The Etiology of Acquired Aplastic Anemia

Abstract

Historically, diverse clinical associations of aplastic anemia with benzene, radiation, medical drug exposure, pregnancy, viral infections and other hematologic diseases have suggested a complex etiology. However, the modern observation that the majority of patients recover with immunosuppressive drug treatment has implicated an immune pathophysiology. The abnormal immune response has been characterized as TH1/TC1, with measurable cytotoxic T-cell activation and excessive production of interferon-γ, tumor necrosis factor and interleukin-2. The result of this aberrant immune response is to induce programmed cell death in hematopoietic target cells through the Fas pathway, resulting in the destruction of a very high proportion of early progenitor and probably also stem cells. While the sequence and character of initiating events have remained elusive, a role for exogenous antigens may be inferred from preceding hepatitis or a convincing history of suspect pharmaceutic drug use; endogenous antigens have been inferred from the strong association of bone marrow hypocellularity with myelodysplasia and deficient marrow function with paroxysmal nocturnal hemoglobinuria. In addition to exposure, host susceptibility factors must influence the aberrant immune response and a few histocompatibility antigens have been linked to aplastic anemia. Early interruption of the process of immune-mediated hematopoietic cell destruction, as well as preservation of residual marrow cells from continuing subclinical destruction by T cells, are the goals of advanced approaches to immunosuppressive therapy.