Although the ultimate diagnosis of AA rests on the interpretation of an adequate BM biopsy specimen, important clues to the cause of pancytopenia can be obtained from the history, physical examination, and laboratory data. Pancytopenia that is not primarily hematologic in origin but secondary to other disease processes is usually an obvious diagnosis. Patients with severe liver disease and splenomegaly, systemic lupus erythematosus, or overwhelming sepsis can have low blood cell counts, but the clinical presentation is not subtle. Similarly, BM aplasia following cytotoxic drug therapy for cancers and a variety of nonmalignant diseases is anticipated. In the challenging case, obvious medical causes of pancytopenia have usually already been excluded. Pancytopenia almost never results from peripheral blood cell destruction alone. In AA, the blood smear does not show reticulocytosis, band forms, or the large platelets typical of increased compensatory BM efforts.
Immune AA is a disease of younger people, as is constitutional aplasia. Patients with FA often, but not always, have physical abnormalities. In the absence of a suggestive family history or the presence of physical anomalies, the distinction between acquired and constitutional dis ease depends on the results of a clastogenic-stress culture of peripheral lymphocytes (for FA), and the telomere length of leukocytes (for the telomeropathies), and in recent years genomic panels that incorporate dozens of genes etiologic in constitutional syndromes.
In older patients the major differential diagnosis is between AA and myelodysplasia. There is a gray area between hypocellular myelodysplasia and moderate AA, and even competent hematologists might not agree on the final diagnosis. BM cytogenetics, genomic screens of peripheral blood leukocytes, can help in establishing the proper diagnosis.
Myelofibrosis can also lead to pancytopenia, but the BM is not aspirable, the spleen is often enlarged, and the peripheral blood smear shows characteristic abnormalities. Acute leukemia in children and the elderly can manifest as BM hypocellularity, requiring a careful search for lymphoblasts or myeloblasts, including phenotypic analysis by flow cytometry. Blood flow cytometry for glycophosphoinositol-anchored proteins should be performed to diagnose PNH.
The patient’s history can provide clues, such as benzene exposure for myelodysplasia and acute leukemia, or a suspicious drug history for AA. Discontinuation of exposure to the incriminated drugs or chemicals is mandatory, and in some instances, patients may then recover. However, given the difficulty of assigning blame with absolute certainty to environmental agents, we treat all patients similarly and do not advocate protracted observation for possible spontaneous recovery. For patients with severe disease (see Table 1), early preparation for stem cell transplant should be undertaken or immunosuppression begun, whereas for those with moderate disease, the clinical status should be evaluated, and serial blood cell counts are required to assess progression of the disease.
Table1. Severity of Aplastic Anemia as Defined by Laboratory Studies
