital awaiting or recovering from an operation, or bed-bound for any other reason. They are also used in obstetric APS both before and after delivery of the baby.
Treatment of a blood clot
If you have a blood clot (and have APS), it is treated in exactly the same way as if you did not have APS. This usually means supportive and anticoagulant treatment. This may mean treatment with warfarin, dabigatran, apixaban, rivaroxaban, heparin or aspirin (or a combination).
Stroke and heart attacks are managed in the normal way initially but you may need to take the anticoagulant (warfarin, dabigatran, apixaban or rivaroxaban) on a long-term basis afterwards.
Pregnancy-related complications are also managed normally. For example, if a pregnant woman has pre-eclampsia, her blood pressure may be treated with medication. Depending on how many weeks pregnant she is, she may be induced (to have the baby early). Similarly, if the baby were shown to have restricted growth, suggesting a placental problem, labour may be induced early.
Treatment of catastrophic APS
This form of APS is extremely dangerous but, fortunately, rare. People with this condition will be nursed in an intensive care unit (ICU). Life support systems will be used - often ventilators to help them breathe, and a special type of dialysis (called haemofiltration) to clean the blood, and do the job of the failing kidneys.
Treatments might include anticoagulation (usually with intravenous heparin), steroids and infusions of antibodies (called gammaglobulins) to support the immune system. Sometimes, the watery part of the blood (called the plasma) is separated from the blood cells and removed. It is replaced in a type of transfusion called plasma exchange. This is because the harmful antiphospholipid antibodies are in the plasma. Sometimes medicines such as cyclophosphamide are used.
If you have APS it is really important that pregnancies should be planned. You should ensure safe contraception unless you are prepared for pregnancy. Consult your doctor when you are thinking about trying to have a baby. You may need to alter your medication or start medication before you start to try.
If you are trying to have a baby and are on long-term warfarin, you should be switched to heparin. You can stay on heparin throughout pregnancy.
What is the outlook for antiphospholipid syndrome?
The severity of APS varies from person to person so the outlook (prognosis) is also variable. APS can cause life-threatening or life-limiting illness - depending on whether a blood clot causes a serious problem in your body.
Long-term anticoagulation does seem to improve prognosis in APS. With the appropriate medication and a healthy lifestyle, most people with primary APS can lead a normal healthy life.
Secondary APS has a similar prognosis. It does depend on which rheumatological disease it is associated with and how severely that disease affects you.
What else can I do?
It is important to reduce any other factors that might increase your risk of having a blood clot. In general, this means following a healthy lifestyle. This includes:
- Weight control and avoiding being overweight.
- Keeping to a healthy diet that is low in saturated fats.
- Cholesterol - you may need medication to keep your cholesterol level low.
- If you smoke, stopping smoking is strongly advised. This is a risk factor for many diseases, including arterial disease (such as heart disease). In the presence of antiphospholipid antibodies it increases your risk of a blood clot even further.
- Blood pressure. If you have high blood pressure (hypertension) then it is important that this should be controlled. This may mean taking medication.
- Diabetes control. If you have diabetes, it is important that your blood sugars should be tightly controlled.
- Alcohol. You should keep your drinking to within the recommended limits. This is no more than 14 units per week.
You should also avoid oestrogen-containing medicines such as the combined oral contraceptive (COC) pill (often called 'the pill') and hormone replacement therapy (HRT). This is because these medicines increase your risk of having a blood clot.
Further reading and references
Guidelines on the investigation and management of antiphospholipid syndrome; British Committee for Standards in Haematology (2012)
Khamashta M, Taraborelli M, Sciascia S, et al; Antiphospholipid syndrome. Best Pract Res Clin Rheumatol. 2016 Feb30(1):133-48. doi: 10.1016/j.berh.2016.04.002. Epub 2016 May 4.
Chaturvedi S, McCrae KR; The antiphospholipid syndrome: still an enigma. Hematology Am Soc Hematol Educ Program. 20152015:53-60. doi: 10.1182/asheducation-2015.1.53.
Maher GM; Immune thrombocytopenia. S D Med. 2014 Oct67(10):415-7.
Purpura; DermNet NZ
Thrombophilia due to Thrombin Defect, THPH1; Online Mendelian Inheritance in Man (OMIM)
HI all I have been tested 3 times for the IIG4 and been positive all 3 times but the doctor told me it's nothing because its not very high. Does that sound odd? I have sjogrens, Gi bleeds, bowel...agenamarie
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