Having an accurate diagnosis of aplastic anemia (AA) is critical to disease management. A recent review published in Blood Advances found that germline predisposition to the disease is more common than previously thought and is an important part of diagnosis.

Mortality from severe AA approaches 70% at 2 years for patients who do not receive optimal treatment. The review authors note that with advances in diagnostic testing and recognition of genetic predispositions, the diagnostic algorithm for AA is complex.

No test exists to definitively diagnose AA, so it is a diagnosis of exclusion. Patients often present with fatigue, weakness, pallor and headaches. They may also have petechiae of the skin and mucous membranes, epistaxis or gum bleeding.

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About 70% of new AA cases are acquired and occur in about 2 people per million in Western countries. The incidence of inherited cases is rising, possibly because of a better ability to test for inherited bone marrow failure disorders (BMFD).

The authors reviewed existing criteria for diagnosing AA and provided examples of 4 patients.

A few diagnostic findings that indicate AA include:

  • The presence of PNH clones. Further examination is needed to distinguish AA from classical PNH disease.
  • “Empty” marrow in histology with a bone marrow biopsy and aspirate.
  • Depression of peripheral blood counts. AA is classified by the severity of depression.
  • Clinical and family history suggestive of inherited BMFD, although about 40% of patients do not have a family history of BMFD.

Detecting somatic mutations with next-generation sequencing may aid in a diagnosis of AA, but many mutations in AA are also present in myelodysplastic syndrome (MDS). Mutations may have prognostic significance, but research in this area is ongoing.

The authors recommend real-time differentiation of AA from a BMF because of an inherited BMFD to ensure the patient receives appropriate treatment. Patients younger than 40 should also be screened to rule out short telomere syndrome (STS) and Fanconi anemia (FA).

Offering a consistent work-up to patients with suspected AA helps provide access to appropriate treatment and quality care.


DeZern AE, Churpek JE. Approach to the diagnosis of aplastic anemia. Blood Adv. 2021;5(12):2660-2671. doi:10.1182/bloodadvances.2021004345