Background

Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia. Mild macrocytosis is observed in association with stress erythropoiesis and elevated fetal hemoglobin levels. Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he studied the case of a pregnant woman who died of bone marrow failure. However, it was not until 1904 that Anatole Chauffard named this disorder aplastic anemia. (See Etiology.) Go to Anemia, Chronic Anemia, Megaloblastic Anemia, Myelophthisic Anemia, Hemolytic Anemia, and Sideroblastic Anemias for complete information on these topics.

Complications
Complications of aplastic anemia include infections and bleeding. (See Prognosis.) Complications of bone marrow transplantation (BMT), used in the treatment of aplastic anemia, include graft versus host disease (GVHD) and graft failure. (See Treatment.)

Staging
Staging of aplastic anemia is based on the criteria of the International Aplastic Anemia Study Group, as follows:

Blood - Neutrophils less than 0.5 X 109/L; platelets less than 20 X 109/L; reticulocytes less than 1% corrected (percentage of actual hematocrit [Hct] to normal Hct) Marrow - Severe hypocellularity; Moderate hypocellularity, with hematopoietic cells representing less than 30% of residual cells

Severe aplasia is defined as including any 2 or 3 peripheral blood criteria and either marrow criterion. A further subclassification developed after the recognition that individuals with neutrophil counts lower than 0.2 X 109/L had very severe aplastic anemia (VSAA). This group is less likely than others to respond to immunosuppressive therapy.

Patient education
Patients should maintain hygiene to reduce the risks of infection. Clinicians must stress the need for compliance with therapy. For patient education information, see the Blood and Lymphatic System Center, as well as Anemia.

Etiology

The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment.[1, 2, 3] The distinction between acquired and inherited disease may present a clinical challenge, but more than 80% of cases are acquired. In acquired aplastic anemia, clinical and laboratory observations suggest that this is an autoimmune disease. On morphologic evaluation, the bone marrow is devoid of hematopoietic elements, showing largely fat cells. Flow cytometry shows that the CD34 cell population, which contains the stem cells and the early committed progenitors, is substantially reduced.[2, 4] Data from in vitro colonyculture assays suggest profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even to high levels of hematopoietic growth factors. It was hypothesized that aplastic anemia may be due to a defect at various levels such as an intrinsic defect of hematopoietic cells, external injury to hematopoietic cells, and defective stroma, which is critical for normal proliferation and functioning of hematopoietic cells. Thus, theoretically, all of these mechanisms could be responsible for aplastic anemia. This theory was the basis of many in vitro stem cell culture experiments using a cross-over design in which stem cells from patients with aplastic anemia were cultured with normal stroma and vice-versa. The conclusions from these studies led to the understanding that stem cell defect is the central mechanism in the majority of patients with aplastic anemia.[5, 6] In patients with severe aplastic anemia (SAA), stromal cells have normal function, including growth factor production. Adequate stromal function is implicit in the success of BMT in aplastic anemia because the stromal elements are frequently of host origin. The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia in whom engrafting failed after BMT. Mathe proposed that the immunosuppressive regimen used for conditioning promoted the return of normal marrow function. Since then, numerous studies have shown that, in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function.[3, 7, 8, 9, 10] Immunity is genetically regulated (by immune response genes), and it is also influenced by environment (eg, nutrition, aging, previous exposure).[11, 12] Although the inciting antigens that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen (HLA)-DR2 is overrepresented among European and United States patients with aplastic anemia, suggesting a role for antigen recognition, and its presence is predictive of a better response to cyclosporine. Suppression of hematopoiesis is likely mediated by an expanded population of the cytotoxic T lymphocytes (CTLs) CD8 and HLA-DR+, which are detectable in the blood and bone marrow of patients with aplastic anemia. These cells produce inhibitory cytokines, such as gammainterferon and tumor necrosis factor, which can suppress progenitor cell growth. Polymorphisms in these cytokine genes, associated with an increased immune response, are more prevalent in patients with aplastic anemia. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing by inducing Fas-mediated apoptosis. In addition, these cytokines induce

nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immunemediated cytotoxicity and the elimination of hematopoietic cells. Constitutive expression of Tbet, a transcriptional regulator that is critical to Th1 polarization, occurs in a majority of aplastic anemia patients.[7] Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural-killer cells. Mutations in the perforin gene are responsible for some cases of familial hemophagocytosis[13] ; mutations in SAP, a gene encoding for a small modulator protein that inhibits undefined-interferon production, underlie X-linked lymphoproliferation, a fatal illness associated with an aberrant immune response to herpesviruses and aplastic anemia. Perforin and SAP protein levels are markedly diminished in a majority of acquired aplastic anemia cases. Apart from immunological, toxin/drug-related, and infectious etiopathologies, around 10-15% of patients with apparently acquired aplastic anemia may have shortened telomeres in blood lymphocytes. This was initially presumed to reflect stressed hematopoiesis, but, subsequently, telomerase gene complex mutations have been demonstrated in such individuals as well as their healthy family members. These apparently healthy family members were subsequently tested and found to have normal or near-normal blood counts, along with hypocellular marrow fragments.[14]

