Aplastic anemia is a disorder in which the bone marrow fails to make enough blood cells. The bone marrow is the soft, inner part of bones where the 3 types of blood cells are made:
- red blood cells, which carry oxygen to the tissues from the lungs
- white blood cells, which fight infection
- platelets, which seal damaged blood vessels to prevent bleeding
These cells are made by blood-forming stem cells in the bone marrow. In aplastic anemia, the stem cells are damaged and there are very few of them. As a result, too few blood cells are produced. In most cases of aplastic anemia, all 3 types of blood cells are low (which is called pancytopenia). Rarely, just one of the cell lines, such as red cells, white cells, or platelets, is abnormal.
Aplastic anemia is not a type of cancer but may be associated with certain cancers (especially those affecting the bone marrow, such as leukemia) or cancer treatments. A small number of patients with aplastic anemia may develop leukemia.
Aplastic anemia can be inherited or acquired. Acquired aplastic anemia is much more common than the inherited type.
Inherited aplastic anemia
Aplastic anemia is considered inherited when it is caused by gene mutations (abnormal copies of genes) that have been passed on from the parents to their child. Inherited aplastic anemia is more common in children and young adults.
Fanconi anemia
The most common cause of inherited aplastic anemia is called Fanconi anemia. There are many different genes that can cause Fanconi anemia. They are called FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN. In order to get FA, a child must inherit 2 abnormal copies of one of these genes -- one from each parent. Someone with only one abnormal copy will not develop the disease and is called a "carrier."
The genetic material (DNA) in our cells is packaged into chromosomes. In FA, the chromosomes are easily damaged by toxins in the environment. This can lead to aplastic anemia, leukemia, and other cancers. Cancers of the mouth and throat, esophagus, and the vulva (female genital area) are seen at a higher rate and at a younger age in those with Fanconi anemia (as compared with people who don't have FA).
In many cases, Fanconi anemia is suspected when a child is born because s/he is missing a thumb or a bone in the arm called the radius. A child with Fanconi anemia also may not grow well (called growth retardation) or have a small head (called microcephaly). Dark spots on the skin (called café au lait spots) can be another symptom of FA. In some cases though, the child will look completely normal. People with Fanconi anemia can start to have low blood counts at a very early age. The low blood counts may be treated with medications called androgens at first, but only a bone marrow transplant can actually cure aplastic anemia in someone with Fanconi anemia.
Some people with Fanconi anemia do not develop low blood counts (or aplastic anemia), but may be diagnosed with FA when they get cancer. In order to diagnose Fanconi anemia, a chromosome breakage test will be ordered. For this test, a small sample of blood is taken from the patient. Then some of the cells in the blood (called lymphocytes) are exposed to a certain chemical to see if it causes the chromosomes in the cells to break and rearrange. Chromosomes in normal cells aren't damaged easily, but the chromosomes in FA cells will be damaged.
Dyskeratosis congenita
Another inherited cause of aplastic anemia is called dyskeratosis congenita. Defects in some of the genes that help protect the chromosomes cause this disease. The chromosomes in our cells are fitted with caps at each end called telomeres. These caps help protect the ends of the chromosomes from being damaged. Telomerase is the protein that maintains the telomeres. Two different genes, called TERC and TERT, are needed to make telomerase. An abnormal copy of either one of these genes can cause dyskeratosis congenita. Another gene, DKC1, makes a protein called dyskerin that is needed for telomerase to work. Abnormalities in this gene also cause dyskeratosis congenita. Symptoms of this disorder include abnormal skin pigmentation, abnormal nails, and white patches in the mouth (called leukoplakia). People with this problem have a high risk of developing aplastic anemia and certain cancers. People with dyskeratosis congenita have higher rates of cancer of the mouth and throat and cancer of the anus. Some people are only diagnosed with dyskeratosis congenita when they come in with aplastic anemia and are found to have abnormal telomerase genes. These people may not have any of the other signs or symptoms of dyskeratosis congenita.
Other causes of inherited aplastic anemia
Another cause of inherited aplastic anemia is called the Diamond-Blackfan syndrome. In this disease, red blood cells are low, but the number of other blood cells is normal.
A fourth disorder is the Shwachman-Diamond syndrome, which is caused by abnormal copies of a gene called SDS. Here, the major problem is poor production of white blood cells, although the other cell lines can also be abnormal. In both of these, patients will often have other problems such as short stature and other bone abnormalities.
