Aplastic Anemia

How to Cite This Chapter: Dalmia S, Crowther M, Khalaf D, Podolak-Dawidziak M. Aplastic Anemia. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.15.1.7. Accessed April 24, 2024.
Last Updated: December 26, 2023
Last Reviewed: December 26, 2023
Chapter Information

Also see Anemia: General Considerations.

Definition, Etiology, PathogenesisTop

Aplastic anemias (AAs) are a group of bone marrow failure syndromes characterized by pancytopenia with complications of life-threatening infections in the setting of neutropenia, bleeding due to thrombocytopenia, and severe anemia leading to transfusion dependence. These conditions are clinicopathologic diagnoses and must be differentiated from other causes of pancytopenia such as nutritional deficiency and hypoplastic myelodysplastic syndrome (MDS).

AA can be either inherited or acquired; this is typically due to damage to hematopoietic stem cells or the bone marrow microenvironment, which leads to the inhibition of cellular proliferation and differentiation.

Causes 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, (red cell aplasia), familial AA. Patients may exhibit dysmorphic features, hyperpigmentation, or skeletal abnormalities, or may have a concomitant lung, liver, or pancreatic disease or other physical stigmata including nail and skin changes. Pancytopenia and the associated symptoms may be the presenting features. Biochemical testing and confirmatory genetic testing can be helpful.

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

a) Idiopathic factors (>50%).

b) Infectious causes: Viral hepatitis (usually acute hepatitis A, B, or C that may occur 2-3 months prior to AA), Epstein-Barr virus, HIV, parvovirus B19 (eg, in the setting of sickle cell disease), mycobacteria. Sometimes the offending organism is not identified.

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/or thrombocytopenia. A history of thrombosis may indicate concomitant PNH and medication history can be useful to correlate with drug exposure.


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) and a relative lymphocytosis, thrombocytopenia (<50×109/L). Comparison with previous laboratory results may indicate an acquired etiology.

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 serologies (see above). In specialized centers some other test could be performed: chromosomal studies, telomere length analysis, and specific enzyme levels (eg, pancreatic isoamylase) for inherited bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome. Molecular mutational panels or next-generation sequencing, if available, can be helpful for confirmation or diagnosis of other rare inherited causes of AA. 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 lymphoproliferative diseases; chest radiography and abdominal ultrasonography may be helpful as a starting point.

3. Bone marrow examination: Cell markers and flow cytometry to detect underlying high-grade malignancy (eg, acute leukemia), myelodysplasia, or large granular lymphocytes. PNH testing may be optimally done via flow cytometry for CD55/CD59 or fluorescein-labeled proaerolysin (FLAER) testing from peripheral blood. Aspirate usually reveals decreased numbers of hematopoietic cells (<30%), a ratio of fat cells to hematopoietic cells of >3, and no malignant cells. Trephine biopsy specimens reveal a few cellular fields in a generally hypocellular marrow.

Diagnostic Criteria

Peripheral blood cytopenias (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, 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), MDS, PNH, hypersplenism, bone marrow infiltrates (inflammatory diseases, metastatic malignancy), lymphoproliferative disorders with bone marrow involvement (eg, hairy cell leukemia).


1. General measures:

1) Promptly refer the patient to a hematology center.

2) Transfusion support: Leukoreduced packed red blood cells (PRBCs) and platelets should be used only when considered essential (eg, platelet count <109/L or bleeding). 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 treatment (IST). 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 70 years of age with severe AA for whom a human leukocyte antigen (HLA)-matched sibling donor is available (or using haploidentical options). Allogeneic HSCT is curative in 60% to 90% of patients. If IST is pursued, in case of no response after 6 months, allogeneic HSCT should be considered. Related donors are generally preferred to unrelated donors. Special care for conditioning is required for patients with chromosomal fragility (eg, Fanconi anemia).

3. IST is indicated in patients who are not considered for allogeneic HSCT. It results in improvement in 60% to 80% of cases. First-line agents include equine 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. Glucocorticoids are not effective for IST but can be used for prevention of serum sickness.

4. Eltrombopag is an oral small-molecule agonist targeting the thrombopoietin (TPO) receptor that is expressed on hematopoietic stem cells. Although the exact mechanism is unclear, there are data supporting its use in combination with IST for patients with AA. Liver function needs to be monitored.

5. Androgens (eg, oxymetholone 2.5 mg/kg/d) may be effective in patients with Fanconi anemia or acquired AA with refractoriness or contraindications to IST; 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.

6. 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, the 2-year mortality rate is 80%. The most frequent causes of death are severe bacterial or fungal infections. Patients with AA may develop overt PNH or transform to MDS and acute leukemia in some cases due to clonal evolution.

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