Antiphospholipid Syndrome: An In-Depth Overview

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

Michael D. Lockshin, MD
Michael D. Lockshin, MD

Attending Rheumatologist, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medical College
Director, Barbara Volcker Center for Women and Rheumatic Disease

A syndrome is a collection of events that constitute a specific illness. Antiphospholipid syndrome (APS), also known as antiphospholipid antibody syndrome, includes a series of symptoms as follows:

  1. Repeated clotting in veins (for example, a pulmonary embolus) or arteries (examples include a stoke, a blood clot in an arm or a leg, or a heart attack).
  2. Recurring pregnancy loss, usually in mid to late pregnancy rather than early pregnancy.
  3. An antibody test that is strongly positive. Having a weak or trace positive test is fairly common in the general population and is not enough to diagnose the syndrome.

The above symptoms are specifically characteristic of APS. However, there are a lot of other symptoms that are also associated with APS. Such symptoms include skin changes and low platelets.

You may have heard different terms used when referring to tests for the antibody. The more general term is antiphospholipid antibody. The anticardiolipin antibody refers to a type of phospholipid. Another test for the antibody is the Lupus Anticoagulant Test. These terms are all equivalent from the patient's point of view. In other words, they all test for the same thing. The only difference is in the type of measurement.

In the 1900s, certain people had false positive test results for syphilis. This was a curiosity without clinical importance at the time, but rediscovered in the 1940s. By the 1950s, it was concluced that this false-positive syphilis test had something to do with lupus. Today, although it is known as a clue to diagnosis, a false-positive syphilis test alone is not sufficient to make a diagnosis of lupus or APS.

In the 1950s and 1960s it was realized that the antiphospholipid antibodies had something to do with blood clots. In 1983, Hughes, Gharavi, and Harris developed a simple test for the antibodies called an ELISA. Clinical descriptions of various things that happened to people who had this antibody were also noted. In 1985, descriptions of what happened in pregnancy for people with this antibody were also noted.

Up until 1989, it was thought that APS was a subset of lupus. However, there were enough recorded cases where people had APS without having Lupus, that it was decided that APS should be categorized as a separate illness. Several names have been used to describe it, including primary antiphospholipid syndrome (PAPS),  antiphospholipid antibody ayndrome, and Hughes syndrome. In 1990, the B2-Glycoprotein 1 was discovered. The importance of this protein will be reviewed later.

A phospholipid is a type of fat. It contains phosphate and lipids (lipid means fat).

Cardiolipin is a type of phospholipid. The cardio term in cardiolipin has nothing to do with your own heart. Rather, it originated from the syphilis test, which used a chemical derived from beef heart in the original test.

The Lupus Anticoagulant Test is a clotting test that measures how long it takes for blood to clot in a test tube. There are ways of measuring the reasons why the blood does not clot fast enough. For example, blood takes longer to clot if it contains an anticoagulant. For the Lupus Anticoagulant Test, blood is put in a test tube containing phospholipids. If the patient's blood contains the antibody to these phospholipids, it will bind to the phospholipids in the test tube, and the blood will not clot.

Note: Having a positive Lupus Anticoagulant Test does not necessarily mean you have Lupus.

All cells in the body have membranes that are made of phospholipids. These membranes hold the cell together. Bacteria and viruses also have phospholipids. They occur everywhere in nature.

The illustration shows that the cell has a membrane, and contains a nucleus that also has a membrane. Phospholipids make up the membrane and, as seen in the illustration, two layers are set opposed to one another on the outside and inside of the membrane. There is a difference between the phospholipids on the outside and inside. This will be an important issue in discussion below.

B2-glycoprotein 1 is bound to internal phospholipids that have flipped to the outside of the cell. Under certain circumstances, such as when a cell is excited or injured, the inside phospholipids will flip to the outside. B2-glycoprotein 1 then binds to these phospholipids.

People with infections, such as syphilis, will make antibody directed against the phospholipids surrounding the cell. But in people with APS, the immune system makes antibodies directed against the B2-glycoprotein 1, which binds to the phospholipid.

  • 30% of people with systemic lupus erythematosus (SLE) also have the antiphospholipid antibody.
  • There are differences between those who get SLE and those who get APS.
  • 90% of the people who develop SLE are women. However, only 70% to 80% of people with APS are women.
  • SLE is more frequent in African Americans than Caucasians. However, APS is seen more in Caucasians and Asians than in people of African descent.

What happens when you get the antibody? The antibody may be in the blood stream for years before you see anything. Some people live a lifetime with the antibodies and show no symptoms.

