The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (43 page)
Authors: Rita Baron-Faust,Jill Buyon
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A Fury in the Blood—Antiphospholipid Syndrome, Immune Thrombocytopenia, and Vasculitis
It took me almost 10 years to get a diagnosis. I had a history of headaches and started having blood clots in my legs in 1986. The vascular surgeon I was seeing found that my platelets were sky high, and I was told I had essential thrombocytosis. He put me on Coumadin to thin my blood. Almost immediately, my headaches went away, and after a while I stopped having the leg clots. My platelet count went back to normal, so they took me off the Coumadin, and right away I started having headaches again, and I had a mini-stroke. But when I told my primary care physician about it, he said that a stroke was unlikely for a woman my age with good blood pressure and cholesterol. He said it was probably an episode of low blood sugar, and didn’t do any tests.
I was in my daughter’s room when I had another stroke. I felt this stabbing pain in my head, like an ice pick. I thought I was speaking normally, my words sounded normal to me. But my daughter said, “Mom, your words are slurry and one side of your mouth is droopy. You’re having a stroke,” and she called 911. When we got to the ER the doctor on duty didn’t think I had had a stroke (he also said I was too young, my blood pressure was too good, and so on) and sent me home. But the next day I couldn’t get out of bed, and we went to another hospital closer by. They did an MRI and it showed that I had actually
had five small strokes. They ordered a bunch of blood tests; one of them was a cardiolipin antibody test. The odd thing was that years before, my ophthalmologist had asked if I had had a cardiolipin workup. He said that anybody with unusual clotting under age 40 should have the test. . . . And in the hospital, after my stroke, the neurologist I saw suspected I had antiphospholipid syndrome. It took me months to get the results of the blood test they did after that stroke. By that time I had gone to a bigger hospital in the city to see a specialist, and he was the one who actually made the diagnosis of antiphospholipid syndrome.M
ARGARET
, 56
Antiphospholipid syndrome (APS)
is a disorder in which autoantibodies promote blood clots that can affect virtually any area of the body—causing seemingly unrelated problems like miscarriages and stroke.
First identified in the mid-1980s, antiphospholipid syndrome is an insidious disease that may not be diagnosed until after a woman has suffered several strokes, as in Margaret’s case. In fact, APS is now thought to account for one-third of all strokes in people under age 50, as well as 20 percent of clots in the veins of the legs (
deep vein thrombosis, DVT
), and up to 15 percent of recurrent miscarriages. APS may have more widespread effects in the body than systemic lupus, since blood clots can block just about any blood vessel, from the tiniest capillaries in the eyes to the large vessels supplying the heart and brain.
1
The formation of blood clots involves
platelets
(or
thrombocytes
), which originate in the bone marrow along with white and red blood cells, and proteins called
coagulation
or
clotting factors
. When you have a cut, platelets rush to the area to start plugging up the wound. First, each platelet adheres to the damaged blood vessel and becomes activated so they attach to each other (
aggregate
). Platelets are activated partly by chemicals secreted when a blood vessel is injured and by
thrombin
, a protein released during the clotting process itself (activated platelets also secrete chemicals needed for clotting). These chemicals stimulate coagulation factors in the blood and form a stringy
protein called
fibrin
, creating long filaments that enmesh the platelets and other blood cells to form a semisolid plug in the wound that stops bleeding. Abnormal clot formation occurs when a blood vessel has not been punctured or cut, in other words, when there’s no reason to clot.
This “coagulation cascade” is a complex process; anything that interferes with one step can cause either a tendency to abnormal bleeding or formation of blood clots (
thromboses
). In APS it is thought that autoantibodies react with proteins involved in the coagulation cascade and through still-unknown mechanisms disturb this process, leading to abnormal clot formation in veins or arteries.
APS can cause
venous thromboembolisms (VTEs)
, clots in leg veins called deep vein thromboses (DVTs) that can travel to the lungs (
pulmonary embolus
), or clots in major arteries leading the brain causing strokes or “mini-strokes” (
transient ischemic attacks, TIAs
), or heart attacks. In pregnant women, these autoantibodies can lead to clots in the placenta that block blood flow to the fetus, causing recurrent second trimester (or later) miscarriages.
