Aplastic anemia is a disease of the young, with a median incidence at about 25 years of age (excluding aplasia secondary to cancer chemotherapy). It must be a leading diagnosis in the pancytopenic adolescent or young adult. The bone marrow is usually readily aspirated but appears dilute on smear. The biopsy specimen, often grossly pale, shows mainly fat under the microscope, with hematopoietic cells occupying by defini-tion less than 25 per cent of the marrow space and, in the most serious cases, 0 to 5 per cent. Prognosis is determined by the degree of blood count depression. The commonly accepted standard for severe disease requires two of the following three values; ¢Ù absolute neutrophil count (percentage of polymor-phonuclear and band forms multiplied by the total white blood cell count) of less than 500 per cubic millimeter; ¢Ú platelets less than 20,000 per cubic millimeter; and ¢Û reticuloeyte count(correeted for hematocrit) in the presence of anemia of less than 1 per cent (or an absolute retieuloeyte count less than 40,000 per cubic millimeter).

Bicytopenia and Single-lineage Failure States Some pa-tients present with bone marrow hypocellularity and depression of only two of the three major blood lines; many progress to typical aplastic anemia. Failure of a single lineage also occurs, as in pure red blood cell aplasia (rare), amegakaryocytic thrombocytopenia (extremely rare), and agranulocytosis (not rare but usually an idiosyncratic drug reaction). Single-lineage failures show a characteristic absence of a single set of recog-nizable precursor cells in an otherwise cellular bone marrow, and in this way they are differentiated from the much more common causes of anemia (such as vitamin or iron deficicncy and hemolysis) or thrombocytopenia (from peripheral destruc. tion of platelets). The pathophysiology of the more restricted marrow failure states is probably similar to that of general bone marrow failure, but with a more mature target cell.

Constitutional (Fanconi' s) Anemia Fanconi scribed children with inherited pancytopenia and marrow hypocellular-ity with associated anomalies of the skeletal and urogenital sys-terns. Fancom s anemia now is defined by specific chromoso-real aberrations in cultured cells after clastogenic stress. In-deed, cytogenetic analysis of families of children with Fanconi's anemia has shown that the majority of patients tack associated anomalies and that the disease can manifest in adults, in the third and fourth decades or even later. Congenital pure red cell aplasia (Diamond-Blackfan syndrome) lacks a cytogenetic marker or associated physical abnormalities, and distinction from acquired aplastic anemia after infancy is possible only by family history. Isolated neutropenia or thrombocytopenia oc-curs in a number of pediatric syndromes.

Etiology

In the majority of patients, aplastic anemia is diagnosed as "idiopathic. " There is little to distinguish these cases clini-cally from those with a presumed etiology, like exposure to a drug or chemical. Even when clinical associations are estab-lished, they should not automatically be equated with etiology and pathophysiology: Association is not equivalent to cause, nor does it define a mechanism.

Radiation Marrow aplasia is a major acute sequela of ra-diation exposure. Radiant energy damages DNA. The bone marrow, as a tissue dependent on active mitosis, is particularly susceptible to its effects. Nuclear accidents and radiation injury can involve not only power plant workers but also employees of hospitals, laboratories, and industry (e. g, food sterilization, metal radiography, and so forth), as well as those innocent persons exposed to stolen, mislaced, or misused radiation sources. The radiation dose can be approximated from the rate and degree of decline in blood counts; dosimetry by reconstruc-tion of the exposure can help to estimate the patient's progno-sis and also to protect medical personnel from contact with ra-dioactive tissue and excreta. Myelodysplasia and leukemia, but not aplastic anemia, are late effects of irradiation.

