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
Director, Barbara Volcker Center for Women and Rheumatic Disease

A syndrome is a collection of events or symptoms 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 for the antiphospholipid antibody. Having a weak or trace positive test is fairly common in the general population and is not enough to diagnose this syndrome.

The above symptoms are specifically characteristic of APS, but many other symptoms are also associated with APS, such as 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 term anticardiolipin antibody refers to a specific type of phospholipid. Another test for the antibody is the lupus anticoagulant test. From the patient's point of view, these terms are all equivalent: They all test for the same thing. The only difference is in the type of measurement used to make a diagnosis.

Discovery and History of the Antiphospholipid Antibody

In the early 1900s, some people had false-positive test results for syphilis. (This means they tested positive for syphilis even though they did not have the disease.) At the time, this was just a medical curiosity without clinical importance. But after being rediscovered in the 1940s, medical pratcitioners in the 1950s concluded that this false-positive syphilis test had something to do with a disease called systemic lupus erythematosus ("lupus" or "SLE"). Today, although it is known to be a clue to a possible diagnosis, a false-positive syphilis test alone is not enough to make a conclusive diagnosis of SLE or APS.

In the 1950s and 1960s it was realized that the antiphospholipid antibodies had something to do with blood clots. In 1983, researchers Graham Hughes, Aziz Gharavi and Nigel 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 SLE. However, there were enough recorded cases where people had APS without having SLE, 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 syndrome, and Hughes syndrome. In 1990, the β2-glycoprotein 1 was discovered. The importance of this protein will be reviewed later.

What Is a Phospholipid?

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 the human heart. Rather, it comes from the original syphilis test, which used a chemical derived from a beef heart.

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 SLE.

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 below left 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 versus those on the inside. This will be an important issue in discussion further down on this page. As shown in the illustration below right, the β2-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.

Illustration of human cell, showing phospholipids in the membrane.           Illustration of human cell, showing phospholipids flipped to the outside of the membrane.

The β2-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 β2-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 frequently in people of African descent than in Caucasians. However, APS is seen more in Caucasians and Asians than in people of African descent.

What Happens When You Get the Antiphospholipid Antibody?

The main resulting symptom is blood clots. The antibody may be in the blood stream for years before you experience clotting symptoms. Some people have these antibodies throughout their lives but never develop. What causes the clotting? One theory is that the antibody itself irritates the cells of the blood vessels, causing the phospholipids to flip from the inside to the outside of the cell membrane. 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 in both scenarios is that a clot forms.

The antibody runs in families and is found in families of patients who have SLE or primary antiphospholipid syndrome (PAPS). 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. There are two different theories explaining why people develop the antiphospholipid antibody.

  1. 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 β2-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 β2-glycoprotein 1 and cause clotting.
    Illustration of the bacterium theory of antiphospholipid syndrome.
  2. The second theory states that the antiphospholipid antibody is normally present in the body, in small quantities. 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 β2-glycoprotein 1 is abnormal. The illustration below 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 β2-glycoprotein 1 and throws the damaged cells away. When something is abnormal with the antibody or the β2-glycoprotein 1, a blood clot develops.
    Illustration showing a normal cell dying and transformation of normal antibody to abnormal antibody.

Although blood clotting is the chief symptom and health risk of APS, in women, pregnancies are also commonly lost because blood clots form in the placenta. This starves the fetus by cutting off nutrition (food). Treatment is the use of an anticoagulating medication (heparin is used in the case of pregnant women). This gives the fetus an 80% to 90% chance of survival, which a drastic improvement compared to a 20% rate of fetal survival as recently as the 1980s. However, pregnancies that go to term are not normal in people with APS. A 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. 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. 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.

Warfarin (Coumadin) can also be used to prevent blood clots. This medication is commonly used for people with strokes and heart attacks, but 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. One experimental therapy is called intravenous immunoglobulin. New studies are testing safer methods of preventing blood clotting.

Questions and Answers about Antiphospholipid Syndrome

Does APS:

  • Turn Into SLE (lupus)? No.
  • Cause hardening of the arteries? We used to think yes, but now the answer is pretty clearly no.
  • Cause heart valve disease? The answer is almost certainly 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. We do not know why it would happen, or the mechanism by which it would happen.

Unanswered Questions Remain

  • Is it caused by infection? Science is looking into this. So far, only in mice can we produce the antibody by certain infections.
  • What is the relationship between lupus and APS? Thirty percent of lupus patients have the antiphospholipid antibody, but it is not known why.
  • Why people with PAPS not also have lupus?

We need better APS treatments 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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