The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (46 page)

ITP is an unpredictable disease. Some women simply have lowered platelet counts, but never progress to bleeding or other symptoms, and no treatment is needed. Other women may have platelet counts so perilously low that they are in danger of cerebral hemorrhage or other life-threatening bleeds, and immediate intervention is needed.

“There are really no hard-and-fast numbers. But in general, if your platelets are greater than 30,000, we don’t start treatment unless you have symptoms, bleeding, need to undergo surgery, or are participating in at-risk activities like sports, or are fatigued without another explanation,” says Dr. Bussel. “For
newly diagnosed women whose platelets are under 10,000 or with bleeding symptoms, we would give IVIG in combination with prednisone. In some cases the platelet count will return to normal levels and retreatment may not be needed. Unfortunately, there’s no way to predict which women will respond and which will need more therapy.”

The most effective treatment to rapidly increase platelet counts—
intravenous immunoglobulin (IVIG)
,
intravenous Rh (D) immune globulin (IV RhIG, WinRho)
, and steroids—interfere with the destruction of platelets. Removing the spleen (
splenectomy
), and in certain cases rituximab, are the only curative treatments for ITP; splenectomy eliminates the main site of platelet destruction.

However, after the surgery, the destruction of platelets can resume in other organs, like the liver, even after many years of normal platelet counts. For this reason, it is generally accepted that there may be long-term remissions, but there is no “cure” for ITP, explains Dr. Sandler. Oral corticosteroids are the most commonly used nonsurgical treatment to maintain the platelet count.

Because of the serious side effects, women cannot continually take high doses and, in some patients, a short course of steroids followed by IVIG or WinRho will bring about a long-term remission.

Corticosteroids
, most often prednisone, suppress overall immune function, decreasing the destruction of platelets and possibly increasing platelet production. The usual dose is 1 milligram of prednisone per kilogram of body weight (2.20 pounds) a day for up to two weeks until platelet counts come up to a “safe” level (over 30,000). The drug is then tapered off.

“No medication that can be taken orally has been shown to get the count up higher and quicker than prednisone. For this reason, it is usually part of all initial treatments for ITP,” remarks Dr. Sandler. “Steroids are more useful for acute treatment, which we call induction, than they are for keeping platelet counts up over the long term, which we call maintenance.”

Because of the side effects of high-dose steroids, they are not optimally continued for more than four weeks at a time. However, some women may need repeated cycles or prolonged use of steroids, increasing the risk of hypertension, diabetes, cataracts, and bone loss.

Intravenous immunoglobulin (IVIG)
is prepared from human plasma and contains immunoglobulins for IgG, or gamma globulin. IVIG may work by blocking the receptors on macrophages that look for platelets coated with the
IgG antiplatelet antibody. “On these receptors there’s a lock-and-key mechanism. If we flood the circulation with these other IgG molecules, then they’re going to fit into the lock on that receptor and let the platelets go free,” explains Dr. Sandler. “We call it a medical splenectomy. The spleen can’t do two things at once, and if you occupy it with some other molecule, it won’t eat platelets. You’re really taking the spleen out of action.” Recent research suggests that IVIG actually turns on inhibitory receptors and in that way prevents platelets from getting destroyed. IVIG may also increase the rate at which antibodies to platelets remain in the circulation. Thus, there are many possible mechanisms to explain the efficacy of IVIG.

Although IVIG can raise platelet counts within a day or so, large doses are required, which take three or more hours to be infused into the body. IVIG is also expensive—around $5,000 or more per infusion. Adverse side effects can include sudden headaches, backaches, flushing, chills, and (rarely) irritation of the membranes around the brain (
aseptic meningitis
) or kidney dysfunction and failure. The platelet count starts going down within days of an infusion as receptors become cleared of the IgG, so by the end of two to four weeks another infusion may be needed. However, the side effects are not as toxic as those of high-dose steroids (and IVIG doesn’t cause bone loss).

Intravenous Rh (D) immune globulin
(IV RhIG, WinRho)
is also prepared from human immunoglobulins in plasma, but contains a specific antibody to a marker on red blood cells called D, making them a target instead of platelets. The drug is dubbed
anti-D.

RhD is a protein (called an
antigen
) on the surface of the blood cells of 85 percent of people; they are considered Rh-positive. If you don’t have it, you’re Rh-negative.