Congenital or inherited causes

Congenital or inherited causes of aplastic anemia (20%) include the following:

Patients usually have dysmorphic features or physical stigmata; on occasion, marrow failure may be the initial presenting feature. Fanconi anemia Dyskeratosis congenita Cartilage-hair hypoplasia Pearson syndrome Amegakaryocytic thrombocytopenia (thrombocytopenia-absent radius [TAR] syndrome) Shwachman-Diamond syndrome Dubowitz syndrome Diamond-Blackfan syndrome Familial aplastic anemia

Acquired causes
Acquired causes of aplastic anemia (80%) include the following:

Idiopathic factors Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), parvovirus, and mycobacteria Toxic exposure to radiation and chemicals, such as benzene Transfusional GVHD Orthotopic liver transplantation for fulminant hepatitis

Pregnancy Eosinophilic fasciitis

Drugs and elements, such as chloramphenicol, phenylbutazone, and gold, may cause aplasia of the marrow. The immune mechanism does not account for the marrow failure in idiosyncratic drug reactions. In such cases, direct toxicity may occur, perhaps due to genetically determined differences in metabolic detoxification pathways. For example, the null phenotype of certain glutathione transferases is overrepresented among patients with aplastic anemia. Paroxysmal nocturnal hemoglobinuria (PNH) is caused by an acquired genetic defect limited to the stem-cell compartment affecting the PIGA gene. Mutations in the PIGA gene render cells of hematopoietic origin sensitive to increased complement lysis. Approximately 20% of patients with aplastic anemia have evidence of PNH at presentation, as detected by means of flow cytometry. Furthermore, patients whose disease responds after immunosuppressive therapy frequently recover with clonal hematopiesis and PNH.

Prognosis
The outcome of patients with aplastic anemia has substantially improved because of improved supportive care. The natural history of aplastic anemia suggests that as many as one fifth of patients may spontaneously recover with supportive care; however, observational and/or supportive care therapy alone is rarely indicated. The estimated 5-year survival rate for the typical patient receiving immunosuppression is 75%. The rate for those receiving a BMT from a matched sibling donor is greater than 90%. However, in cases of immunosuppression, relapse and late clonal disease are risks. In a single institution analysis of 183 patients who received immunosuppressive treatments for severe aplastic anemia, the telomere length of peripheral blood leukocytes was unrelated to treatment response. In a multivariate analysis, however, telomere length was associated with risk of relapse, clonal evolution, and overall survival. Additional studies are needed to validate these findings and to determine how this information might be incorporated into treatment algorithms.[15]

Mortality/morbidity
The major causes of morbidity and mortality from aplastic anemia include infection and bleeding. Patients who undergo BMT have additional issues related to toxicity from the conditioning regimen and GVHD.[12, 16, 17, 18, 19, 20] With immunosuppression, aplastic anemia in approximately one third of patients does not respond. For the responders, relapse and late-onset clonal disease, such as PNH, MDS, and leukemia, are risks.[8, 21, 22, 23, 24]

History

The clinical presentation of patients with aplastic anemia includes symptoms related to the decrease in bone marrow production of hematopoietic cells. The onset is insidious, and the initial symptom is related to anemia or bleeding, although fever or infections are also often noted at presentation. Anemia may manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling. Thrombocytopenia may result in mucosal and gingival bleeding or petechial rashes. Neutropenia may manifest as overt infections, recurrent infections, or mouth and pharyngeal ulcerations. Although the search for an etiologic agent is often unproductive, an appropriately detailed work history, with emphasis on solvent and radiation exposure should be obtained, as should a family, environmental, travel, and infectious disease history. In the absence of obvious phenotypic features, the presentation of a patient with an inherited marrow-failure syndrome is subtle, and a thorough family history may first suggest the condition. With regard to environmental agents, the time course of aplastic anemia and exposure to the offending agent varies greatly, and only rarely is an environmental etiology identified. Physical examination may show signs of anemia, such as pallor and tachycardia, and signs of thrombocytopenia, such as petechiae, purpura, or ecchymoses. Overt signs of infection are usually not apparent at diagnosis. A subset of patients with aplastic anemia present with jaundice and evidence of clinical hepatitis.[25, 26] Findings of adenopathy or organomegaly should suggest an alternative diagnosis (eg, hepatosplenomegaly and supraclavicular adenopathy are observed more frequently in cases of leukemia and lymphoma than in cases of aplastic anemia). In any case of aplastic anemia, look for physical stigmata of inherited marrow-failure syndromes, such as skin pigmentation, short stature, microcephaly, hypogonadism, mental retardation, and skeletal anomalies. The oral pharynx, hands, and nail beds should be carefully examined for clues of dyskeratosis congenita. Oral leukoplakia in dyskeratosis congenita is shown in the image below.