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:
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.
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.
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.
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.
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.
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.
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.
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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.