Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (45 page)
Immune thrombocytopenia (ITP)
is a disorder in which the immune system attacks and destroys platelets in the blood, interfering with normal blood clotting. The disorder was formerly called
idiopathic thrombocytopenic purpura
(
purpura
refers to bruising or bleeding under the skin). It is sometimes referred to as autoimmune thrombocytopenic purpura. In this chapter, we’ll use the term
immune thrombocytopenia
.
As discussed previously, when you get a cut, platelets gather in the area and almost immediately start to form a clot to seal off the area and limit bleeding. It’s kind of like plugging up a leaky pipe. But if you don’t have the materials to create that plug, the pipe keeps leaking. In ITP there’s a shortage of platelets to form the plug because the immune system has targeted them for destruction in the spleen. As a result, blood clots don’t form properly, allowing bleeding to continue for longer periods.
The spleen is a kidney bean–shaped organ located in the upper left abdomen, just behind your ribs, that produces some of the antibodies and immune cells that help fight off infections and removes worn-out red blood cells and antibody-coated particles like bacteria. Normally, platelets circulate in the blood for 10 days before being cleared by the spleen and replaced by others produced in the bone marrow. In women with ITP, this process of platelet clearance is sped up by autoantibodies at the same time as fewer platelets are made. These antibodies bind to platelets and cause the spleen and other organs to remove them from the blood prematurely. So platelets remain in the blood for only a short time, depending on how severe the disease is. The platelets are destroyed faster than they can be replaced.
A
thrombocyte
is a clotting cell,
penia
means low blood levels; thus
thrombocytopenia
means low platelets.
Since platelets are essential for stopping leakage of blood from damaged blood vessels, severe thrombocytopenia can cause bleeding, especially from smaller blood vessels in the skin and other parts of the body.
Low platelets can lead to prolonged and heavy menstrual periods, and bleeding from tiny blood vessels in mucosal surfaces such as the nose or gums. Bleeding can occur even with a minor injury that doesn’t break the surface of the skin, so you bruise easily. Small bleeds can arise from blood vessels beneath the surface of the skin or mucosa, producing small red spots called
petechiae
inside of the mouth and on the legs. When the platelet count gets too low, bleeding can occur without provocation in the intestines or even the brain.
Normally you have 150,000 to 450,000 platelets per microliter of blood (usually written with Greek symbol µL). In severe cases of ITP, platelets are so depleted that the count can be close to zero; in milder cases, your platelet count may hover around 100,000 µL. However, bleeding (beyond bruising) usually does not occur until platelet counts fall below 30,000 to 50,000.
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Platelets have another function that has nothing to do with clotting. They store the mood-elevating brain chemical
serotonin
, which has effects not only in the brain but also in the body. Serotonin is involved in mood regulation, appetite, biological rhythms, and our sleep-wake cycle. So another consequence of having too few platelets can be a low level of serotonin, which may cause depression and fatigue. Whether this is the cause of the fatigue that is common in patients with ITP is not known.
ITP can occur at any age, but in adults it most often occurs between ages 20 and 40, affecting three times as many women as men. It can also occur in the elderly. In some cases, ITP occurs along with other autoimmune diseases
such as lupus, antiphospholipid syndrome, rheumatoid arthritis, inflammatory bowel disease, and thyroid disease (see
page 374
).
While ITP can develop slowly in adults, in children it can come on suddenly (usually between ages two and four)—sometimes a couple of weeks after a viral illness—and may resolve on its own after a few weeks or months.
The destruction of platelets and inhibition of platelet production are caused by autoantibodies called
antiplatelet antibodies
. But this autoantibody doesn’t directly attack the platelet cell; it binds to the cell membrane and makes the cell a target for destruction by macrophages in the spleen.
You’ll recall that macrophages (the “big eaters”) are programmed to recognize foreign antigens like bacteria, ingest them, and take them out of circulation. While some macrophages patrol the bloodstream, some are produced by the spleen to help fight infectious agents there. When a receptor called the Fc receptor on those macrophages targets the antiplatelet antibody (which has an Fc part capable of being bound by the Fc receptor) on the surface of a platelet, the macrophage thinks it’s a foreign cell and gobbles up the platelet, explains hematologist S. Gerald Sandler, MD, professor of medicine and pathology at MedStar Georgetown University Hospital in Washington, D.C.
Antiplatelet antibodies are produced by B cells in the sponge-like outer layer (
capsule
) of the spleen, lymph nodes, and bone marrow. Even after the spleen is removed, people with ITP may have elevated antiplatelet antibodies. So those B cells must also be present in other organs, like the liver and bone marrow, and in the circulation. The number of antibody-producing B cells may be increased in women with ITP, says Dr. Sandler, who’s also director of transfusion medicine in the hospital’s Department of Laboratory Medicine.
