OVERVIEW: What every practitioner needs to know about severe aplastic anemia

Are you sure your patient has severe aplastic anemia? What are the typical findings for this disease?

Aplastic anemia is a rare and potentially fatal disorder that is defined by pancytopenia with a hypocellular bone marrow. Aplastic anemia is a heterogeneous disease, with great diversity in possible causes. While 15%-20% of cases are associated with a constitutional syndrome, a majority of cases have no defined etiology and are classified as idiopathic. Therefore, idiopathic aplastic anemia is a diagnosis of exclusion. The clinical severity of aplastic anemia is classified based on peripheral blood counts and results of bone marrow examinations.

The signs and symptoms of aplastic anemia are primarily those associated with pancytopenia. Children may present with fatigue and pallor that is the result of anemia, bruising, and easy bleeding that is the result of thrombocytopenia and fever and infections that are the result of neutropenia. Typically, the onset of anemia is gradual. Parents and others who see the child frequently may not appreciate the severity of the child’s pallor, whereas others who see the child less frequently may be impressed by the degree of paleness.

Classification of Severe Aplastic Anemia

Several classification systems have been proposed and used to assess the clinical severity of aplastic anemia. These systems aid in diagnosis and have prognostic value. Recently, Davies and Guinan proposed definitions for aplastic anemia based on peripheral blood cytopenias and bone marrow results.

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In this classification schema, children with severe aplastic anemia have bone marrow cellularity less than 25% of normal, and two or more of the following: peripheral blood neutrophil count less than 0.5 x 109/L, or peripheral blood platelet count less than 20 x 109/L, or peripheral blood reticulocyte count less than 20 x 109/L.

Children with very severe aplastic anemia have all of these same findings, in addition to a peripheral blood neutrophil count less than 0.2x 109/L.

Children with nonsevere aplastic anemia have a hypocellular bone marrow without this severity of peripheral blood findings.

What other disease/condition shares some of these symptoms?

The differential diagnoses for severe aplastic anemia is extensive. When evaluating a child wtih pancytopenia, considerations include:

Inherited Bone Marrow Failure Syndromes:

Fifteen to 20% of children with severe aplastic anemia have an inherited bone marrow failure syndrome, most often Fanconi anemia. Other inherited bone marrow failure syndromes to consider include dyskeratosis congenita, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia and Seckel syndrome.


Infectious agents that can cause aplastic anemia include cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes virus, varicella virus, human immunodeficiency virus (HIV), human herpes virus 6 (HHV6), hepatitis viruses, parvovirus, and visceral leishmaniasis.

Drugs and Toxins:

Agents that are traditionally cited as causing aplastic anemia include benzene, phenytoin, phenylbutazone, chloramphenicol and carbamazepine. However, an extremely large number of drugs can affect the production of blood; therefore, as a part of the diagnostic evaluation, a complete history for all drug and toxin exposures should be obtained. Based on this history, clinicians should investigate associations between all drug or toxin exposures obtained in the patient’s history and the potential for aplastic anemia.

Malignant and Pre-malignant Conditions:

A number of malignant diseases may present with aplastic anemia, including: myelodysplasia, myelofibrosis, paroxsymal nocturnal hemoglobinuria (PNH), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), Hodgkin disease, and various solid tumors.


Other considerations include: aplastic anemia associated with pregnancy, ionizing radiation, histiocytic disorders (hemophagocytic lymphohistiocytosis), osteopetrosis, storage diseases, Pearson syndrome (mitochrondial deletions), rheumatologic and autoimmune diseases, anorexia nervosa and acquired vitamin and nutritional deficiencies.


While the differential diagnoses are extensive, in a majority of children with severe aplastic anemia, no etiology is identified, so most cases are classified as idiopathic.

Diagnostic Approach to the Child with Severe Aplastic Anemia

The diagnostic approach to children with severe aplastic anemia is based on the history of the child and family, physical examination and laboratory tests.