Rh is used in blood typing, along with blood grouping (whether or not there are specific antigen markers on blood cells that make your blood type A, B, O, or AB as well as Rh positive or negative), to match donor blood with a recipient. Blood antibodies react to the antigens of the
same
type, causing blood cells to clump together and clog blood vessels. Type A blood has the A antigen, and type B has the B antigen. So if you have type A blood you can only accept a transfusion of type A blood; type B can only receive type B.
¹⁸

There are two exceptions. Someone with type O Rh-negative blood is considered a “universal donor” because Type O has
no
antigens for type A or B blood and
no
antigens to Rh. Type AB positive blood is the “universal
recipient” because that blood type has
both
A and B antigens, as well as Rh antigens. So “cross-matching” between blood types is vital.

(Rh becomes important in pregnancy. If an Rh-negative mother is pregnant with an Rh-positive fetus, the mother’s blood develops antibodies to the fetus’ Rh antigens. It’s usually not a problem in the first pregnancy, but in subsequent pregnancies, the anti-Rh antibodies will clump the fetal blood. So the mother will need treatment with another special immune globulin preparation to destroy any Rh-positive cells of fetal blood that may get into her circulation, so the mother’s immune system will not produce antibodies to Rh.)

When the “anti-D” drug is given to Rh (D)-positive women with ITP who haven’t had a splenectomy, it prompts the immune system to order macrophages to target the D protein marker on red blood cells. “Anti-D goes onto normal red blood cells much as the IgG antibody attaches to platelets. Red cells are larger than platelets, and since these people have a normal red count, there are more coated red cells than platelets. So the red cells go in and literally stuff the mouth of the macrophage and the platelets are spared,” explains Dr. Sandler.

The normal life of a red cell is around 120 days; WinRho accelerates the process of removal and keeps the macrophages in the spleen busy gobbling red cells. Platelet counts begin to rise within one to two days after an infusion of WinRho, and peak within a week or two. The response can last up to 30 days before another infusion is needed.

Studies of anti-D have shown a response rate of over 70 percent, bringing platelet counts to over 100,000 in many people, depending on the dose. It also contains special “detergents” and solvents that destroy viruses (such as hepatitis B and C) and remove other viruses, ensuring the drug’s safety (since it’s made from human plasma). WinRho takes around five minutes to infuse (a quick infusion is called a
push
), has fewer side effects, and is less costly than IVIG. But again, it works only in Rh (D)-positive women and those who have not had a splenectomy. In rare cases, WinRho may also cause excessive red cell breakdown. When red cells are broken up too quickly, hemoglobin is released in the bloodstream and excreted in urine, turning it pink.

The direct Coombs test may be able to identify patients at risk for excess hemolysis. A dose of prednisone before an infusion will help prevent fever and chills.

Anti-D may be used in adults as maintenance therapy. Studies show around 75 percent of patients respond, and continued treatments as needed will lead
to resolution within six months in one-third to one-half of people, who will then need no further treatment, says Dr. Bussel.

WinRho is as effective as IVIG for maintaining remissions and is less toxic. However, only 85 percent of patients are Rh (D)-positive. For the remaining 15 percent of women who are Rh (D)-negative, infusions of IVIG may be used as maintenance therapy. However recent information suggests that IVIG may have mild curative effects.

If IVIG or WinRho infusions every three or four weeks maintain a safe platelet count, there’s no reason to consider immediate splenectomy in most cases, remarks Dr. Sandler.

Splenectomy
is 80 percent effective in bringing up platelet counts within days, and up to 65 percent of patients will have a lasting and substantial increase in platelets. Despite its function as a blood filter and fighter of infections, the spleen is actually not an essential organ. Once it’s removed, many of its jobs are taken over by other parts of the lymphatic system; the liver filters the blood, and antibodies can be produced elsewhere. And the destruction of platelets will also take place elsewhere in the body, notably in the liver. You may also have small “accessory” spleens, which must be removed with the primary spleen. Splenectomy also carries a very small risk of serious infections.

The surgery can now be done laparoscopically, using small incisions, rather than as major abdominal surgery; you remain in the hospital for one to three days and can resume most normal routines in a week. Splenectomy may be riskier in older people and is done less frequently after age 65.

Unfortunately, some women’s platelet counts do not go back up after treatment with prednisone, IVIG or WinRho, and splenectomy. “These are the most difficult people to treat, so we use a combination of drugs, which is more effective than single agents but can be more toxic,” says Dr. Bussel. These can include a male hormone,
danazol (Danocrine)
; immune-suppressing agents such as
azathioprine (Imuran)
,
mycophenolate mofetil (CellCept)
; and chemotherapy drugs
vincristine (Oncovin)
or
vinblastine (Velban)
,
cyclophosphamide (Cytoxan)
, and
rituximab (Mabthera)
.

