Information on the following diseases can be found in the Related Disorders section of this report:

• Fanconi's Anemia
• Dyskeratosis Congenita
• Anemias, Other

The symptoms of acquired aplastic anemia occur as a consequence of the bone marrow failing to produce enough functioning blood cells. The specific symptoms and progression of the disorder vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications.

Red and white blood cells and platelets are formed in the bone marrow. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding. A low level of circulating red blood cells is known as anemia. A low level of white blood cells is known as leukopenia. A low level of platelets is known as thrombocytopenia.

Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with leukopenia have an increase in their risk of contracting bacterial and fungal infections. Individuals with thrombocytopenia are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose. Women may develop increased menstrual blood loss (menorrhagia).

Some individuals with acquired aplastic anemia also have another disorder, at the same time, called paroxysmal nocturnal hemoglobinuria (PNH). Acquired aplastic and PNH have an extremely close relationship that is not fully understood by researchers. It is believed that PNH arises in the setting of autoimmune acquired aplastic anemia and bone marrow failure. Individuals affected with acquired aplastic anemia are also at risk that it will evolve into another similar disorder known as myelodysplasia. In rare cases, acquired aplastic anemia may eventually evolve into leukemia. PNH is caused by an acquired genetic defect affecting the PIGA gene, limited to the stem cells. The PIGA gene mutations cause blood cells to become sensitive to increased destruction by complement, a blood immunity protein. Approximately 20% of patients with aplastic anemia have evidence of PNH at presentation, as detected by flow cytometry. Furthermore, patients who respond following immunosuppressive therapy frequently recover with clonal hematopiesis and PNH. There are a minority of MDS patients with an incompletely functional (hypoplastic) bone marrow, as seen in acquired aplastic anemia. These conditions are often mistaken for each other, so whether one is transformed to another is uncertain. The same holds for acute leukemia as well, which may present first as hypoplastic MDS and be mistaken for AA. (For more information on these disorders, see the Related Disorders section of this report.)

Approximately 50 percent of cases of acquired aplastic anemia occur unrelated to any identifiable causes, or for unknown reasons (idiopathic). Researchers believe that most of these cases actually occur due to the immune system mistakenly targeting the bone marrow (autoimmunity). Autoimmune disorders are caused when the body’s natural defenses against "foreign" or invading organisms begin to attack healthy tissue for unknown reasons. Tests to confirm this in any individual case are not very readily available, but there is much evidence to support this pathogenic mechanism.

The bone marrow contains specialized cells called hematopoietic stem cells. These stem cells eventually divide, differentiate and become red or white blood cells or platelets. In aplastic anemia, a precipitating event (usually immune-mediated) leads to the nearly complete destruction of hematopoietic stem cells. It is believe that certain immune system cells (T-lymphocytes) target and destroy the most primitive cells capable of developing into blood cells, hematopoietic stem cells. Since stem cells are destroyed in vast quantities, individuals with aplastic anemia do not have enough stem cells to produce mature blood cells. In some cases, the bone marrow, with no blood cell production, becomes replaced by large quantities of fat. Affected individuals eventually develop a deficiency of red and white blood cells and platelets (pancytopenia). It is interesting that hypoplastic MDS may respond to immunotherapy, similar to AA, and that Benzene also can damage genes (genotoxic) and cause the condition to be converted to leukemia (leukemic transformation), so the overlap between these syndromes is becoming more apparent.

In the past, acquired aplastic anemia has been linked to a variety of environmental factors including exposure to toxic environmental chemicals such as benzene, pesticides or insecticides; the use of certain drugs; and certain viral infections including hepatitis, parvovirus B19, and infectious mononucleosis. These environmental factors are believed to set off or trigger the immune system response that mistakenly destroys hematopoietic stem cells. However, most cases of acquired aplastic anemia have no identifiable environmental trigger.

Acquired aplastic anemia affects males and females in equal numbers. Most cases affect older children, teen-agers or young adults. The incidence of aplastic anemia in Europe and Israel is 2 in 1 million people. The incidence rate is two or three times greater in Asia. The exact incidence rates exist for the United States is unknown although some sources say that approximately 500-1,000 new cases of aplastic anemia are diagnosed each year.