Chemicals Benzene has been clearly linked to bone mar-row failure, including aplastic anemia, acute leukemias, and probably multiple myeloma. The occurrence of hematologic ab-normalities is roughly correlated with cumulative exposure, but there must also be an important element of susceptibility, as 0nly a minority of even heavily exposed workers develop evi-dence of benzene myelotoxicity. A history of past employment is importhant, especially in "open" industries in which benzene is used for a secondary purpose (usually as a solvent) rather than in "closed" industries for chemical production. Benzene-related blood diseases have declined with regulation of industri-al exposure, and benzene is not generally available as a house-hold solvent. However, the benzene content of gasoline has been increased with its unleading. The association of marrow failure with other chemicals that contain a benzene ring is much less well substantiated; some, like the insecticide lin-dane, were probably contaminated with benzene during manu-facture.

Drugs Many of the common cancer chemotherapeutic drugs suppress the bone marrow. The mechanisms by which these drugs act offer useful clues to the pathophysiology of "id-iopathic" aplastic anemial. A very large and diverse group of drugs is related to aplastic anemia by rare but serious idiosyn-cratic reactions. These associations, which rest mainly on case reports, are tenuous at best. For example, some incriminated drugs may have been used to treat the first symptoms of hone marrow failure (antibiotics for fever or the preceding viral ill-ness) or may have provoked the first symptom of a preexisting disease (petechiae produced by nonsteroidal anti-inflammatory agents administered to a thrombocytopenic individual). In the context of total drug employment, idiosyncratic reactions, while individually devastating, are very rare events.

Chloramphenicol, the most infamous culprit, reportedly produced aplasia in only about 1 of 60,000 therapeutic cours-es, and even this number is almost certainly an overestimate. Chloramphenicol also consistently causes a dose-related, rather modest marrow depression, mainly reticulocytopenia and al-tered marrow morphology and iron kinetics. This effect of chloramphenicol use is mechanistically unrelated to and clini-cally not predictive of the rare, severe reaction, which occurs 1 to 2 months or longer after its routine use. The introduction of chloramphenicol was thought to have produced a notable in-crease in the number of cases of aplastic anemia, but its dimin-ished use has not been followed by a reduced frequency of aplastic anemia. Chloramphenicol remains a popular antibiotic in less developed countries.

Suspected drug reactions account for only about 20 per cent of cases of aplastic anemia, while virtually all instances of agranulocytosis in the adult are drug related. The drugs associ-ated with agranulocytosis are similar but not identical to those related to generalized bone marrow failure. Myeloid cells may be uniquely susceptible because of their ability to metabolize drugs, often to toxic intermediate compounds. In contrast to drug-associated aplastic anemia, agranulocytosis should sponta-neously resolve with removal of the drug, and the severely neutropenic patient should survive if infection is adequately treated.

Infections Hepatitis is the most common infection pre-ceding aplastic anemia, accounting for about 5 per cent of Western cases and perhaps twice that proportion in Asian se-ries. Typically, severe aplasia occurs in young man who has recovered from a mild bout of hepatitis 1 to 2 months earlier. The hepatitis is most often the non-A, non-B type, and some cases may represent aberrant responses to hepatitis C virus in-fection. Aplastic anemia can rarely follow infectious mononu-cleosis, and Epstein-Barr virus has been found in the marrow of some patients with aplastic anemia, with or without a sug-gestive preceding history. Parvovirus B19 has not been associ-ated with generalized bone marrow failure. Moderate marrow depression occurs commonly in the course of many viral and bacterial infections, but the primary disease is usually overt.

Immunologic Disease Aplasia occurs in immunodeficient children who develop graft-versus-host disease after infusion of unirradiated blood products. Pure red blood cell aplasia is asso-ciated with thymoma, and patients with red cell aplasia or pancytopenia may be hypoimmunoglobulinemic. Immunologic aspects of aplastic anemia are discussed in greater detail below.

Other Associations Aplastic anemia may occur during pregnancy and has sometimes resolved with delivery or with spontaneous or induced abortion. Pancytopenia occurs in about one third of patients with paroxysmal nocturnal hemoglobin-uria (Ch. 135), and perhaps 5 per cent of patients with aplas-tic anemia have a positive Ham's test, often with hematopoiet-ic recovery.