Romiplostim (Nplate)
¹⁹
and eltrombopag (Promacta)
²⁰
are
thrombopoietin receptor agonists
, synthetic proteins that act similarly to thrombopoietin in the body to increase platelet production. They mimic the effects of natural thrombopoietin.

Nplate is given as a weekly injection under the skin.
²¹
Promacta comes in tablet form and needs to be taken on an empty stomach (two hours after a
meal) and four hours before or after calcium intake, including any dairy products.
²²
Both medications can cause increased blood clotting and must be monitored. They are not used in pregnant women, since they would be expected to cross the placenta into the fetus.

Other drugs that can raise platelet counts in severe unresponsive ITP include
colchicine
and
cyclosporine
(which may be more toxic).

Danazol
is a weakened version of testosterone and causes a temporary menopause as well as androgenic side effects like acne, growth of facial hair, and a rise in LDL cholesterol. It may cause liver problems, so liver function tests must be normal before danazol is used and women on this drug must be monitored. For most people, it’s very well tolerated and can help in weaning them off steroids.

If you have any neurological problems, vincristine can’t be given, since it causes nerve damage. If you’ve been in remission and platelets start to fall again, corticosteroids and, in some cases, a combination of vincristine, IVIG, Solu-Medrol, danazol, and/or azathioprine are given.

Rituximab (Rituxan)
, which rapidly depletes peripheral B cells, is also effective in treating ITP, especially when used in combination with high doses of the corticosteroid
dexamethasone
.
²³
Rituximab reduces cells that are the precursors of the antibody secreting type of B cells that produce both antibodies and autoantibodies, including antibodies that attach to platelets.
²⁴

I was diagnosed when I was 22. I was in my senior year in college in California, and I was feeling extremely fatigued. At first I chalked it up to staying up half the night to study; I wanted to graduate with highest honors. But after I had the flu that winter, I never really recovered. And I started to notice these little blood blister things in my mouth and had a couple of bad nosebleeds. I went to the university’s medical center—we had a major medical school there—and the blood tests came back showing that my platelets were extremely low, around 1,900 . . . a hematologist explained that I had thrombocytopenia, that my platelets were disappearing from my body, and that the flu virus had probably made it worse. I figured they would be giving me a blood transfusion or something (that’s how little I knew then), but they put me on steroids, 60 milligrams of prednisone, which they said would bring my platelet count up. It did, but the side effects were awful. My face ballooned, I gained 30 pounds, and I had mood swings. They finally tapered me off it when my counts went up to 230,000. I was thrilled to be off that drug!

I went to our medical library and started reading all I could about this disease, and what I read really scared me to death. I had always had very heavy periods, which seemed to go on forever; I figured that was just me. But I must have had ITP since my teens. The disease changed a lot of my habits; I stopped shaving my legs and used a cream hair remover. I bought an electric toothbrush so I wouldn’t brush my teeth too hard (once I ended up with a mouthful of blood after I accidentally bit my tongue). I stopped playing handball (which I used to love), because I was afraid of the bruising. After I got off the prednisone, I worked hard at losing the weight and my face started to look normal. My fiancé and I had planned to be married at Christmastime and I wanted to look nice. I made it through the wedding, and then my platelets dropped again and I was right back on prednisone. I went through three cycles of the stuff and my platelets finally seemed to stabilize, and I thought I was out of the woods.

When I was 27 I became pregnant. Fortunately, my hematologist referred me to an OB who had handled a number of ITP pregnancies. My platelets stayed in the 90s during my first and second trimester, but when they started falling again, I was back on prednisone. My OB assured me that prednisone would not harm my baby, but there was an outside chance that my baby would be born with ITP. When Callie was born they found she had a
platelet count of 28,000, so they took her to the neonatal intensive care unit, and she stayed there for a few days. She was put on a liquid form of prednisone for four weeks, and her platelet count went up to 250,000 and has stayed normal ever since, thank God. After that, I decided to have a splenectomy—I was tired of the way this disease seemed to dominate my life. My platelets have been normal ever since the surgery, and we hope to have a second child. The only catch is that my ITP could come back during pregnancy. But it’s a chance I guess I’ll take.

A
UDREY
, 32