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Antiphospholipid Syndrome: An In-Depth Overview

Adapted from a talk at The SLE Workshop at Hospital for Special Surgery

The SLE Workshop is a free support and education group held monthly for people with lupus and their families/friends. The HSS presentation from which this content was adapted was originally held on June 2, 2004. It has been periodically updated by the author.

What is antiphospholipid syndrome?

A syndrome is a collection of events or symptoms that constitutes a specific illness. Antiphospholipid syndrome (APS), also known as antiphospholipid antibody, anticardiolipin antibody, lupus anticoagulant, and Hughes’ syndrome, includes these symptoms:

  1. Repeated clotting in veins – such as a deep vein thrombosis (DVT) in an arm or a leg, or a pulmonary embolus (a blood clot in a lung) – or arteries (stroke, heart attack)
  2. Recurring pregnancy loss (miscarriage), usually in mid to late pregnancy rather than early pregnancy
  3. An antibody test that is strongly positive. A weakly positive test is common in otherwise normal people and is not enough to diagnose this syndrome

The above symptoms are specifically characteristic of APS. However, there are many other symptoms that people with APS may experience, including:

  1. Skin changes
  2. Low platelet count (insufficient amount of platelets in the blood)
  3. Some forms of heart, kidney and brain diseases

What is a phospholipid?

A phospholipid is a type of fat (“lipid” means fat) that contains phosphate. Phospholipids form the outside layer of all cells: those of humans, bacteria and viruses. Cardiolipin is a type of phospholipid. The “cardio” part of this word comes from a phospholipid syphilis test, which used a chemical derived from a cow’s heart. (As will be discussed below, clinical tests for syphilis were key to the discovery of antiphospholipid antibodies.) Another phospholipid sometimes used in testing is phosphatidylserine.

What are antiphospholipid antibodies (aPL), and how are they measured?

The general term antiphospholipid antibody (aPL) describes any of three antibodies measured in diagnosing or treating APS.

  1. Lupus anticoagulant (LAC) – An LAC test measures the effect that the antibody has on the time it takes blood to clot. If a patient's blood contains an antiphospholipid antibody (aPL), it will bind to phospholipids in a test tube, and the blood will not clot. Although a positive test is called “lupus anticoagulant,” the name comes from its confused history. It does not mean the patient has lupus, nor does it mean that the blood is prevented from clotting. In fact, in the body as opposed to the test tube, it clots too easily.
  2. Anticardiolipin (aCL) antibody is the most commonly measured antiphospholipid antibody.
  3. Anti-Beta-2-glycoprotein-I (aβ2GPI) measures the antibody to a specific protein (Beta-2-glycoprotein-I) that is required for aCL to bind to cardiolipin.

Anticardiolipin and aβ2GPI each have three subtypes: IgG, IgM, and IgA. These are all different types of immunoglobulin antibodies that people normally make.

When an infection (such as syphilis) is the reason a patient has a positive aPL test, the aPL is part of the body’s response to try to kill the infectious germ. Some infections, as well as lupus, irritate certain types of blood cells and blood vessel cells. A result is that the b2GP1 protein, which floats normally in the blood stream, recognizes that the irritated cells are abnormal, and “calls in” the antiphospholipid antibody, which starts the reaction that leads to blood clots.

From the patient's point of view, all of these measures are equivalent: They all test for antiphospholipid antibodies. In terms of predicting health outcomes and the development of APS, the LAC test is more powerful than the aCL or aβ2GPI tests. Among the aCL or aβ2GPI antibody tests, the IgG subtype is more powerful than IgM, which is more powerful than IgA. For each of these antibody tests, a strongly positive test suggests a worse patient outcome than a weakly positive test.

How was aPL discovered?

In the early 1900s, when a blood test for syphilis became available, doctors recognized that some people had false-positive test results for syphilis, meaning that they tested positive even though they did not actually have the disease. At the time, this was just considered a medical curiosity. It was not recognized as having clinical importance. But during the 1940s and 1950s, medical practitioners concluded that the false-positive syphilis test results occurred most often in patients with systemic lupus erythematosus (usually called just lupus or SLE). Today, a false-positive syphilis test result is a clue to a possible diagnosis of lupus. However, it does not make a conclusive diagnosis of lupus, nor does it – by itself – indicate a diagnosis of APS.

In the 1950s and 1960s it became understood that the false-positive syphilis test result was associated with LAC and its blood clotting abnormalities. In 1983, three lupus researchers in London with ties to HSS – Graham Hughes, Azzudin Gharavi and E. Nigel Harris – developed a much simpler test (now called the aCL ELISA) to replace the cumbersome test for LAC. They tested their SLE patients and found that aCL occurred in patients with spontaneous blood clots and with pregnancy losses. They shared the test with other investigators, including HSS physicians, and by 1985 we and others confirmed their findings.

