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Chapter 30 Aplastic Anemia 399

sensitive to radiation, their rate of decline can be used to estimate the TABLE Classification of Drugs and Chemicals Associated
dose of total body exposure to a level of approximately 3 Gy. At 30.3 With Aplastic Anemia
higher doses, the fall in granulocytes and the severity of thrombocy-
topenia and reticulocytopenia can be used as gauges. The survival of I. Agents That Regularly Produce Marrow Depression as a Major Toxic
some patients who received doses higher than 9 Gy suggests that Effect When Used in Commonly Used Doses or Normal Exposures
autologous BM reconstitution may occur in most persons who Cytotoxic drugs used in cancer chemotherapy
survive the immediate consequences of radiation exposure. Alkylating agents (busulfan, melphalan, cyclophosphamide)
Pancytopenia may be a late consequence of a single radiation dose, Antimetabolites (antifolic compounds, nucleotide analogs) antimitotics
but AA is not well documented as a delayed event after radiation (vincristine, vinblastine, colchicine)
exposure. A variety of hematologic abnormalities are associated with Some antibiotics (daunorubicin, doxorubicin [Adriamycin])
chronic low-level radiation exposure, most commonly lymphocytosis, Benzene (and less often benzene-containing chemicals: kerosene,
neutropenia, dysmorphic leukocytes, and giant platelets (see Fig. carbon tetrachloride, Stoddard solvent, chlorophenols)
30.6). Cytogenetic abnormalities accumulate with time after chronic II. Agents Probably Associated With Aplastic Anemia but With a Relatively
exposure, but they may not be reliably related to dose. Repeated low Low Probability Relative to Their Use
doses of radiation have been associated with AA, but even in these Chloramphenicol
circumstances, only a small proportion of exposed individuals develop Insecticides
hematologic disease. AA does not appear to be more frequent among Antiprotozoals (quinacrine and chloroquine)
nuclear power plant or thorium processing factory workers or among Nonsteroidal antiinflammatory drugs (including phenylbutazone,
residents living close to the plants. Excessive numbers of deaths from indomethacin, ibuprofen, sulindac, diclofenac, naproxen, piroxicam,
AA were reported after therapeutic irradiation of the spine for anky- fenoprofen, fenbufen, aspirin)
losing spondylitis; later analysis has suggested that the risk may have Anticonvulsants (hydantoins, carbamazepine, phenacemide,
been overestimated. AA has not been found in unexpected numbers ethosuximide)
in cancer patients who had received therapeutic irradiation or among Gold, arsenic, and other heavy metals such as bismuth and mercury
persons exposed to higher natural background radiation. Sulfonamides as a class
Antithyroid medications (methimazole, methylthiouracil,
propylthiouracil)
Drugs and Chemicals Antidiabetes drugs (tolbutamide, carbutamide, chlorpropamide)
Carbonic anhydrase inhibitors (acetazolamide, methazolamide,
AA is frequently associated with medical drug use (Table 30.3). At mesalazine)
the end of the 19th century, chemicals were linked to BM function D-Penicillamine
through observations of benzene effects on workers. Establishment 2-Chlorodeoxyadenosine
of a relationship between the analgesic amidopyrine and agranulocy- III. Agents More Rarely Associated With Aplastic Anemia
tosis in the early 20th century and an apparent epidemic of AA after Antibiotics (streptomycin, tetracycline, methicillin, ampicillin,
the introduction of chloramphenicol in the 1960s also supported this mebendazole and albendazole, sulfonamides, flucytosine,
concept. Initially suggested by the accumulation of case reports, drug mefloquine, dapsone)
associations have been established in formal case-control population- Antihistamines (cimetidine, ranitidine, chlorpheniramine)
based epidemiologic studies. In the IAAAS, relative risks were esti- Sedatives and tranquilizers (chlorpromazine, prochlorperazine,
mated for individual drugs and large classes of pharmaceutical agents, piperacetazine, chlordiazepoxide, meprobamate, methyprylon,
including nonsteroidal antiinflammatory drugs (NSAIDs), drugs remoxipride)
affecting thyroid function, certain cardiovascular agents, some psy- Antiarrhythmics (tocainide, amiodarone)
2
chotropics, and sulfa-based antibiotics (Table 30.4). Approximately Allopurinol (can potentiate marrow suppression by cytotoxic drugs)
25% of the cases of AA identified in the IAAAS could be attributed Ticlopidine
to drug use. Drug use as a risk factor was also assessed by similar Methyldopa
methods in Thailand, where the incidence of AA is higher than in Quinidine
the West. Surprisingly, chloramphenicol was not shown to be a risk Lithium
factor; the etiologic fraction of AA was attributed to only 15%. Guanidine
Associations between drug exposure and AA can be divided into Canthaxanthin
two classes. Drugs used in cancer chemotherapy are selected for their Thiocyanate
cytotoxicity, and their regular, dose-dependent induction of BM Carbimazole
aplasia is an expected effect. Most AA associated with medical drug Cyanamide
use in the community is described as idiosyncratic, meaning that its Deferoxamine
occurrences are unexpectedly rare. Many of the drugs implicated in Amphetamines
AA also appear to cause other, milder forms of BM suppression such
as neutropenia. Although difficult to prove, some dose relationship
probably does exist even for idiosyncratic reactions. In most case
reports, patients received normal or high doses of the agent, usually (e.g., benzene toxicity), epoxide hydrolases (e.g., phenytoin toxicity),
for a period of weeks to months. Drug-induced aplasia cannot be S-methylation (e.g., 6-mercaptopurine, 6-thioguanine, azathioprine)
distinguished by history from idiopathic forms of the disease; the and N-acetylation (e.g., sulfa drugs). Genomic approaches have
clinical course, including the favorable response to immunosuppres- revealed the complex role of genetic variation in metabolic pathways
sive therapy, is the same as in idiopathic disease. that process arylhydrocarbons and even links to immune function.
The low probability of developing AA after a course of drugs may
be a reflection of the gene variant frequency for metabolic enzymes
(for direct chemical effects) or immune response genes. The rarity of Benzene
idiosyncratic drug reactions could then arise from the infrequent
combination of unusual circumstances: exposure, genetic variations Benzene exposure is linked to AA. Benzene myelotoxicity can be
in drug metabolism, the physical properties of the agent, enzymatic placed between the predictable effects of chemotherapeutic agents
pathways that chemically alter the drug, and the susceptibility of the and idiosyncratic drug reactions. Industrial emissions add greatly to
host to the action of a toxic compound. Examples of detoxifying the biologic sources of ambient benzene. Significant benzene exposure
enzyme systems directly applicable to BM failure and that also can also occur outside of industry. Although the concentrations of
demonstrate genetic variability include arylhydrocarbon hydroxylase benzene to which consumers are exposed are orders of magnitude