Findings supporting the diagnosis of vitamin B12 deficiency are (1) low serum vitamin B12 levels, (2) normal or elevated serum folate levels, (3) moderate to severe macrocytic anemia, (4) leukopenia with hypersegmented granulocytes, and (5) a dramatic reticulocytic response (within 2 to 3 days) to parenteral administration of vitamin B12. Pernicious anemia is associated with all of these findings plus the presence of serum antibodies to intrinsic factor.
Aplastic anemia is a disorder in which multipotent myeloid stem cells are suppressed, leading to bone marrow failure and pancytopenia. The marrow often is virtually devoid of recognizable hematopoietic elements. It must be distinguished from pure red cell aplasia, in which only erythroid progenitors are affected and anemia is the only manifestation.
The pathogenesis of aplastic anemia is not fully understood, but two major etiologies have been invoked: an extrinsic, immune-mediated suppression of marrow progenitors, and an intrinsic abnormality of stem cells.
Experimental studies have focused on a model in which activated T cells suppress hematopoietic stem cells. It is hypothesized that stem cells are first antigenically altered by exposure to drugs, infectious agents, or other unidentified environmental insults. This provokes a cellular immune response, during which activated TH1 cells produce cytokines such as interferon-γ (IFN-γ) and TNF that suppress and kill hematopoietic progenitors. This scenario is supported by experience with immunosuppressive therapy directed against T cells, which restores hematopoiesis in 60% to 70% of patients.
Alternatively, the notion that aplastic anemia results from an intrinsic stem cell abnormality is supported by observations showing that from 5% to 10% of patients have inherited defects in telomerase, which, as mentioned earlier, is needed for the maintenance and stability of chromosomes. It is hypothesized that the defect in telomerase leads to premature senescence of hematopoietic stem cells. Of further interest, the bone marrow cells in an additional 50% of cases have unusually short telomeres, possibly stemming from as-yet undiscovered defects in telomerase or excessive replication of hematopoietic stem cells. These two mechanisms are not mutually exclusive, because genetically altered stem cells (e.g., those with abnormal telomeres) also might express “neoantigens” that serve as targets for a T cell attack.
Clinical Features. Aplastic anemia affects persons of all ages and both sexes. The slowly progressive anemia causes the insidious development of weakness, pallor, and dyspnea. Thrombocytopenia often manifests with petechiae and ecchymoses. Neutropenia may set the stage for serious infections.
It is important to separate aplastic anemia from anemia caused by marrow infiltration (myelophthisic anemia), “aleukemic leukemia,” and granulomatous diseases, which may have similar clinical presentations but are easily distinguished by examination of the bone marrow. Aplastic anemia does not cause splenomegaly; if present, another diagnosis should be sought.
The prognosis is unpredictable. Withdrawal of an inciting drug sometimes leads to remission, but this is the exception. Hematopoietic stem cell transplantation often is curative, particularly in nontransfused patients younger than 40 years of age. Transfusion sensitizes patients to alloantigens, producing a high rate of engraftment failure; thus, it must be minimized in persons eligible for transplantation. Successful transplantation requires “conditioning” with immunosuppressive radiation or chemotherapy, reinforcing the notion that autoimmunity has an important role in the disease. As mentioned earlier, patients who are poor transplantation candidates often benefit from immunosuppressive therapy.