Until 1989, doctors thought that APS was a subtype of lupus. However, by then enough recorded cases of APS in people without lupus led British, Australian, Italian, and Dutch investigators to argue that APS should be considered a separate illness. They further argued that the name “primary antiphospholipid syndrome” (PAPS) should be used to describe APS in patients who do not have lupus, and “secondary antiphospholipid syndrome (sAPS) be used to describe APS in patients who do have lupus. In 1990, the Beta-2-glycoprotein-I (aβ2GPI) was discovered, the importance of which was reviewed above.

Who gets APS?

There are differences between those who get SLE and those who get APS. Whereas 90% of the people who develop SLE are women, with APS, if you count only the people who develop blood clots, and do not count women who have problems with their pregnancies, about 50% of people with APS are women. But, if you do count people who develop blood clots as well as those who have pregnancy problems, about 70% of APS patients are women. SLE is most frequent in people of African descent, next most frequent in Asians and Hispanics, and least frequent in people of European descent. By contrast, APS is seen more in those of European and Asian descent than in people of African descent. About one third of lupus patients have aPL.

What happens if you have aPL?

The main symptom is blood clots. The antibody may be in the blood stream for years before anything happens, and some people with these antibodies are well for their entire lives. What causes the clotting? One theory is that the antibody itself irritates the cells on the inside of blood vessels. Another theory is that an infection irritates the cells and attracts the antibody. Regardless which theory is correct, the result is that a clot forms.

The antibody runs in families and is often found in families of patients who have SLE or PAPS. In other words, if either SLE or PAPS is present in the family, the likelihood of a blood relative having aPL is increased. Women develop the antibody more often than men, but it is not known why. It is also not known what causes the antibody to appear in the first place. Two different theories explain why people develop the antiphospholipid antibody. The first is that an infection causes people to make the antibody but that nothing happens until something else, such as an injury or another infection, triggers the disease. The second theory states that the antiphospholipid antibody is normally present in the body in small quantities and is used to remove old and dying cells. People with APS may make too much of the antibody or may make an abnormal antibody. Or, in some cases, it may be that the b2GP1 that ties aPL to the targeted irritated cells is abnormal. In some APS patients, it may be that the cells which are irritated are the underlying problem and the aPL antibodies are trying (unsuccessfully) to correct the situation.

Although blood clotting is the chief health risk of APS, in pregnant women the antibody damages the placenta, starving the fetus by cutting off the blood supply that feeds it. Anticoagulating medication like heparin and aspirin protect the blood supply, giving the fetus an 80% to 90% chance of survival. This is markedly better than the 20% survival rate in the 1980s, before APS was known to medical science.

Even with better fetal survival rates and heparin treatment, pregnancies are not always normal in people with APS. Although a normal pregnancy lasts 40 weeks (producing babies bigger than 6 pounds), in APS, premature deliveries (30 to 35 weeks, with babies weighing between 3 to 5 pounds) regularly occur. Once born, however, the babies do fine.

Mouse models can be used to study the antibody. New studies in mice suggest that different forms of treatment that focus on the complement system (a part of the immune system that amplifies its abilities under certain conditions) and other processes – rather than on clotting – may be more effective. HSS rheumatologist Dr. Jane Salmon is a leader in this work.

Warfarin (Coumadin) can prevent blood clots. This medication is commonly used for people with strokes and heart attacks. Aspirin and hydroxychloroquine (Plaquenil) may help. The new, oral anticoagulant drugs rivaroxaban [Xarelto] and apixaban [Eliquis] do not work, and should not be used. In serious cases, an experimental therapy, intravenous immunoglobulin, is helpful.

A rare complication of APS, called catastrophic APS (CAPS), consists of very rapid clotting throughout the body. It is life-threatening and demands immediate in-hospital treatment. This article describes this illness and its treatment.

Frequently asked questions about antiphospholipid syndrome

Q. Does antiphospholipid syndrome turn into lupus (SLE)?

No

Q. Does antiphospholipid syndrome cause hardening of the arteries?

Doctors used to think so, but now it is pretty clear that there is no correlation between APS and hardening of the arteries.

Q. Does antiphospholipid syndrome cause heart valve disease?

The answer is yes in a small number of patients. Some SLE patients without APS also develop leaking heart valve disease, but it appears to occur more often in those with APS. It is not clear why this happens.

Q. Is antiphospholipid syndrome caused by infection?

Scientists are looking into this. So far, researchers have been able to produce the antibody by certain infections only in mice.

Q. What is the relationship between lupus and antiphospholipid syndrome?

About 30% of lupus patients test positive for antiphospholipid antibody. It is not known why. About half of patients with APS have SLE.

Q. Why don’t people with primary antiphospholipid syndrome (PAPS) have lupus as well?

It is not known why.

Conclusion

There are good treatments for antiphospholipid syndrome, but better ones are needed. Doctors can prevent blood clots in people at risk, but we would like to do so in a much safer and more effective fashion than we can right now. Also, we can save most pregnancies, but many are premature. Researchers continue to explore new and imaginative treatments for this disease.

Authors

Headshot of Michael D. Lockshin, MD
Michael D. Lockshin, MD
Attending Rheumatologist, Hospital for Special Surgery
Director, Barbara Volcker Center for Women and Rheumatic Disease
 

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