Antiphospholipid syndrome is five times more common in women than in men, and sometimes runs in families. APS can occur with other autoimmune diseases—40 percent of people with the syndrome also have systemic lupus erythematosus (SLE), and 37 percent of SLE patients have
anti-beta2 glycoprotein I (anti-β2GPI) antibodies
2
but it can also affect otherwise healthy women whose only outward sign may be repeated pregnancy loss.
Antiphospholipid antibodies act against key proteins involved in clotting.
There are three main antiphospholipid antibodies (aPLs)—
anticardiolipin antibodies (aCLs)
, the
lupus anticoagulant (LAC)
, and
anti-beta2 glycoprotein I (anti-β2GPI)
.
3
Recent research has changed our understanding of the targets and actions of these antibodies, so the names originally given to them aren’t really accurate descriptive terms.
For instance, the lupus anticoagulant doesn’t have anticoagulant properties, but produces an increased risk of blood clotting. And, it turns out, aCLs don’t actually bind to
cardiolipin
(a phospholipid found in high concentrations in heart and muscle tissue but present in all tissue). In other words, if you are found to have the LAC it does not mean you have a bleeding tendency. The reason for this paradox is that the autoantibodies react with proteins that in a test tube are needed to make the blood clot, but in the body these antibodies actually promote clots. β2GPI is a protein that binds to cell membranes and has natural anticoagulant properties, so binding to it and preventing its action can be a problem.
These aPLs are present in up to a third of women with lupus, and in women with rheumatoid arthritis, Sjögren’s syndrome, and other autoimmune diseases, but they don’t always cause clotting problems.
Other types of aPLs can be produced after infections (especially in older people) and do not seem to result in a clot. Infections linked to antiphospholipid antibodies include parvovirus (the respiratory virus that causes fifth disease), rubella, mumps, Lyme disease, HIV, and hepatitis A, B, and C. Additionally, aPLs are also found in women with immune thrombocytopenia (a condition in which there are low platelet counts, see
pages 362
to
379
).
There are a number of theories as to how these antibodies may come about. “Perhaps you get an infection, and there’s inflammation and the cell phospholipids turn over and are exposed on the cell surface. But after the infection and inflammation go away, the normal antibody response doesn’t die down, the antibodies start mutating, and sooner or later they start binding to an important blood clotting protein,” suggests Joan T. Merrill, MD, an expert on APS and head of the department of clinical pharmacology at the Oklahoma Medical Research Foundation (OMRF) in Oklahoma City.
An infection may also set off another process that leaves clotting-related proteins exposed to an immune system attack. “When there is inflammation, these proteins bind to the surface of the cells of the bloodstream, and may fold in such a way that exposes little pieces of the protein that aren’t normally seen by the immune system. Antiphospholipid antibodies may be binding to parts of these proteins that normally stay hidden until they are needed to stop blood clotting. So when the protein unfolds and exposes certain areas, instead of stopping blood clotting, the protein is attacked by antibodies,” says Dr. Merrill, an OMRF professor of medicine who also heads up the Registry for the Antiphospholipid Syndrome.
Oxidative stress
, the process by which cells react to and are damaged by oxygen, may also be involved.
2
Young women who have the LAC have an increased risk of stroke, but when there’s also oxidative stress (from smoking, for example) and other physiological disruptions, the odds of a clot-induced stroke skyrocket.
4
There may be something about the placenta itself that attracts anticardiolipin antibodies, which cause cell death and other adverse effects that can lead to fetal loss.
Perhaps molecular mimicry might be involved, where invading microbes have a similar structure to clotting proteins, so the immune system attacks both. While the bacteria are eventually eliminated, in vulnerable women immune cells may continue to target the normal proteins. Recent studies suggest that
Haemophilus influenzae
and other common bacteria may trigger production of certain antiphospholipid antibodies in genetically susceptible women.
3
Several genes are probably involved in APS, and it may run in families. Some of the genes associated with rheumatoid arthritis and other autoimmune diseases (like the DR4 gene) are also found in women with APS, which may explain its coexistence with those diseases. Your genes may also determine the amount of aPLs you make. For example, women with higher levels of aCLs have more clotting events.
5
I can tell you exactly when this all started. It was in February of 1989. I woke up in the middle of the night with a severe headache and joint pain.