One theory is that the antibody itself irritates the blood vessels. When cells are irritated, phospholipids flip from the inside to the outside. Another theory is that an infection triggers the lipids on the inside to flip to the outside of the cell membrane and trap the antibody.

Regardless of which theory is correct, the result both scenarios is that a clot forms.

We know that the antibody runs in families. It is seen in families of patients with SLE or PAPS. It is also known that women more than men have the antibody, but it is not known why. Why the antibody appears in the first place is also unknown.

Mice models can be used to study the antibody. It is possible to immunize mice to make the antibody. Some mice develop it spontaneously. Viruses are given to mice, which forces them to make the antibody. Once mice get the antibody, we can study and measure mice pregnancies. It is more difficult to show that mice develop blood clots. Mice can also be used as models to test our treatment.

There are two different theories explaining why people develop the antiphospholipid antibody.

The first theory is that some infection causes people to make the antibody, and something else triggers the disease. Bacteria, which have phospholipids, attract the B2-glycoprotein 1. An autoimmune antibody is formed which attacks the bacterium in the blood stream, causing a clot. If the phospholipid isn't on the outside of the bacterium, then the anti-infection antibody forms and you do not get a clot.

This theory assumes that there is something about a bacterium that causes it to have the relevant phospholipid on the surface, attract the B2-glycoprotein 1, and cause clotting.

The second theory states that the antiphospholipid antibody is normally present in the body. For example, in the general population you can measure a small amount of this antibody present. It is thought these antibodies remove old and dying cells. People with APS may be abnormal because: (a) they make too much of the antibody, or (b) they make abnormal antibody, or (c) the B2-glycoprotein 1 is abnormal.

The illustration above (labeled "Dying Cell Theory 2") shows a normal cell that is dying. In dying cells, the phospholipids inside flip to the outside. Under normal circumstances, the antibody binds up the B2-glycoprotein 1 and throws the damaged cells away. When something is abnormal with the antibody or the B2-glycoprotein 1, a blood clot develops.

What happens most frequently in APS is blood clotting. Pregnancies are lost because blood clots form in the placenta. This starves the unborn child by cutting off its nutrition (food). Treatment is the use of anticoagulating medication. In pregnancy, heparin is used. This gives the fetus an 80% to %90% chance of survival, a drastic improvement from the 1980s when fetal survival was around 20%.

However, pregnancies are not normal. Normal pregnancy is 40 weeks. In APS, it is more common to deliver the baby between 30-35 weeks, and between 3-5 pounds. Heparin protects the placenta partially, but not fully so that the baby gets enough nutrition to survive longer in the mother. Once born, the babies do fine.

New work in mice – not yet applied to humans – suggests that a completely different form of treatment, based on the complement system (a sort of amplifier of the immune system) rather than on the clotting system, may be even more effective in the future.

Anticoagulation Treatment for people who clot is to also use . There are more options available in this case. Warfarin (Coumadin) can be used with blood clots. This medication is commonly used for people with strokes and heart attacks. It is used differently in use of patients with APS. People with APS must take a fairly high dose; recent work from Canada suggests that the dose of warfarin that results in an INR (international normalized ratio, a test to measure the correct dose) of 2.5 is as effective as, and less dangerous than, higher doses. The goal is to get people to the threshold of having a hemorrhage. Reaching this level of anticoagulation can virtually prevent any new clotting. Sometimes aspirin is used, but this is only partially effective; new studies question whether it has any beneficial effect at all. Other drugs are being tested.

Another treatment is an experimental therapy called IV immunoglobulin. New studies are testing safer methods of preventing blood clotting.

Does APS turn into SLE? No.

Does it cause hardening of the arteries? We used to think yes, but now the answer is pretty clearly no.

Does APS cause heart valve disease? The answer is almost certainly yes, for 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. We do not know why it would happen, or the mechanism by which it would happen.

There are still unanswered questions. Is it caused by infection? Science is looking into this; we do not have the answer. So far, only in mice can we produce the antibody by certain infections. Another unanswered question is the relationship between SLE and APS. Thirty percent of SLE patients have the antibody, but it is not known why. It is also not known why people with PAPS do not have SLE.

We need better treatment than we have now. We can prevent clots in people at risk of hemorrhaging. It is good that we are able to prevent clots, but we would like to do it much more safely and easily than we can right now. Also, we can salvage most pregnancies, but at the cost of having premature pregnancies. Therefore, science is looking for more things to do. In tests right now are other anticoagulant medicines, and other treatments that reduce or remove the antibody.

Learn more about the SLE Workshop, a free support and education group held monthly as HSS.


Summary of a presentation given at The SLE Workshop, a free support and education group held monthly for people with lupus and their families/friends.


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