Review of Anti-Phospholipid Antibody
Adapted from a presentation to the SLE Workshop by Dr. Michael D. Lockshin, MD, Professor of Medicine, Weill Medical College of Cornell University, Attending
Rheumatologist, Hospital for Special Surgery (January 2000)
A syndrome is a collection of events which constitute a specific illness.
Antiphospholipid Antibody Syndrome (APS) includes a series of symptoms as follows:
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 coronary).
Recurrent pregnancy loss , usually in mid to late pregnancy as opposed to early pregnancy.
An antibody test has to be strongly positive. Having a weak or trace positive test is fairly common in the general population.
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 antiphospholipid antibody is the more general term. 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 1900's, certain people had false positive test results for syphilis. This data was a curiosity without clinical importance at the time, but rediscovered in the 1940's. By
the 1950's, it was realized that this false positive syphilis test had something to do with lupus. Today, although known as a clue to diagnosis, a false positive syphilis test
is not sufficient for a diagnosis of lupus or APS.
In the 1950's and 1960's 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 occurred when people 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, enough cases were seen in which people had APS without having Lupus. It was decided that it
should be categorized as a separate illness. Several names have been used to describe it. The most common name is PAPS (primary antiphospholipid syndrome). It is
also sometimes called 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 (which 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 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 which
also has a membrane. Phospholipids make up the membrane and, as seen in the illustration, they 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.
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, people with APS make antibodies directed
against the b2-glycoprotein 1, which binds to the phospholipid.
30% of people with SLE also have the antiphospholipid antibody.
There are differences between who gets SLE and who gets APS.
90% of the people who develop SLE are women. However, 70-80% of people with APS are women.
Lupus is more frequent in African Americans than Caucasians. However, APS is seen more in Caucasians and Asians.
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.
The result of both theories 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. It is not known why that is. It is also not known why the antibody appears in the first place.
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 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 1is abnormal.
The illustration shows a normal cell is dying. In dying cells, the phospholipids inside flip to the outside. Under normal circumstances, the antibody binds up the
b2-glycoprotein 1and throws the damaged cells in the wastebasket. 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 and starve the baby of nutrition. Treatment is the
use of anticoagulation. In pregnancy, heparin is used. This gives the fetus an 80-90% chance of survival, a drastic improvement from the 1980's 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 3-4 pounds.
Heparin protects placenta partially, but not fully so that the baby gets enough nutrition to survive longer in the mother. Once born, the babies do fine.
Treatment for people who clot is to also use anticoagulation. 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 coronaries. It is used differently in use of patients with APS. People with APS must take a very high dose;
moderate doses do not work well. The goal is to get people who are at the threshold of danger, which is a 10% risk every year for having a hemorrhage. Reaching this level
of anticoagulation can virtually prevent any new clotting. Sometimes aspirin is used, but this is only partially effective.
Another treatment is an experimental therapy called IV immunoglobulin.
Does APS turn into SLE? The answer is no
Does it cause hardening of the arteries? The answer is maybe. There may be more
atherosclerosis in this population of patients than others -- but it is unknown at this time. This question is currently being studied.
Does APS cause heart valve disease? The answer is maybe. It is true that some SLE patients develop leaking heart valve disease. It is also probably in some people 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. 30% 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 better 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.