Acquired aplastic anemia
Acquired aplastic anemia usually occurs in adults, although children may also be affected. Most have no gene abnormalities. Scientists have found that some of the people who they thought had acquired aplastic anemia actually have an abnormality in one of the genes responsible for inherited aplastic anemia. The aplastic anemia in these people is not really acquired -- it is inherited. Some cases of aplastic anemia seem to be triggered by a drug or exposure to a toxic chemical. In most cases of aplastic anemia, however, the cause is never found.
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a disease in which some of the stem cells in the bone marrow become damaged and make abnormal red blood cells. The red blood cells in PNH are missing certain proteins that normally help protect the cells. Without these proteins, the red blood cells are killed by the immune system (this is called hemolysis). PNH is caused when the gene called PIG-A is damaged (mutated) in some of the stem cells in the bone marrow. People with PNH have anemia (low red blood cells) along with fatigue, stomach pain, and blood clots. Sometimes the hemoglobin from the destroyed red blood cells will cause the urine to become very dark (like the color of tea). PNH seems to be linked to aplastic anemia. Some patients have small numbers of PNH cells when they are diagnosed with aplastic anemia. Also, some survivors of aplastic anemia will go on to get PNH. PNH can be treated with bone marrow transplant or with a drug that blocks the hemolysis called eculizumab.
What Are the Risk Factors for Aplastic Anemia?
A risk factor is anything that changes your chance of getting a disease. For example, certain cancers have different risk factors. Exposing skin to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for many cancers. But risk factors don't tell us everything. Having a risk factor, or even several, does not mean that you will get the disease. And not having a risk factor doesn't mean that you won't get the disease.We know that certain aplastic anemias are inherited. Having Fanconi anemia or dyskeratosis congenita increases the risk of developing aplastic anemia.
Exposure to certain drugs and chemicals may increase the risk of acquired aplastic anemia. It is important to realize that these medications are safe for most of the people who take them. In some cases, however, people develop aplastic anemia after receiving one of these drugs.
Some of the medicines linked to aplastic anemia include:
� nonsteroidal anti-inflammatory drugs (NSAIDs) -- medicines used to treat pain and inflammation. Examples include indomethacin (Indocin), piroxicam (Feldene), and diclofenac (Voltaren)
� amphetamines including MDMA (Ectasy)
� antibiotics including sulfonamides ("sulfa drugs") and forms of penicillin
� anti-thyroid drugs such as propylthiouracil and methimazole (Tapazole)
� carbonic anhydrase inhibitors including acetazolamide and methazolamide (these are used to treat glaucoma)
� diabetes medication including tolbutamide, carbutamide, and chlorpropamide
� diuretics (water pills) such as furosemide (Lasix) and thiazides
� drugs used against malaria including quinacrine and chloraquine
� phenothiazines (Thorazine, Compazine) -- medicines used for nausea and certain psychiatric problems
� allopurinol (Zyloprim) -- used for treating gout
� ticlopidine -- used to prevent strokes and heart attacks
� anti-seizure drugs like carbemazepine (Tegretol), phenytoin (Dilantin), and valproic acid
� chloramphenicol, an antibiotic (no longer available in the United States)
� mesalazine which is used to treat ulcerative colitis and Crohns disease
This is only a partial list of the drugs most often associated with aplastic anemia. Other drugs may also cause this disease. The best way to avoid aplastic anemia from drugs is to take medicines only if they are necessary.
Exposure to chemicals such as solvents and pesticides at home or in the workplace is also a risk factor. These include:
benzene, which is found in gasoline, automobile exhaust fumes, cigarette smoke, emissions from coke ovens and other industrial processes, and waste water from certain industries, is the most common offender.
industrial pesticides, like organophosphates and carbamates
Other risk factors include:
- hepatitis
- pregnancy
- auto-immune diseases like lupus (systemic lupus erythematosus) and rheumatoid arthritis
- severe radiation poisoning (like seen after an atomic bomb explosion
This information represents the views of the doctors and nurses serving on the American Cancer Society's Cancer Information Database Editorial Board. These views are based on their interpretation of studies published in medical journals, as well as their own professional experience.
The treatment information in this document is not official policy of the Society and is not intended as medical advice to replace the expertise and judgment of your cancer care team. It is intended to help you and your family make informed decisions, together with your doctor.
Your doctor may have reasons for suggesting a treatment plan different from these general treatment options. Don't hesitate to ask him or her questions about your treatment options.
Treatment for aplastic anemia is either primary or supportive. Primary treatment is aimed at curing the disease. Common primary treatments are stem cell transplant and immune suppression. Supportive treatment is aimed at helping the symptoms of aplastic anemia without actually trying to cure it. Treating anemia with transfusions is a type of supportive treatment.
