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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.
Slide 12
 
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.
Slide 18
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
Slide 20
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.
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