Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 3) pdf

Chapter 102. Aplastic Anemia, Myelodysplasia, and
Related Bone Marrow Failure Syndromes
(Part 3)

Radiation
Marrow aplasia is a major acute sequela of radiation. Radiation damages
DNA; tissues dependent on active mitosis are particularly susceptible. Nuclear
accidents can involve not only power plant workers but also employees of
hospitals, laboratories, and industry (food sterilization, metal radiography, etc.), as
well as innocents exposed to stolen, misplaced, or misused sources. While the
radiation dose can be approximated from the rate and degree of decline in blood
counts, dosimetry by reconstruction of the exposure can help to estimate the
patient's prognosis and also to protect medical personnel from contact with
radioactive tissue and excreta. MDS and leukemia, but probably not aplastic
anemia, are late effects of radiation.
Chemicals
Benzene is a notorious cause of bone marrow failure. Vast quantities of
epidemiologic, clinical, and laboratory data link benzene to aplastic anemia, acute
leukemia, and blood and marrow abnormalities. The occurrence of leukemia is
roughly correlated with cumulative exposure, but susceptibility must also be
important, as only a minority of even heavily exposed workers develop benzene
myelotoxicity. The employment history is important, especially in industries
where benzene is used for a secondary purpose, usually as a solvent. Benzene-
related blood diseases have declined with regulation of industrial exposure.
Although benzene is no longer generally available as a household solvent,
exposure to its metabolites occurs in the normal diet and in the environment. The
association between marrow failure and other chemicals is much less well
substantiated.
Drugs
(Table 102-3) Many chemotherapeutic drugs have marrow suppression as a
major toxicity; effects are dose-dependent and will occur in all recipients. In

contrast, idiosyncratic reactions to a large and diverse group of drugs may lead to
aplastic anemia without a clear dose-response relationship. These associations
rested largely on accumulated case reports until a large international study in
Europe in the 1980s quantitated drug relationships, especially for nonsteroidal
analgesics, sulfonamides, thyrostatic drugs, some psychotropics, penicillamine,
allopurinol, and gold. Not all associations necessarily reflect causation: a drug
may have been used to treat the first symptoms of bone marrow failure (antibiotics
for fever or the preceding viral illness) or provoked the first symptom of a
preexisting disease (petechiae by nonsteroidal anti-inflammatory agents
administered to the thrombocytopenic patient). In the context of total drug use,
idiosyncratic reactions, while individually devastating, are rare events.
Chloramphenicol, the most infamous culprit, reportedly produced aplasia in only
about 1/60,000 therapy courses, and even this number is almost certainly an
overestimate (risks are almost invariably exaggerated when based on collections of
cases; although the introduction of chloramphenicol was perceived to have created
an epidemic of aplastic anemia, its diminished use was not followed by a changed
frequency of marrow failure). Risk estimates are usually lower when determined
in population-based studies; furthermore, the low absolute risk is also made more
obvious: even a ten- or twentyfold increase in risk translates, in a rare disease, to
but a handful of drug-induced aplastic anemia cases among hundreds of thousands
of exposed persons.
Table 102-
3 Some Drugs and Chemicals Associated with Aplastic
Anemia

Agents that regu
larly produce marrow depression as major toxicity in
commonly employed doses or normal exposures:
Cytotoxic drugs used in cancer chemotherapy: alkylating agents
,

antimetabolites, antimitotics, some antibiotics
Agents that frequently but not inevitably produce marrow aplasia:
Benzene
Agents associated with aplastic anemia but with a relatively low
probability:
Chloramphenicol
Insecticides
Antiprotozoals: quinacrine and chloroquine, mepacrine
Nonsteroidal anti-inflammatory drugs (including phenylbutazone
,
indomethacin, ibuprofen, sulindac, aspirin)
Anticonvulsants (hydantoins, carbamazapine, phenacemide, felbamate)
Heavy metals (gold, arsenic, bismuth, mercury)

Sulfonamides: some antibiotics, antithyroid drugs (methimazole,
met
hylthiouracil, propylthiouracil), antidiabetes drugs (tolbutamide,
chlorpropamide), carbonic anhydrase inhibitors (acetazolamide and
methazolamide)
Antihistamines (cimetidine, chlorpheniramine)
D-Penicillamine
Estrogens (in pregnancy and in high doses in animals)
Agents whose association with aplastic anemia is more tenuous:

Other antibiotics (streptomycin, tetracycline, methicillin, mebendazole,
trimethoprim/sulfamethoxazole, flucytosine)
Sedatives and tranquilizers (chlorpromazine, prochlo
rperazine,
piperacetazine, chlordiazepoxide, meprobamate, methyprylon)
Allopurinol

Methyldopa
Quinidine
Lithium
Guanidine
Potassium perchlorate
Thiocyanate
Carbimazole

Note: Terms set in italic show the most consistent associatio
n with aplastic
anemia.