Aplastic Anemia: Introduction for the General Physician

Aplastic anemia is a hematologic disorder characterized by a decrease in the cellular elements of the peripheral blood. This results from underproduction of peripheral blood elements due to bone marrow failure. Aplastic anemia develops before age 30-40 in patients who are predisposed due to a congenital chromosomal abnormality such as Fanconi’s anemia or dyskeratosis congenita. Acquired aplastic anemia may be caused by toxic chemicals, radiation, or by idiosyncratic reactions to medications or infections. However, in over 50% of cases there is no identifiable cause and the condition is then referred to as idiopathic aplastic anemia.

Making the Diagnosis

Patients with aplastic anemia generally present with symptoms of bleeding or bruising due to the thrombocytopenia (low platelets), tiredness or pallor due to the anemia (low hemoglobin), or infection due to the neutropenia (low white blood cell count). A complete blood count and reticulocyte count usually show depression of all blood elements (pancytopenia). The peripheral blood smear shows no abnormal cells. The diagnosis is confirmed by a bone marrow biopsy with an assessment of cellularity. The bone marrow is also evaluated for the degree of maturation of all cell lines.

Aplastic anemia is usually categorized as severe if, in addition to a hypocellular bone marrow for age, two of the three following criteria are present: a platelet count of less than 20,000/mm3, a corrected reticulocyte count of less than 1%, and a granulocyte or absolute neutrophil count [ANC = total white count x (segs + bands)] of less than 500/mm3. Patients With pancytopenia, but not severe enough to meet the above criteria, have mild or moderate aplastic anemia. Very severe aplastic anemia exists if the ANC or granulocyte count is less than 200/mm3.

When aplastic anemia is diagnosed, all drugs or medications the patient is on should be stopped if possible. Tests to exclude specific causes of aplastic anemia should be done including a sugar water or a Ham test to rule out paroxysmal nocturnal hemoglobinuria (PNH), B12 and folate levels and Hepatitis A, B, and C serologies. Bone marrow chromosomes should be done to rule out a cytogenetic abnormality that may suggest a diagnosis of myelodysplastic syndrome. Peripheral chromosome analysis using diepoxybutane or mitomycin C should be done to rule out Fanconi’s anemia in patients under 40 years of age. Patients who are under 55 years of age and their siblings and parents, if available, should be HLA typed at diagnosis to see if a bone marrow transplant is a therapeutic option.


Patients with mild or moderate aplastic anemia generally do not require immediate treatment. Indeed, it is not known if they would benefit from early use of any of the therapies described below. They should be watched carefully for any decline in their blood counts. If such patients require transfusions, a decision should be made whether any of the below therapies should be employed even though they do not meet strict criteria for severe aplastic anemia.
For the patient with severe aplastic anemia, treatment should begin within 4 weeks after presentation. Spontaneous increase in blood counts after 2-3 weeks is less likely and potential for mortality and morbidity increase rapidly. Three types of therapy are known to have benefit. These are bone marrow transplantation, immunosuppression with medicines such as antithymocyte globulin (ATG) and/or cyclosporine, and hematopoietic growth factors such as granulocyte colony stimulating factors (G-CSF), granulocyte monocyte colony stimulating factor (GM-CSF), or other cytokines.

A bone marrow transplant is the treatment of choice for patients with severe or very severe aplastic anemia less than 55-65 years of age in good medical condition who have an HLA identical family member. In this procedure the patient is given toxic doses of chemo- and/or radiotherapy and then infused with bone marrow from their HLA identical donor. If there is no family member, a search of the unrelated bone marrow transplant donor registries should be initiated even though the patient will initially be treated with another modality. A bone marrow transplant center should be contacted to provide further information and to discuss specific patient needs prior to referral.

The mainstay of initial therapy for the patient without HLA identical sibling donor is immunosuppression. ATG, and anti-T cell agent, is given intravenously over 4 to 10 days according to various inpatient protocols. This medicine frequently results in high fevers, moderate patient discomfort during its administration, and may transiently increase transfusion requirements. More recently, ATG is being given in combination with cyclosporine-A, an oral anti-T cell agent, and sometimes with prednisone as well. The combination of medicines seems to result in a higher frequently of clinical response than any of the medications given alone. However, even in patients who respond to these agents blood cell production, although usually adequate to maintain a reasonable quality of life, frequently is not normal even many years later.

More recently, therapy has been attempted with bioengineered molecules that increase the production of blood cell elements. All of these medications are administered either subcutaneously or intravenously and usually must be continued indefinitely once a response is obtained. G- and GM-CSF stimulate the white blood cells and in a few cases with prolonged use have resulted in small increments in platelets and red blood cells as well. Erythropoietin may increase red blood cell production, but most patients with aplastic anemia already have a very high erythropoietin level. Other cytokines such as interleukin-3 (IL-3), IL-6 and IL-11 may also have a role in raising platelet and white cell counts but these agents are currently available only as part of clinical research trials.


Most patients with aplastic anemia will require transfusions of red blood cells and/or platelets. Transfusions should come from the fewest donors possible. If bone marrow transplantation is even a remote possibility, transfusions should not come from family members. Because most patients will require many transfusions over time, all blood products starting with the first transfusion should be leukocyte depleted. That is, all red cells and platelets should be either filtered through a white cell leukocyte depletion filter or be washed prior to administration to the patient. If possible, all blood products should be irradiated as well.

Blood and platelet transfusions should be given as infrequently as possible. Many patients with aplastic anemia do not receive routine platelet transfusions. Rather, they should be given such products only when there is evidence of clinical bleeding or prior to invasive procedures. Healthy young patients may tolerate a hemoglobin of between 5 and 7 grams/dl without difficulty. Patients with heart disease or other medical conditions may need higher hemoglobin levels. Patients who become alloimmunized (fail to raise their platelet count in response to platelet transfusions) may have less bleeding symptoms if the hemoglobin is kept between 8 and 10 gm rather than at the lower values.

Natural History and Prognosis

Patients with severe or very severe aplastic anemia are at greatest risk from overwhelming infection due to the low number of white blood cells. Such patients should be advised to seek medical attention for any febrile illness. When a fever develops, it is recommended that a blood culture be obtained and that they receive parenteral antibiotics active against gram-positive and gram-negative bacteria for at least 48 hours or until the fever ends and the blood cultures are negative. If the patient appears clinically ill or the fever is prolonged, anti-fungal and/or anti-viral agents should also be considered. Even with this approach many patients with low granulocyte counts succumb to overwhelming infections. Other patients may have life-threatening bleeding episodes.
Classically it was reported that one-third to one-half of all patients diagnosed with severe or very severe aplastic anemia would be dead in six months regardless of therapy. However, HLA-identical sibling donor bone marrow transplantation in large centers has a long-term survival rate exceeding 80%. Newer combined modality immunosuppressive therapy shows a response rate over 60%.

In summary, the prognosis for the patient with aplastic anemia today is improving. Patients faced with such a diagnosis may be helped by the peer support and educational materials available from the Aplastic Anemia Foundation of America (AAFA). Members of the AAFA Medical Board are also willing to advise physicians about their patient’s specific situation.