Symptoms of the following disorders can be similar to those of acquired aplastic anemia. Comparisons may be useful for a differential diagnosis:

Myelodysplastic syndromes (myelodysplasias, MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). As with acquired aplastic anemia, general symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. It is sometimes difficult to distinguish acquired aplastic anemia from MDS. The main difference between the two disorders is that in aplastic anemia the major problem is almost complete absence of any blood-producing cells in the marrow while in MDS the marrow contains some blood cells and their precursors, which are defective and abnormal, as well as a marked overgrowth of fibrous tissue, or scarring. Both processes result in failure of the marrow to deliver working blood cells into the bloodstream. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown. (For more information on this disorder, choose "myelodysplastic syndromes" as your search term in the Rare Disease Database.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder.

Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective "PNH" blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. (For more information on this disorder, choose "paroxysmal nocturnal hemoglobinuria" as your search term in the Rare Disease Database.)

Myelofibrosis is a condition characterized by formation of fibrous tissue (fibrosis, or scarring) within the bone marrow. Bone marrow is a sponge-like tissue found within the bones of the body and is responsible for the production of all blood cells (i.e., red and white blood cells and platelets). Myelofibrosis occurs in all myeloproliferative disorders secondary to abnormal stem cell proliferation: in Polycythemia Vera, Chronic Myeloid Leukemia, even in MDS and acute leukemia, in the megakaryoblastic form. In many cases, the cause of myelofibrosis is unknown (idiopathic). In myelofibrosis, the ability of the bone marrow to produce red blood cells will be impaired. A form of myelofibrosis occurs in agnogenic myeloid metaplasia, in which blood formation takes place outside the bone marrow (extramedullary hematopoiesis), in the liver and spleen, causing theme to become quite enlarged, However, it is generally felt that myelofibrosis per se is a reactive process to the abnormal stem cell present, possibly because they secrete abnormal cytokines stimulating fibroblast proliferation.

Symptoms of myelofibrosis may include weight loss, weakness and fatigue due to replacement of normal bone marrow cells, and/or episodes of severe pain in the abdomen, bones, and joints. Other findings may include abnormally low levels of circulating red blood cells (anemia), an abnormally large spleen (splenomegaly), an abnormally large liver (hepatomegaly),. (For more information on this disorder, choose "myelofibrosis" as your search term in the Rare Disease Database.)

Certain forms of acute leukemia may be associated with bone marrow failure. Leukemia is form of cancer affecting the bone marrow and blood. It is characterized by the uncontrolled accumulation of cancerous blood cells. Acute forms of leukemia often result in low levels of red and white blood cells and platelets (pancytopenia).

Aplastic anemia may also occur as part of an inherited disorder such as Fanconi’s anemia, Schwachman-Diamond syndrome, ataxia-pancytopenia syndrome, or dyskeratosis congenita. Fanconi’s anemia is most important differential diagnosis of these genetic disorders.

Fanconi’s anemia, also known as aplastic anemia with congenital anomalies, is a rare genetic disorder that may be apparent at birth or during childhood. In some cases, Fanconi’s anemia may not be diagnosed until adulthood. It is an inherited predisposition to gene mutations, probably because of poor ability to repair chromosome damage, and predisposes to damage to stem cells and eventually to leukemic transformation. The disorder is characterized by deficiency of all bone marrow elements including red blood cells, white blood cells, and platelets (pancytopenia). Fanconi’s anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities, as well as patchy, brown discolorations (pigmentation changes) of the skin. There are several different subtypes (complementation groups) of Fanconi’s anemia, each of which is thought to result from abnormal changes (mutations) to different genes. Each subtype appears to share the same characteristic symptoms and findings (phenotype). Fanconi’s anemia has autosomal recessive inheritance. (For more information on this disorder, choose "Fanconi’s Anemia" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of acquired aplastic anemia may be suspected when an otherwise healthy individual has low levels of all three blood cell types (pancytopenia). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests, including a bone marrow biopsy. During this procedure, a small specimen of bone marrow tissue is surgically removed, usually from the hip or pelvis, and studied under a microscope. In acquired aplastic anemia this sample will show a dramatic reduction or complete lack of cells (acellularity). Additional tests may be necessary to rule out other disorders such as leukemia.