Primary treatment
Allogeneic stem cell transplant
Allogeneic stem cell transplant is considered the best treatment for younger people with aplastic anemia. Transplantation works best in children and young adults. As people get older, it's harder for them to tolerate this procedure. For people older than 30 or 40, many doctors prefer using immune therapy as the first treatment. In order for transplant to be an option, you need to have a donor who is matched to you. Someone who is closely related to you, like a brother or sister, is generally the best choice. In aplastic anemia, this stem cell transplant is successful up to 80% to 90% of the time if cells from a matched related donor are used.
Matching is determined by a type of test called HLA typing, which is done in the laboratory. If there is no match from a brother or sister, sometimes an unrelated donor will match. A transplant from a matched-unrelated donor is riskier than using a sibling match. Another option is to use stem cells from the umbilical cord of a newborn baby. A nationwide registry of potential stem cell donors and stored umbilical cord blood has been developed (http://www.marrow.org). Many doctors recommend using a non-related donor only if immune treatments described below don�t work.
For a stem cell transplant, you will first receive chemotherapy. The chemotherapy drugs used most often include cyclophosphamide (Cytoxan®) and fludarabine (Fludara®). A drug to suppress your immune system, like anti-thymocyte globulin (ATG) or alemtuzumab (Campath®), is also given. This immune treatment is important to keep your immune system from killing the new bone marrow (like it killed your original bone marrow). Immune treatment is also important to prevent the new bone marrow from attacking your body (this is called graft-versus-host disease and is discussed later in this section). You may also get a low dose of radiation therapy to your whole body.
Soon after the radiation and/or chemotherapy, you will receive a transfusion with blood-forming stem cells from a donor. The stem cells can be obtained from the donor by removing bone marrow in the operating room while he or she is under general anesthesia. Sometimes a procedure called apheresis is used to remove stem cells from the bloodstream. Apheresis uses a machine that is hooked up to a large vein (through a catheter) and removes stem cells from the blood (returning the other cells). No matter which way they are collected, the stem cells are infused through your vein into the blood and then travel to the bone marrow, where they will grow
Stem cell transplantation is a major procedure with many risks and side effects. Some people may die during this procedure. The most serious side effects often occur during the first few weeks after the transplant. With advances in this treatment, however, death from these early side effects is less common. The chance of severe side effects increases with the age of the patient.
In the first few weeks after the transplant there are usually side effects from the chemotherapy or radiation therapy. Very low blood counts requiring red blood cell and platelet transfusions are common. You can develop nausea, vomiting, diarrhea, and mouth sores from the treatment. ATG can cause serious allergic reactions while it is being given. These reactions can be skin rashes or sometimes problems breathing. Generally, these side effects can be controlled with medicines. Serious infections can also occur and are treated with large doses of antibiotics. These all generally go away in 3 to 4 weeks when the transplanted blood-forming stem cells start to produce normal blood cells.
A very serious side effect of a stem cell transplant is graft-versus-host disease (GVHD). This occurs when the transplanted donor cells attack your own cells through an immune reaction. GVHD is more common with unrelated or mismatched donors. The risk of GVHD is also higher in older patients. GVHD can occur very early after the transplant. This is called acute GVHD. When GVHD develops later on or lasts a long time it is called chronic GVHD. Early signs of GVHD include skin rashes with severe itching and bowel disturbances such as diarrhea. There may be abnormal lab tests showing liver damage. GVHD is treated with medications (like prednisone, methotrexate, or tacrolimus) to try to suppress the immune system. In some cases, GVHD goes away and the medications can be stopped. In other cases, GVHD is only partly controlled, and medications are needed for a long time. GVHD can sometimes be very disabling and occasionally even cause death.
For more information, please see the American Cancer Society document, Bone Marrow and Peripheral Blood Stem Cell Transplants.
Immunosuppressive therapy
If you are not able to have a transplant (because of age or because you do not have a matched donor), doctors will recommend immunosuppressive treatment. Most cases of acquired aplastic anemia are caused by the immune system attacking the bone marrow. This treatment helps stop the immune system from killing the bone marrow cells. This type of treatment is not usually helpful for cases of inherited aplastic anemia because they are not caused by the immune system.
The major drugs used are antithymocyte globulin (ATG) and cyclosporine. ATG contains antibodies against human T-lymphocytes. This medicine is given in the hospital through an intravenous (IV) line. ATG decreases (suppresses) your immune system function by lowering the number of T-cells in the body. The antibodies in ATG come from an animal (like a horse or a rabbit), so there is a risk of a serious allergic reaction when the ATG is given. Sometimes patients getting ATG also receive a corticosteroid medicine (like prednisone) to reduce the chance that a serious reaction will occur. A newer drug, alemtuzumab (Campath®), is sometimes used instead of ATG. It has a lower risk of serious allergic reactions, but doctors aren't sure that it works as well as ATG. Often a second drug called cyclosporine is also given to suppress the immune system. The combination of ATG and cyclosporine improves the blood counts in about 70% of patients with the most severe disease. The aplastic anemia is not actually cured in most of these patients. Some of the time, the blood counts do not become completely normal, but they do improve enough for the patient to feel well and live a normal life. Often, after a period of remission, the aplastic anemia will come back. Usually, it will respond again to immune treatment, which can be safely repeated.