  • History: A detailed history, including a complete family history, is critically important in the evaluation of a child with severe aplastic anemia. The history should ascertain signs and symptoms associated with pancytopenia, including: activity level, exercise intolerance, fatigue, sleep patterns, pallor, diet, appetite, fever, and recent infections. In addition, the history should include questions about exposures to toxins, drugs and radiation, and foreign travel. Finally, the clinician should inquire about a family history of inherited bone marrow failure syndromes and other family members with anemia.

  • Physical Examination: Examination of children with severe aplastic anemia typically reveals signs of pancytopenia, including paleness, lethargy, bruises, petechiae and bleeding, tachypnea and tachycadia. In children with an inherited bone marrow failure syndrome, characteristic physical anomalies may be present. For example, children with Fanconi anemia may have abnormalities of the upper extremities, characteristic facies, short stature, and cafe-au-lait lesions. Children with dyskeratosis congenita may have reticular skin pigmentation, abnormalities of the nails, and oral leukoplakia.

  • Laboratory Studies: Diagnostic laboratory studies in children with severe aplastic anemia fall into two major categories: 1) complete blood count (CBC) and bone marrow aspiration and biopsy for all children, and 2) additional testing based on the child’s history, family history, physical examination and results of the CBC and bone marrow. Given the extensive and diverse diseases that comprise the differential diagnosis for severe aplastic anemia, additional diagnostic testing is an iterative process, directed according to the results of prior findings. In children with no identifiable etiology, a diagnosis of idiopathic severe aplastic anemia becomes the diagnosis of exclusion.

  • Fanconi Anemia: All children with severe aplastic anemia should be screened for Fanconi anemia.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • In children with severe aplastic anemia, a CBC will show pancytopenia, with anemia, reticulocytopenia, thrombocytopenia and neutropenia. Red blood cells are frequently macrocytic. There should be no evidence of peripheral blood blasts.

  • Examination of the bone marrow in children demonstrates hypocellularity with increased fat, macrophages and plasma cells. Erythrocytes, megakaryocytes and granulocyte precursors are reduced or absent. In idiopathic severe aplastic anemia, dysplastic changes in the erythroid lineage may be present, but rarely are dysplastic changes seen in the megakaryocytic and granulocytic lineages. In children with idiopathic severe aplastic anemia, the marrow has no evidence of an infiltrative process (e.g., malignancy) or fibrosis.

  • In addition to a CBC and bone marrow aspiration and biopsy, additional tests may include but are not limited to:

  • Liver function tests (e.g., hepatitis)

  • Screening tests for viruses and other infectious causes of marrow failure (e.g., hepatitis viruses, HIV, CMV, etc.)

  • Cytogenetics, to assess for clonal abnormalities including myelodysplastic syndrome

  • Diepoxybutane (DEB) or mitomycin C (MMC) assays to assess the patient for Fanconi anemia

  • Mutation analysis for inherited bone marrow failure syndrome

  • Flow cytometric analysis for paroxysmal nocturnal hemoglobinuria

Would imaging studies be helpful? If so, which ones?

  • Skeletal surveys and ultrasound examinations of the abdomen may aid in the identification of congenital anomalies associated with inherited bone marrow failure syndromes.

Confirming the diagnosis

  • As described above, the approach to diagnosis of the causes of severe aplastic anemia is an iterative process, built upon results of the patient’s history, the family history, physical examination, results of the CBC, and bone marrow examination.

If you are able to confirm that the patient has severe aplastic anemia, what treatment should be initiated?

The approach to the treatment of severe aplastic anemia is based on the identified cause of disease. Specifically, for children with an inherited bone marrow failure syndrome, treatment, complications and outcomes are disease-specific. For children with severe aplastic anemia that is not the result of inherited bone marrow failure syndromes, there are three major approaches to the treatment: supportive care, immunosuppressive therapy (IST) and allogeneic hematopoietic stem cell transplantation (SCT).

  • Supportive Care: As a result of pancytopenia, children with severe aplastic anemia may have life-threatening anemia, bleeding and infections. Therefore, the clinician who initially sees these children should focus their care on the stabilization of the child. Transfusions of blood and platelets may be required as initial stabilization of the child and as a part of the long-term care of the patient. The goal of transfusions is to maintain a safe hemoglobin level and platelet count, while attempting to minimize excessive exposure to transfusions. Since these children may subsequently need to be treated with an allogeneic transplant, all blood products should be CMV-safe and irradiated, even those given after IST.