Treatment
Treatment of acquired aplastic anemia varies, depending upon the individual’s age, general health, and the severity of aplastic anemia. Treatment aims to correct the bone marrow failure, as well as to treat the patient’s immediate signs and symptoms. The two main forms of specific treatment are bone marrow transplantation and immunosuppressive therapies.

Initial treatment of acquired aplastic anemia may be directed toward improving the symptoms that may result from low blood counts. Such treatment consists of giving red blood cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding, and antibiotics to treat or prevent infections. Affected individuals who are eligible for a bone marrow transplant should not, if possible, receive blood transfusions because blood transfusions reduce the chances of a successful transplant.

Bone marrow transplantation, specifically an allogeneic transplant, is the treatment of choice in children and younger individuals. During an allogeneic bone marrow transplant, an affected individual’s abnormal bone marrow cells are eradicated or destroyed by chemotherapy and/or radiation, and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted by injecting the cells of the donor intravenously into the patient’s body, where it travels to the patient’s bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is an identical twin, sibling or close relative, who shares most of the same genetic makeup as the patient. However, in many cases, a search for an unrelated, matched donor is necessary.

A similar procedure called peripheral hematopoietic stem cell transplantation may also be used to treat individuals with acquired aplastic anemia. In this procedure, healthy stem cells are taken from a donor by collecting them from the donor’s bloodstream rather than the bone marrow. These are then injected intravenously into the patient’s bloodstream.

Graft rejection and graft-versus-host disease are potential complications with any transplant procedures, including bone marrow transplant. Complications of graft-versus-host disease from a bone marrow transplant may range from mild to life threatening. Drugs may be used to prevent or treat graft rejection or graft-versus-host disease. (For more information on this disorder, choose “graft versus host disease” as your search term in the Rare Disease Database.)

Individuals who are not candidates for a bone marrow transplant, either because of advanced age or lack of a suitable donor, may respond to immunosuppressive treatment. In this case, drugs are used to suppress the activity of the immune system. Since many cases of acquired aplastic anemia are believed to result from an individual’s immune system mistakenly attacking bone marrow, suppressing the activity of the immune system often allows the bone marrow to recover and eventually to begin producing new blood cells. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG) and cyclosporin.

Immunosuppressive therapy can restore an affected individual’s blood count to normal or near normal levels for prolonged periods. However, the improvement is often not permanent and the treatment must be repeated if relapses of aplastic anemia occur. In addition, individuals who successfully respond to immunosuppressive therapy are still at risk of eventually developing PNH, myelodysplasia, or leukemia.

Approximately one-third of individuals treated with immunosuppressive drugs do not respond to therapy (refractory aplastic anemia). In these cases, treatment with hematopoietic stem cell transplantation may be considered. Treatment with substances that stimulate blood cell production, called growth factors, may be also be beneficial in refractory aplastic anemia. Growth factors are substances normally found in the body that assist in the production of blood cells. They include granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO). These growth factors stimulate the production of neutrophils, neutrophils and macrophages (both types of white blood cells that fight infection), and red blood cells, respectively. In some cases, treatment of refractory aplastic anemia with growth factors had led to clinically beneficial improvement in blood cell counts.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Several studies related to aplastic anemia currently are listed on this NIH website. Current clinical trials also are listed on the website of the Aplastic Anemia and MDS International Foundation (see Resources section of this report). Studies for which patients are being recruited include the following:

Researchers at Johns Hopkins Oncology Center are studying the use of high doses of cyclophosphamide in treating severe aplastic anemia. For information about research related to aplastic anemia in the oncology center, contact Richard L. Jones at (410) 995-2006 or check the Clinical Trials website listed above.

The National Heart, Lung and Blood Institute (NLHBI) of the National Institutes of Health is sponsoring several studies related to aplastic anemia. For information on these studies, use the NIH tollfree telephone number or the Clinical Trials website listed above.

The National Cancer Institute and Roswell Park Cancer Institute in Buffalo, NY, are sponsoring a study of chemotherapy followed by peripheral stem cell transplantation in treating patients with hematologic cancer or aplastic anemia. For information, contact Arif Alam, MD, at the Roswell Park Cancer Institute at (716) 845-8707 or use the NIH contact information.

The National Cancer Institute and Ireland Cancer Center in Cleveland, Ohio, are also sponsoring a study of chemotherapy followed by peripheral stem cell transplantation in treating patients with aplastic anemia. For information, contact Mary J. Laughlin, MD, at the Ireland Cancer Center at (216) 844-8609 or use the NIH contact information.