Using high doses of cyclophosphamide (Cytoxan®) for immunosuppression is controversial. Cyclophosphamide is a chemotherapy drug that can suppress the immune system and damage T-lymphocytes. Although this treatment can be effective, many experts believe that it is more dangerous than ATG. Most doctors in the United States prefer to delay using cyclophosphamide until ATG and cyclosporine are no longer working.
Immunosuppressive therapy can have serious side effects. Holding back the immune system impairs the body's ability to fight infection. People on immunosppression can get life-threatening infections with bacteria, viruses, and fungi. The drugs used in this therapy also have serious side effects. For example, ATG can cause serious allergic reactions with symptoms including skin rashes, low blood pressure, and problems breathing. Generally, these side effects can be controlled with medicines. Also, about 15% of patients develop leukemia or myelodysplasia several years after getting ATG. Myelodysplasia is a disorder of the bone marrow that is similar to leukemia (see the American Cancer Society document, Myelodysplastic Syndromes). Side effects of cyclosporine include high blood pressure as well as kidney and liver damage. To help prevent these problems, the doctor will check the level of cyclosporine in the blood regularly. Blood tests will also be done to check kidney and liver function. Corticosteroids (like prednisone) can cause increases in blood sugar (like diabetes), high blood pressure, weight gain, changes in mood, and weak bones.
Supportive treatment
Transfusion
While your blood counts are low, you may need transfusions of red blood cells or platelets. Although blood transfusions are generally safe, their long-term use creates problems. The main problem is that the red cells contain iron. The transfused cells only live a few weeks and iron from these cells builds up in the body. Eventually this will result in a high level of body iron, which is toxic. Although this can be treated with drugs, these aren�t always successful and some organs, mainly the liver and heart, can become damaged. Also, getting tranfusions before a stem cell transplant increases the chance that the transplant won't work. For this reason, doctors avoid giving transfusions when a transplant is planned.
Antibiotics
Because of your low white blood cell count, you may develop an infection and need antibiotics. Infection is the major cause of death from aplastic anemia. Treatment with antibiotics should be started as soon as infection is suspected. Treatment with white blood cell transfusions is not practical. It is not possible to get enough white blood cells from normal donors to raise a person�s white blood cell count.
Growth factors
Drugs can be given to increase the white blood cell count. These are called filgrastim (also called G-CSF or Neupogen®), pegfilgrastim (Neulasta®), and sargramostim (also called GM-CSF or Leukine®). These work only slightly for most patients with aplastic anemia.
Androgens
Some patients with early or mild aplastic anemia can be treated with androgens (instead of stem cell transplantation or ATG). Androgens are often the first treatment given to patients with inherited forms of aplastic anemia (like Fanconi anemia and dyskeratosis congenita). Androgens are male sex hormones that also stimulate blood production. They are the reason that men have higher red blood cell counts than do women. Although they can be effective in improving blood counts, they do not cure aplastic anemia. Also, using androgens for a long time has been linked to liver tumors and liver cancer. Androgens are male hormones, so women taking this medicine can develop masculine characteristics such as facial hair, balding, deepening voice, etc.
General considerations in treating aplastic anemia
Many years ago, aplastic anemia was considered a fatal disease unless the patient recovered without treatment (spontaneously). Now that we understand this is generally an immune disease, treatments have been devised that have a high success rate.
The other major long-term side effect is that a small number of people with aplastic anemia will develop leukemia or other cancers after several years. However, it isn�t clear that this is always caused by the treatment. It may be caused by a problem with the blood cells themselves.
Because treating aplastic anemia is so specialized, it may best be done at a major medical center where they have experience with this disease. This is particularly true for stem cell transplants.
Sometimes the first treatment isn't successful and will need to be repeated. Often the second treatment will be effective, even if the first wasn't. Also, the treatment may be only partially effective, and the blood counts may not return to normal. In this situation, many people can still lead a normal life and not need treatment. Their blood counts, although not normal, will be high enough for a normal life.
Sometimes, none of the treatments is successful. In this case a person with aplastic anemia might want to consider taking part in a clinical trial, that is, a study of a new therapy that hasn't yet been proven successful.
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