Most cases of aplastic anemia of so-called known etiology follow exposure to chemicals and drugs. With some agents the marrow damage is predictable, dose related and in most instances reversible when the use of the offending agent is stopped . Best documented as known myelotoxins are benzene, chloramphenicol, alkylating agents and antimetabolites. In most cases the pancytopenia appears as an apparent idiosyncratic reaction to very small doeses of known myelotoxins (e.g., chloramphenicol) or after the use of such drugs as phenybutazone, methylphenylethylhydantion , steptomycin and chlorpromazine, which are generally without effect in other individuals. In such idiosyncratic reactions the aplasia may be severe and sometimes irreversible and fatal.

Whole body irradiation is an obvious mechanism for destruction of hematopoietic stem cells. The effects of ratdiation are dose related . Persons at risk are those who receive therapeutic irradiation and individuals exposed to nuclear explosions or nuclear plant accidents.

Although aplastic anemia may appear after a variety of infections , it most commonly follows viral hepatitis of the non ? A , non-B, non-C, non-g type. Why certain individuals develop this hematologic complicationin the course of their infection is not understood but it is not related to the severity of infection.

Fanconi anemia is a rare autosomal recessive disorder characterized by defects in DNA repair. In these patients the marrow hypofunction becomes evident early in life and is accompanied by multiple congenital anomalies, such as hypoplasia of the kidney and spleen and hypoplasstic anamalies of bone, particularly involving the thumbs or radii.

Despite all these possible causal influences no provocative factor can be identified in fully 65% of the cases and hence they are lumped into the idiopathic category.

The pathogenesis of aplastic anemia is not fully understood. Indeed it is unlikely that a single mechanism underlies all cases of marrow aplasia. Two major mechanisma have been invoked an immunologically mediated suppression and an intrinsic abnormality of stem cells.

Recent studies suggest that in a large proportion of cases perhaps in as many as 70% marrow failure results from inhibition of stem cell proliferation and differentiation by activated T cells. It is postulated that at first the stem cells are antigenially alteredby exposure to drugs, infectious agents or other undentified environmental insults. This then evokes a T cell-mediated immune rsponse during which cytokines such interferon ?and TNF-? are produced by activated T cells. These cytokines are known to be potent inhibitors of stem cell function. This scenario is supported by activated T cells. These cytokines are non to be potent inhibitors of stem cells function. This scenario is supported by the observation that immunosuppressive therapy with anthymocyte globulin combined with drugs such as cyclosporine has a salutary effect in 60^ to 70% of patients.

The notion that aplastic anemia results from a fundamental stem cell abnormality is supported by studies that indicate that in may cases of aplastic anemia cells in the peripheral blood are clonal descendants of a single stem cell. Some forms of marrow insult presumably cause genetic damage that results in the generation of stem cell with poor proliferative and differentitative capacity. If one such altered stem cell dominates the resultant picture that of aplastic anemia. The occasional transformation of aplastic anemia into acute leukemia lends further credence to this hypothesis. These two mechanisms are not mutually exclusive. The genetically altered stem cells not only may have poor proliferative capacity but also may be antigenically altered thus inducing a secondary T cell mediated suppression.

Clinical Course

Aplastic anemia may occur at any age. The onset is uaually gradual but in some cases the disorder strikes with suddenness and great severity. The initial manifestations vary somewhat , depending on the cell line predominantly affected. Anemia may cause the progressive onset of seakness pallor and dyspnea. Petechiae and ecchymoses may herald thrombocytopenia. Granulocytopenia may manifest itself only by frequent and persistent minor infections or by the sudden onset of chills, fever and prostration. Splenomegaly is characteristically absent and if it is present the diagnosis of aplastic anemia should seriously questioned. The red cells are typically normocytic and normochromic although slight macrocytosis is occasionally present reticulocytosis is absent.