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Chapter 30 Aplastic Anemia 401

estimated AA case rate of approximately 1 in 200,000 treated patients, Retrospective studies of AA associated with drugs and viruses and
have led to questions concerning the relationship between carbam- the observation of the occasional patient with serially monitored
azepine and AA. blood counts suggest a latent period of 6–8 weeks between the
inciting event and the onset of pancytopenia. The interval can be
more prolonged when pancytopenia is well tolerated or moderate.
Gold and Heavy Metals With identification of genetic risk factor, the family history has
assumed great importance in the evaluation of pancytopenia. Leuke-
Gold salts have an extraordinarily high frequency of fatal adverse mia and myelodysplastic syndrome (MDS) can occur in FA and DKC
reactions, estimated at 1.6 cases per 10,000 prescriptions. Dose- pedigrees. In the telomeropathies secondary to TERT and TERC
dependent leukopenia is common, but several dozen cases of AA have mutations, hematologic findings in other family members may be
been reported. In the IAAAS, exposure to gold salts was the most mild, such as modest thrombocytopenia or macrocytosis with or
significant drug association for developing AA, with a relative risk of without anemia. These mutations also contribute to the development
29 and an excess risk of 23 cases per 1 million users in 1 week. of cirrhosis and pulmonary fibrosis, which may be present as diagno-
Spontaneous recovery rarely occurs. Patients have been successfully ses in the pedigree. Early graying of the hair is sometimes prominent
treated with stem-cell transplantation or immunosuppressive therapy; in telomere disease pedigrees. Inherited mutations in other genes
chelation usually has not been helpful. predispose to BM failure and myeloid neoplasms. Mutations in
GATA2 also lead to susceptibility to specific infections (which may
manifest as warts). Germline mutations in RUNX1, ETV-6, CEBP1a
TYPICAL AND ATYPICAL PRESENTATIONS and MPL cause AA or leukemia, in childhood. Genetic testing for
genes that are mutated in constitutional BM failure is commercially
Most patients with AA seek medical attention for symptoms that available.
occur as a result of low blood counts (Fig. 30.7 and Table 30.5). Some Findings on physical examination usually reflect the severity of
patients are diagnosed incidentally and often show few symptoms the pancytopenia (Table 30.6). However, patients with severe disease
despite severely depressed blood counts. All of the blood elements can look well. The patient can present with subtle variations from
can be depressed or a single lineage cytopenia can dominate. The normal or with a dramatic, even toxic appearance. Petechiae are often
differential diagnosis of pancytopenia includes a variety of diseases present over the pretibial surface of the lower legs and the dorsal
(see Table 30.1). Most patients do not have systemic symptoms: aspects of the forearms and wrists; a few petechiae can be seen in the
weight loss, persistent fever, pain, and loss of appetite point to an oropharynx and on the palate. Scattered ecchymoses typically appear
alternative diagnosis. in areas exposed to minor trauma. With severe thrombocytopenia,
Bleeding is the most alarming manifestation of pancytopenia and retinal hemorrhages can be observed on funduscopic examination,
frequently sends the patient to a doctor. Thrombocytopenia usually there can be gingival oozing or blood in the nares, and hemorrhage
does not cause massive bleeding. Instead, the patient reports easy can be apparent at the uterine cervical os. The stool can contain traces
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 TABLE Presenting Symptoms of Aplastic Anemia
urine may be reported that is caused by free hemoglobin, but visible 30.5
bleeding from the genitourinary and gastrointestinal tracts is rare. Symptoms Number of Patients
Extensive hemorrhage from any organ can occur but usually late in
the course of the disease and almost always associated with infections, Bleeding 41
drug therapy, or invasive procedures. Anemia 27
The ability to adapt to a gradual reduction in hemoglobin con- Bleeding and anemia 14
centration is remarkable. The anemic patient might mention fatigue, Bleeding and infection 6
lassitude, shortness of breath, or ringing in the ears, but some indi-
viduals can tolerate astonishingly low hemoglobin levels without Infection 5
complaint. Even abrupt cessation of erythropoiesis leads to only a Routine examination 8
slow decline in hemoglobin. Total 101
Infection is an uncommon presentation in patients with AA. The
sore throat of agranulocytosis is not often observed, presumably Adapted from Williams DM, Lynch RE, Cartwright GE: Drug induced aplastic
anemia. Semin Hematol 10:195, 1973.
because other alarming symptoms appear earlier.

A B C

Fig. 30.7 CLINICAL PRESENTATIONS OF APLASTIC ANEMIA. (A) Ecchymosis in pancytopenic
women. (B) Submucosal hematomas. (C) Petechial eruptions in a thrombocytopenic patient.