Most patients with AA seek medical attention for symptoms that occur as a result of low blood counts (Table 1). Some patients are diagnosed incidentally and often show few symptoms despite severely depressed blood counts. All of the blood elements can be depressed or a single lineage cytopenia can dominate. The differential diagnosis of pancytopenia includes a variety of diseases. Most patients do not have systemic symptoms: weight loss, persistent fever, pain, and loss of appetite point to an alternative diagnosis.
Table1. Presenting Symptoms of Aplastic Anemia
Bleeding is the most alarming manifestation of pancytopenia and frequently provokes the patient to see a doctor. Thrombocytopenia usually does not cause massive bleeding. Instead, the patient reports easy bruisability and the appearance of red spots, especially over dependent surfaces; gum bleeding with tooth brushing and episodic nose bleeds are common. Heavy menstrual flow or irregular vaginal bleeding can occur in younger women. In AA associated with PNH, red or dark urine is due to hemoglobinuria, but generally visible bleeding from the genitourinary and gastrointestinal tracts is rare. Extensive hemorrhage from any organ can occur but usually late in the course of the disease and almost always associated with infections, drug therapy, or invasive procedures.
The ability to adapt to a gradual reduction in hemoglobin con centration is remarkable. The anemic patient might mention fatigue, lassitude, shortness of breath, or ringing in the ears, but some individuals can tolerate a very low hemoglobin levels without complaint. Even abrupt cessation of erythropoiesis leads to only a slow decline in hemoglobin.
Infection is an uncommon initial symptom in patients with AA. The sore throat associated with agranulocytosis is not often observed, presumably because other alarming symptoms appear earlier.
Retrospective studies of AA associated with drugs and viruses and the observation of the occasional patient with serially monitored blood counts suggest a latent period of 6 to 8 weeks between the inciting event and the onset of pancytopenia. The interval can be more prolonged when pancytopenia is well tolerated or moderate.
With identification of genetic etiologies, the family history has assumed great importance in the evaluation of pancytopenia. Leukemia and myelodysplastic syndrome (MDS) can occur in FA and TBD pedigrees. In the telomeropathies secondary to TERT and TERC mutations, hematologic findings in other family members may be mild, such as modest thrombocytopenia or macrocytosis with or without anemia. These mutations also cause cirrhosis and pulmonary fibrosis, which may be present as diagnoses in the pedigree. Early graying of the hair is sometimes prominent in TBD pedigrees. Inherited mutations of other genes predispose to BM failure and myeloid neoplasms. For instance, germline mutations in runt-related transcription fac tor 1 (RUNX1), ETS variant transcription factor 6 (ETV-6), CCAAT enhancer binding protein alpha (CEBPa), and myeloproliferative leukemia protein (MPL) cause childhood AA or leukemia. Germline mutations in sterile alpha motif domain containing 9 (SAMD9) and sterile alpha motif domain containing 9 like (SAMD9L), or GATA binding protein 2 (GATA2) cause BM failure and later evolution to MDS associated with monosomy-7 or deletion 7q. Genetic testing for genes that are mutated in constitutional BM failure is commercially available as genomic screening.
Findings on physical examination usually reflect the severity of the pancytopenia (Table 2). However, patients with severe disease can look well. The patient can present with subtle variations from normal or with a dramatic, even toxic appearance. Petechiae are often present over the pretibial surface of the lower legs, the dorsal aspects of the forearms and wrists, in the oropharynx, and on the palate. Ecchymoses typically appear in areas exposed to minor trauma. With severe thrombocytopenia, retinal hemorrhages can be observed on funduscopic examination, there can be gingival oozing or blood in the nares, and hemorrhage can be apparent at the uterine cervicalos. The stool can contain traces of heme. Pallor is common and is best appreciated on the mucous membranes and palmar surfaces. The newly diagnosed patient can be febrile, but specific or localizing signs of infection are uncommon on presentation. Cachexia, splenomegaly, and lymph adenopathy are not associated with AA, and these findings should strongly suggest another diagnosis. The examiner should look carefully for café-au-lait spots and other physical anomalies of FA, typical nail changes, leucoplakia, and hypopigmentation of the skin and gray hair of telomere disease in children and adults.
Table2. Severity of Aplastic Anemia as Defined by Laboratory Studies
Several atypical presentations of AA should be noted. A physician might encounter an elderly patient with pancytopenia in whom subsequent BM examination reveals dysplastic features (see box on Diagnostic Algorithm in Aplastic Anemia and Table 3). Although the history of the illness in a newly diagnosed patient is typically short—in the range of months—some patients may recall a longer history of bruising, anemia, and low blood-cell counts reported to them by previous physicians during routine examinations. These patients can have a moderately severe, chronic disease, and pancytopenia from childhood should suggest a constitutional AA.
Table3. Bone Marrow Morphologic and Molecular Findings That Discriminate Myelodysplasia From Aplastic Anemia
