Aplastic Anemia

How to Cite This Chapter: Khalaf D, Crowther M, Podolak-Dawidziak M. Aplastic Anemia. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.15.1.7. Accessed November 29, 2023.
Last Updated: June 23, 2019
Last Reviewed: June 2, 2020
Chapter Information

Also see Anemia: General Considerations.

Definition, Etiology, PathogenesisTop

Aplastic anemia (AA) is type of bone marrow failure that leads to pancytopenia, life-threatening infections in the setting of neutropenia, bleeding due to thrombocytopenia, and severe anemia leading to transfusion dependence.

The primary cause of AA is either an inherited anomaly or acquired injury of hematopoietic stem cells or the bone marrow microenvironment, which leads to the inhibition of cellular proliferation and differentiation.

Classification of AA:

1) Congenital or inherited causes are responsible for ≥25% of cases among children and up to 10% of cases among adults. Examples: Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, familial aplastic anemia. Patients may exhibit dysmorphic features, hyperpigmentation, skeletal abnormalities, or other physical stigmata. Pancytopenia and the associated symptoms may be the presenting features.

2) Acquired AA (up to 80% of cases):

a) Idiopathic factors (>50%).

b) Infectious causes: Viral hepatitis (usually acute hepatitis A, B, or C 2-3 months earlier), Epstein-Barr virus (EBV), HIV, parvovirus B19 (eg, in the setting of sickle cell disease), sometimes the offending virus is not known; mycobacteria.

c) Exposure to ionizing radiation.

d) Transfusion-associated graft-versus-host disease (GVHD): Donor T cells cause GVHD in patients with hematologic malignancies who receive purine analogues such as bendamustine or fludarabine; after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

e) Chemicals such as benzene, organic solvents, trinitrotoluene, pesticides, and herbicides.

f) Autoimmune or connective tissue diseases.

g) Anorexia nervosa, severe nutritional deficiencies (vitamin B12, folate).

h) Paroxysmal nocturnal hemoglobinuria (PNH).

i) Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs), busulfan, cyclophosphamide, anthracyclines, methotrexate, antibiotics such as chloramphenicol and sulfonamides, gold compounds, chloroquine, chlorpropamide, phenytoin, allopurinol, and thiazides.

j) Pregnancy (rare).

Clinical Features Top

Symptoms of AA may develop rapidly (within several days) or slowly (several weeks or months). Clinical manifestations of AA result from anemia, neutropenia, and thrombocytopenia.


Diagnostic Tests

1. Complete blood count (CBC) and peripheral smear: Normocytic (sometimes macrocytic) and normochromic anemia, very low reticulocyte counts (<10×109/L), leukopenia with neutropenia (usually <1.5×109/L), thrombocytopenia (<50×109/L).

2. Exclude other causes: Measurements of vitamin B12, folate, copper (ceruloplasmin), and zinc to exclude nutritional deficiency; liver function tests to exclude hepatitis; hemolytic screen; viral serology (see above); chromosomal studies to exclude Fanconi anemia. Exclude autoimmune diseases; test for antinuclear antibodies and double-stranded DNA (dsDNA) if a connective tissue disease is suspected. Imaging studies are used to assess for infections or lymphoma; chest radiography and abdominal ultrasonography may be helpful.

3. Bone marrow examination: Cell markers and flow cytometry to detect a PNH clone, large granular lymphocytes, or MDS. Aspirate usually reveals decreased numbers of hematopoietic cells (<30%), a proportion of fat cells to hematopoietic cells >3, and no malignant cells. Trephine biopsy specimens reveal few cellular fields in a generally hypocellular marrow.

Diagnostic Criteria

Peripheral blood cytopenia (affecting ≥2 of 3 lineages) and hypocellular bone marrow without infiltrative or fibrotic process after other causes have been excluded (see below). At least 2 out of 3 cytopenias: hemoglobin (Hb) <100 g/L, platelet count <50×109/L, and/or absolute neutrophil count (ANC) <1.5×109/L.

Severity of AA as per the modified Camitta criteria:

1) Severe AA: Marrow cellularity <30% with ≥2 of the following: ANC <0.5×109/L; platelet count <20×109/L, reticulocyte count <20×109/L.

2) Very severe AA: ANC <0.2×109/L.

Differential Diagnosis

Acute leukemia (particularly acute lymphoblastic leukemia), hairy cell leukemia, MDS, PNH, hypersplenism, bone marrow infiltrates (cancer), lymphomas.


1. General measures:

1) Promptly refer the patient to a hematology center.

2) Transfusion support: Leukoreduced packed red blood cells (PRBCs) and platelets used only when this is considered essential. HSCT may be compromised by prior transfusion therapy. Seek consultation with a transfusion medicine specialist regarding transfusion of phenotype-matched blood to reduce the risk of alloimmunization.

3) Iron chelation therapy is used when indicated due to iron overload with transfusions. Patients who undergo successful HSCT may require regular phlebotomies.

4) Initiate prophylactic antifungal treatment in patients with prolonged neutropenia (<0.2×109/L for >1 week). Antiviral treatment should be offered to patients receiving immunosuppressive therapy. Defer initiation of granulocyte colony-stimulating factor (G-CSF) therapy until the patient is seen by a hematologist and bone marrow examination is completed to exclude acute leukemia. Broad-spectrum antibiotics with antipseudomonal coverage should be started in case of febrile neutropenia.

2. Allogeneic HSCT is the treatment of choice for otherwise eligible patients up to 50 years of age with severe AA for whom a human leukocyte antigen (HLA)-matched sibling donor is available. Allogeneic HSCT is curative in 60% to 90% of patients. In case of no response to 6-month immunosuppressive treatment, allogeneic HSCT should be considered. Related donors are generally preferred to unrelated donors.

3. Immunosuppressive treatment is indicated in patients who are not considered for allogeneic HSCT. It results in improvement in 60% to 80% of cases. Use antithymocyte globulin (ATG) combined with cyclosporine (INN ciclosporin). In patients treated with ATG, all transfused PRBCs and platelets must be irradiated to avoid transfusion-associated GVHD.

4. Androgens (eg, oxymetholone 2.5 mg/kg/d) may be effective in patients with Fanconi anemia or acquired AA with refractoriness or contraindications to immunosuppressive treatment; however, the drugs should be discontinued if no improvement is achieved within 4 to 6 months. In patients with good response to treatment, the dose is tapered down slowly to discontinuation.

5. Alemtuzumab: In patients with recurrent AA the drug has efficacy similar to ATG combined with cyclosporine.


In patients with severe AA who are not treated with allogeneic HSCT, 2-year mortality rate is 80%. The most frequent causes of death are severe bacterial or fungal infections. AA may transform to MDS, acute leukemia, or PNH.

We would love to hear from you

Comments, mistakes, suggestions?

We use cookies to ensure you get the best browsing experience on our website. Refer to our Cookies Information and Privacy Policy for more details.