Numbers are also increased of “helper” T cells, which signal B cells to produce autoantibodies, perhaps telling other B cells to secrete antiplatelet antibodies. Platelet destruction can also occur in the liver (another organ that helps cleanse the blood).
What prompts the formation of these autoantibodies is not known. When the body is invaded by viruses or bacteria, production of antibodies called immunoglobulins may be stimulated. These antibodies may also act against
proteins on platelets and function as antiplatelet antibodies. Most of the platelets destroyed in the spleen in this situation have been coated with these antiplatelet antibodies. The amount of platelet surface antiplatelet antibody correlates with the degree of thrombocytopenia.
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The structure of the platelets is thought to be totally normal in ITP; it’s the antiplatelet coating that’s not. “The macrophage is really looking for bacteria coated with the antibacteria immunoglobulin, the body’s normal defense. And it will take bacteria and eat it up, get it out of the circulation, if it’s got the antibody on it as part of the defense. In this case, we’ve also got a platelet that’s cruising through with an abnormal antiplatelet antibody on it, so that’s what’s going to get picked up by the Fc receptor on the macrophage,” says Dr. Sandler. “So what you have is a disorder where normal-looking platelets get taken out of the circulation by a cell in the spleen because they are coated with an antibody that shouldn’t be on their surface.”
At the same time, animal studies suggest ITP may in part be due to a problem with the development of platelets from stem cells, the cells in bone marrow that also develop into red and white blood cells.
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A growth factor produced in the liver called
thrombopoietin (TPO)
acts on stem cells to transform (or
differentiate
) them into cells called
megakaryocytes
, which mature into platelets and are released into the bloodstream. TPO levels are not increased sufficiently to compensate for low platelets. This compounds the situation and may be one reason platelets are destroyed faster than new ones are made.
Infections and medications can also cause formation of antibodies. Since some cases of ITP are caused by drugs, occur after a virus, or worsen after a viral infection may mean that there are environmental triggers. ITP has been associated with Lyme disease,
cytomegalovirus
,
Epstein-Barr virus (EBV)
,
mycoplasmal
pneumonia, hepatitis C, and the ulcer-causing bacteria
Helicobacter pylori (H. pylori)
. Urea breath tests for
H. pylori
can determine if you’ll need to be treated for that infection.
“There are infections that you don’t completely clear that are associated with ITP. When you suppress them, it makes the thrombocytopenia better. For example, antiviral therapy boosts platelet counts in people with ITP with HIV-related thrombocytopenia or in hepatitis C,” says hematologist James B. Bussel, MD, professor of pediatrics and director of the Platelet Disorders Center at the Weill Medical College of Cornell University.
There may be genes involved that increase the risk of developing ITP, but they have not been isolated yet. Potential genetic variations could include a gene that affects the Fc receptor, TPO, or other components of the immune system. “If we could find such genes it would then allow us to do tests in people and determine the optimal treatment for that individual,” comments Dr. Bussel.
Joan’s story continues:
If I had four hours a day when I could actually do something, that was a good day. I was incredibly fatigued; I couldn’t walk out to get my mail. . . . I was obsessed with the marks on my body. I had red spots on my legs, and I would get enormous bruises. I had blood blisters in my mouth that looked like grapes. I went to my doctor to get a platelet count twice a week. Once it was zero; it was very frightening. I tried to keep my brain active with crosswords. I changed my diet, I adopted a macrobiotic diet, and that seemed to help a little bit. Then I got the flu, and my platelets fell to 10. . . . I had a number of treatments, but nothing seemed to work for me. Finally, I agreed to have a splenectomy . . . but two weeks after that, my platelets were as low as they were before. I tried herbs, I went on a macrobiotic diet, I did many other things to improve my health and tried a new regimen of drugs . . . and finally my platelets came back to a normal level.
ITP typically develops over months or years in adults, and there’s typically no spontaneous bleeding until platelets fall below a certain level, usually around 30,000 to 50,000.
Your first symptoms may be heavy periods that last longer than usual. You may have nosebleeds (
epistaxis
), and your gums may bleed during normal brushing or routine dental work. Bleeding can occur even with a minor injury that doesn’t break the surface of the skin, so you bruise easily (
purpura
is the Latin word for purple and refers to discoloration from bleeding under the skin). Sometimes this bruising (
thrombocytopenic purpura
) can occur on the arms or legs with no provocation at all, as it did with Joan.
Skin lesions develop as the tiny blood vessels beneath the surface of the skin or mucous membranes bleed, forming small red or purple spots (
petechiae
) inside the mouth and on the ankles and legs. The petechiae don’t itch, and they’re not raised (in contrast to those in
vasculitis
). Petechiae can merge together and form large bruise-like areas (
purpura
), which may occasionally develop into hemorrhagic blisters (
bullae
).