I had had a little fever all week, I developed a kind of rash on my arm, and I was extremely tired. I went to bed that Friday night, and must have
awakened around two in the morning in such pain that I couldn’t bear to have the sheets on me. It was that bad and that fast. It was like I went to bed and woke up someone else. And the fatigue the next day was just crushing. Not like when you’ve cleaned your whole house and you’re very tired. More like you’ve been turned inside out. But we thought it was the flu, because that’s how flu hits. I had also had periods of confusion before that; I’d be at the grocery store and just stop and wonder what I was doing there with these coupons and this list. I went to my family doctor and he tested me for lupus, for Lyme disease, for mono, everything. But the tests all came up negative . . . and if you’re a woman, they say, “Are you premenstrual, are you premenopausal, are you depressed?” Well, I wasn’t depressed. I was very happy. I had just met a wonderful man. We don’t live far from Yale (where it turns out they were studying this disease). I went there, and tested positive for antiphospholipid antibodies. They also did an MRI and saw evidence that I had had multiple small strokes. They counted a dozen lesions in the midbrain; they looked like little grains of rice on the MRI. This explained the confusion. And that was a relief, because after they run all those tests and find nothing, you begin to feel as if you really are going crazy.E
LAINE
, 58
Elaine’s and Margaret’s stories are not that unusual. “Women with APS tend to have dramatic case histories,” remarks Robert A. S. Roubey, MD, an associate professor of medicine at the University of North Carolina at Chapel Hill. “A woman comes into the office and says ‘I have been pregnant five times and lost all the babies, and I have never been able to carry a pregnancy to term.’ Or a young woman has a stroke out of the blue. Or a young woman has recurrent DVTs. Those are the three key symptoms of APS, and they are striking,” says Dr. Roubey.
Recurrent miscarriages occur at specific points in a pregnancy in APS. “The most typical fetal loss associated with antiphospholipid antibodies occurs in the second trimester or later, which is a very unusual time to have a
miscarriage. Perhaps 10 to 15 percent of these losses are associated with antiphospholipid antibodies,” says Dr. Roubey. “While some women experience very early losses, before 10 weeks, they are not characteristic of APS and they can have many other causes, so it’s difficult to make an association with these antibodies.”
Repeated episodes of blood clots in leg veins (especially in the deep veins) and strokes (major and mini) are the other major symptoms of APS. Deep vein thromboses are dangerous because a piece of the clot can break off and travel to the lungs. Around 40 percent of women with APS experience DVTs, more often in primary APS.
6
A third of women with APS also have reduced platelet counts (
thrombocytopenia
), often detected during routine bloodwork.
5
Although these women have longer than usual clotting times, they typically don’t have bleeding episodes, Dr. Roubey points out.
Other complications of APS include heart attacks (often before age 45), likely due to blood clots in arteries that may be already narrowed by atherosclerosis, epileptic-type seizures, headaches (often migraines), vision problems caused by blockages (
infarcts
) in the tiny blood vessels of the eye, memory problems or dementia caused by mini-strokes (
multi-infarct dementia
), blood clots in the lungs (
pulmonary embolism
), and heart valve disease.
2
“With heart valve disease in APS, you have fibrin deposits on the valves, most often the mitral valve, which thickens the valve so it doesn’t close properly—this allows some blood to flow backward, which we call regurgitation,” explains Dr. Roubey. “These fibrin deposits can break off and cause occlusions, and clots can also form on the valve. This also occurs in lupus, and is associated with anticardiolipin antibodies.”
APS can cause skin problems, including a red or bluish rash on the legs (
livedo reticularis
), which looks like a “mesh network of veins underneath the skin,” says Dr. Roubey.
These problems can appear sporadically, separated by months or years, and seem unrelated.
In some women, a series of clotting-related events affecting multiple organs (especially the kidneys and the heart) suddenly occurs over a period of days or weeks, sometimes after infections, surgery, or giving birth. This is called
catastrophic APS (CAPS)
, and it can be life threatening because clots can quickly affect multiple organs.
7
When APS occurs by itself it is sometimes called
primary antiphospholipid syndrome (PAPS)
and is more common in younger women with recurrent, unexplained miscarriages.
Secondary APS
is associated with underlying autoimmune diseases, notably SLE and Sjögren’s syndrome, and can even be drug induced. More recently they are being referred to as APS with or without associated rheumatic diseases.
1
Patients are generally categorized by age, sex, and the complications they have, since symptoms may be caused by an underlying problem rather than by APS itself. Finding out whether other family members have APS may help some women to recognize symptoms and be treated earlier.
Around 20 percent of women with aPLs who suffer recurrent miscarriages may go on to develop leg clots.