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

Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes Part 3 Radiation Marrow aplasia is a major acute sequela of radiation.. MDS and leukemia, but probably not a

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 regularly 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, methylthiouracil, 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, prochlorperazine, piperacetazine, chlordiazepoxide, meprobamate, methyprylon)

Allopurinol

Methyldopa

Quinidine

Lithium

Guanidine

Potassium perchlorate

Thiocyanate

Carbimazole

Note: Terms set in italic show the most consistent association with aplastic

anemia