As your platelet count falls, there may be blood in the urine (
hematuria
), gastrointestinal bleeding, and, in rare cases, bleeding in the brain (
cerebral hemorrhage
).
Some women may become alarmed at the frequency of bruising and seek medical care. In an estimated in 50 percent of cases, ITP is diagnosed during routine blood tests that happen to include a platelet count that show abnormally low numbers. In most of these cases when an abnormally low platelet count is detected incidentally by a routine blood test, the platelet count is not in the very low range and returns to normal in a few weeks of “watchful waiting.”
A diagnosis of thrombocytopenia is made when an abnormally low platelet count cannot be attributed to another cause such as a coincidental infection, a drug, or disease known to be associated with thrombocytopenia. What
isn’t
so simple is excluding other diseases that may be responsible for the low platelet count. But keep in mind that levels of platelets between 100,000 and 150,000 do not carry any risk of bleeding. With regard to lupus, the platelet count has to be below 100,000 to be considered one of the criteria for lupus. A number of diseases can cause low platelet counts, including lupus, antiphospholipid syndrome, Crohn’s disease, Graves’ disease, and
primary biliary cirrhosis
. Other diseases that can cause low platelet counts include
chronic lymphocytic leukemia
,
B-cell lymphoma
, and
Hodgkin’s disease
. In some cases, a low platelet count occurs without apparent cause or other diseases (which is where the term
idiopathic
comes from, but it’s often used interchangeably) or
nonimmune
thrombocytopenic purpura.
Secondary immune thrombocytopenia
occurs in a number of multisystemic autoimmune and other diseases. At least 30 percent of women with systemic
lupus erythematosus also have ITP and, in certain cases, it may be the first symptom that presents itself, says Dr. Bussel. Low platelet counts can also occur in rheumatoid arthritis and scleroderma.
However, unlike diseases where antibody testing can help make a diagnosis, testing for antiplatelet antibodies isn’t useful in diagnosing ITP. “The diagnosis is based on a platelet count under 150,000, large platelets seen on a blood smear, and an otherwise normal blood count and physical exam, except for signs of bleeding, such as petechiae,” explains Dr. Bussel.
Complete blood count (CBC)
is the most important test for diagnosing thrombocytopenia. But you need the CBC, not just a platelet count, stresses Dr. Bussel. “You need to know the white cell count, the level of hemoglobin, the size of the red blood cells, the mean cell volume, all the red cell indices, to see if there are abnormal cells circulating,” he explains.
In some people with thrombocytopenia, either red blood cells may be cleared faster by the spleen because of antibodies directed against them or there’s bleeding from heavy menses, so a red blood cell count may be lower than normal.
Hematocrit
(percent of red cells per volume of blood) and level of
hemoglobin
(the oxygen-carrying component of red cells) also indicates the amount of red blood cells.
A
peripheral blood smear
can reveal enlarged platelets (
megathrombocytes
), which are frequently seen with ITP and may be a sign that platelets are being destroyed and new large ones rushed out of the blood marrow to compensate. In the test, a blood sample is smeared onto a slide, stained, and viewed under a microscope.
A
direct Coombs test
may be done to see whether red cells have an antibody or complement on their surface (which is important in treatment with a drug called
WinRho
,
pages 371
to
373
). “You can have the same problem with red blood cells as you do with platelets, where there’s an antibody that causes them to be broken down faster by the spleen,” explains Dr. Bussel. “We might do this test to determine which patients could receive a treatment that places an immunoglobulin antibody on the red cells to make them a target
instead of platelets. But if the red cells already have antibody on their surface, the drug would cause more red cell breakdown, or aggravated hemolysis.”
Bone marrow aspiration
may be needed in some cases to determine whether the number of
megakaryocytes
, the precursor cells to platelets, is normal. If megakaryocytes are increased, it can indicate that platelets are being destroyed by the spleen.
Myelodysplasia
(abnormal growth of bone marrow), a preleukemic syndrome found more often in people over age 60, can lead to abnormal megakaryocytes and low platelet counts and can be picked up with a bone marrow test. Bone marrow aspiration can also detect leukemia or marrow failure. However, bone marrow tests are not done routinely when tests look entirely like ITP.
Lupus autoantibody
testing is highly advisable even if symptoms of arthritis do not exist with thrombocytopenia. Moreover, in some cases other autoantibodies are present (such as antiphospholipid antibodies), such as in lupus. “If other organ systems appear to be involved, it may be appropriate to see whether a woman has lupus. In this case, the thrombocytopenia would be the tip of the iceberg,” says Dr. Bussel. Key autoantibodies in lupus include
antinuclear antibodies
,
anti-DNA antibodies
, and
antiphospholipid antibodies
(see
pages 72
to
73
.)
Thyroid stimulating hormone (TSH)
tests may also be done, since there’s as much as a 10 percent overlap with hypothyroidism in ITP, Dr. Bussel adds (see
page 374
).