    It is best to avoid transfusions from family donors, which may increase the risk of allosensitization. In patients who require a large number of red cell transfusions, clinicians should monitor for iron overload and implement iron chelation strategies when indicated. Febrile children and those with identified infections should be treated with antibiotics. Prophylaxis for fungus infection should be considered for children with severe neutropenia.

  • Matched-Related Donor SCT: HLA-typing of the patient and family members should be performed as soon after diagnosis as possible. Children and young adults (up to age 40 years) who have an HLA-matched related donor should proceed to allogeneic SCT. Conditioning regimens are typically cyclophosphamide-based to minimize the short- and long-term toxicities associated with radiation-based transplant preparative regimens. With modern transplant methods, survival in children receiving a matched-related donor transplant now exceeds 90%.

  • Immunosuppressive Therapy: In children who do not have an HLA-matched related donor, IST therapy is initiated, most often with the multi-agent regimen of antithymocyte globulin (ATG) and cyclosporine. The addition of hematopoietic growth factors (e.g., filgrastim, granulocyte colony-stimulating factor [G-CSF]) to ATG and cyclosporine-based regimens has not been proven to improve the response rate for IST. Both horse and rabbit ATG products are in clinical use, but there is currently little data to suggest superiority of one ATG source over the other.

    The response rate to ATG and cyclosporine IST regimens is approximately 50%-80%. Therefore, many modifications of this regimen have been attempted, including the addition of mycophenolate mofetil, danazol, and sirolimus, with little evidence of improved response rates. Newer regimens, including the use of alemtuzumab, with or without cyclosporine, are under investigation.

    The pattern of response to ATG and cyclosporine is variable, with no response in some children; responsive disease that allows for a taper and eventual discontinuation of cyclosporine in some patients; and responsive disease that requires long-term maintenance with cyclosporine in others. Approximately 10% of responsive patients will have a relapse of disease, and 10%-15% of patients will develop clonal abnormalities and a malignant disease. In patients with relapse of severe aplastic anemia, 10%-70% of patients will respond to another course of IST treatment.

  • Alternate Donor Allogeneic SCT (Donors other than HLA-matched related donors): Children who do not have an HLA-matched related donor and who have a failure of immunosuppressive therapy (no response, refractory disease, failure of a second course of IST following relapse) may receive an allogeneic SCT from an alternate donor, if a suitably matched donor can be identified. Outcomes for alternate donor SCT for severe aplastic anemia have traditionally been poor, with survival in less than 50% of patients. However, with advances in transplantation, current survival for children with severe aplastic anemia who receive alternate donor transplants now exceeds 50%, and in some series over 80%.

What are the adverse effects associated with each treatment option?

Supportive Care: With the long-term use of blood and platelet transfusions, patients may develop iron overload and allosensitization.

Immunosuppressive Therapy: Infectious complications and need for continued transfusions while awaiting a response to IST constitute the greatest risks to this form of therapy.

Allogeneic Hematopoietic Stem Cell Transplantation: Allogeneic transplantation is associated with a high probability of morbidity and mortality. Risks include, but are not limited to, death, infections, bleeding, graft-versus-host disease, and the development of secondary malignancies.

What are the possible outcomes of severe aplastic anemia?

Outcomes for children with severe aplastic anemia that are the result of inherited bone marrow failure syndromes are disease-specific. As discussed above, for children with idiopathic severe aplastic anemia, outcomes are very good, with survival in 80%-90% of children who receive a matched related donor transplant; response rates of 50%-80% in children who receive IST therapy; response rates of 10%-70% with a second course of IST therapy following a relapse; and improving results for alternate donor allogeneic transplantation for children who fail treatment with IST.

What causes this disease and how frequent is it?

  • Severe aplastic anemia in children is rare. For all ages, the incidence is approximately 3 cases per million in the United States.

  • Causes of severe aplastic anemia are described above.

How do these pathogens/genes/exposures cause the disease?


Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?