In 2002, The National Cancer Institute launched the largest epidemiological study of people in North America with rare inherited bone marrow failure syndromes (IBMFS), and their immediate family members. This study, called the NCI IBMFS Cohort, is designed to follow families over a long period of time. It will study the underlying genetic disorders of those diagnosed with IBMFS, and their families, and analyze how certain factors may affect the course of these syndromes. IBMFS are disorders that involve some form of aplastic anemia, and people with these syndromes are at increased risk for cancers such as leukemia or various specific solid tumors. For information about the study contact:

Ms. Lisa Leathwood, RN
Tel: (800) 518-8474
Email: lisaleathwood@westat.com.
Information is also provided on the study web site: http://marrowfailure.cancer.gov.

Young NS. Acquired Aplastic Anemia. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:364.

Young NS. Acquired aplastic anemia. In: Young NS, ed. Bone Marrow Failure Syndromes. WB Saunders. Philadelphia, PA. 2000:1-46.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:862-63.

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:1002.

Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:831-37.

Hoffman R, Benz Jr EJ, Shattil SJ et al. Eds. Hematology: Basic Principles and Practice. 2nd ed. Churchill-Livingstone, Inc. New York, NY; 1995:299-349.

Frank MM, Austen KF, Claman HN, et al. Eds. Samter’s Immunological Diseases. 5th ed. Little Brown and Company, Boston, MA; 1995:1478-81.

REVIEW ARTICLES
Sleijfer S, Lugtenburg PJ. Aplastic anaemia: a review. Neth Med J. 2003;61:157-63.

Fruchtman S. Stem cell transplantation. Mt. Sinai J Med. 2003;70:166-70.

Dokal I. Inherited aplastic anaemia. Hematol J. 2003;4:3-9.

Greenberg PL, Young NS, Gattermann N. Myelodysplastic syndromes. Hematology. (Am Soc Hematol Educ Program). 2002;:136-61.

Alter BP. Bone marrow failure syndromes in children. Pediatr Clin North Am. 2002;49:973-88.

Locasciulli A. Acquired aplastic anemia in children: incidence, prognosis and treatment options. Paediatr Drugs. 2002;4:761-66.

Paquette RL. Diagnosis and management of aplastic anemia and myelodysplastic syndrome. Oncology (Huntingt). 2002;16(9 Suppl 10):153-61.

Myer SA, Oliva J. Severe aplastic anemia and allogeneic hematopoietic stem cell transplantation. AACN Clin Issues. 2002;13:169-91.

Choudry VP, Gupta S, Gupta M, et al. Pregnancy associated aplastic anemia—a series of 10 cases with review of the literature. Hematology. 2002;7:233-38.

Young NS. Immunosuppressive treatment of acquired aplastic anemia and immune-mediated bone marrow failure syndromes. Int J hematal. 2002;75:129-40.

Young NS. Acquired aplastic anemia. Ann Intern Med. 2002;136:534-46.

Brodsky RA. High-dose cyclophosphamide for aplastic anemia autoimmunity. Curr Opin Oncol. 2002;14:143-46.

FROM THE INTERNET
Cohen EEW. Idiopathic aplastic anemia. MEDLINEplus. Update date: 4/25/2003. 3pp.
www.nlm.nih.gov/medlineplus/ency/article/000554.htm

Elstrom R. Secondary aplastic anemia. MEDLINEplus. Update date: 10/10/2001. 3pp.
www.nlm.nih.gov/medlineplus/ency/article/000529.htm

Acquired Aplastic Anemia: Basic Explanations. Aplastic Anemia & MDS International Foundation, Inc. 2003. 16pp, www.aplastic.org

The Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins. 3pp.
www.hopkinskimmelcancercenter.org/cancertypes/aplastic-anemia.cfm?cancerid=14

CenterWatch. Summary: Study of transplantation using umbilical cord and placental blood. 9/11/2003. 3pp.
www.centerwatch.com/patient/studies/stu8053.html

CenterWatch. Summary: Study of standard chemotherapy and radiotherapy before allogenic stem cell transplantation. 9/11/2003. 3pp.
www.centerwatch.com/patient/studies/stu8057.html