Are additional laboratory studies available; even some that are not widely available?

There are an increasing number of mutation analyses under development for the inherited bone marrow failure syndromes that cause severe aplastic anemia.

How can severe aplastic anemia be prevented?

For parents with a child with an inherited bone marrow failure syndrome, genetic counseling is very important. Parents also have the opportunity to create unaffected children with the utilization of preimplantation genetic diagnosis.

Avoidance of exposure to drugs, toxins, radiation, and infectious agents serve to minimize the risk of severe aplastic anemia.

What is the evidence?

Davies, JK, Guinan, EC. “An update on the management of severe idiopathic aplastic anemia in children”. Br J Haematol. vol. 136. 2007. pp. 549-64.

Niemeyer, CM, Baumann, I. “Classification of childhood aplastic anemia and myelodysplastic syndrome”. Hematology Am Soc Hematol Educ Program. vol. 2011. 2011. pp. pp. 84-9.

DeZern, AE, Guinan, EC. “Therapy for aplastic anemia”. Hematology Am Soc Hematology Educ Program. vol. 2011. 2011. pp. 82-3.

Führer, M, Rampf, U, Baumann, I. “Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival”. Blood. vol. 106. 2005. pp. 2102-4.

Guinan, EC. “Diagnosis and management of aplastic anemia”. Hematology Am Soc Hematology Educ Program. vol. 2011. 2011. pp. 76-81.

Gurion, R, Gafter-Gvili, A, Paul, M. “Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy–systematic review and meta-analysis”. Haematologica. vol. 94. 2009. pp. 712-9.

Kamio, T, Ito, E, Ohara, A. “Relapse of aplastic anemia in children after immunosuppressive therapy: a report from the Japan Childhood Aplastic Anemia Study Group”. Haematologica. vol. 96. 2011. pp. 814-9.

Marsh, JC, Ball, SE, Cavenagh, J. “Guidelines for the diagnosis and management of aplastic anaemia”. Br J Haematol. vol. 147. 2009. pp. 43-70.

Scheinberg, P, Wu, CO, Nunez, O, Young, NS. “Long-term outcome of pediatric patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine”. J Pediatr. vol. 153. 2008. pp. 814-9.

Scheinberg, P, Wu, CO, Nunez, O. “Treatment of severe aplastic anemia with a combination oof horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study”. Haematologica. vol. 94. 2009. pp. 348-54.

Scheinberg, P, Nunez, O, Wu, C, Young, NS. “Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil”. Br J Haematol. vol. 133. 2006. pp. 606-11.

Scheinberg, P, Wu, CO, Nunez, O, Young, NS. “Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia”. Br J Haematol. vol. 144. 2009. pp. 206-16.

Tamary, H, Alter, BP. “Current diagnosis of inherited bone marrow failure syndromes”. Pediatr Hematol Oncol. vol. 24. 2007. pp. 87-99.

Yoshida, N, Yagasaki, H, Hama, A. “Predicting response to immunosuppressive therapy in childhood aplastic anemia”. Haematologica. vol. 96. 2011. pp. 771-4.

Afable, MG, Tiu, RV, Maciejewski, JP. “Clonal evolution in aplastic anemia”. Hematology Am Soc Hematol Educ Program. vol. 2011. 2011. pp. 90-5.

Deeg, HJ, O’Donnell, M, Tolar, J. “Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy”. Blood. vol. 108. 2006. pp. 1485-91.

Kosaka, Y, Yagasaki, H, Sano, K. “Prospective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia”. Blood. vol. 111. 2008. pp. 1054-9.

Perez-Albuerne, ED, Eapen, M, Klein, J. “Outcome of unrelated donor stem cell transplantation for children with severe aplastic anemia”. Br J Haematol. vol. 141. 2008. pp. 216-23.

Viollier, R, Socié, G, Tichelli, A. “Recent improvement in outcome of unrelated donor transplantation for aplastic anemia”. Bone Marrow Transplant. vol. 41. 2008. pp. 45-50.

Ongoing controversies regarding etiology, diagnosis, treatment

Among the greatest challenges facing investigators is predicting treatment response and clinical course.