Aplastic Anemia

Etiology

Injury to bone marrow occurs in a multitude of settings (table 1). The most common etiology, idiopathic, accounts for 65%. Fanconi anemia is the most common hereditary cause. It presents in the late first decade with pancytopenia, organ hypoplasia, and bone defects including abnormal radii, absent thumbs, and short stature. Seronegative hepatitis is responsible for 5% to 10% of total cases. Telomerase defects are found in 5% to 10% of adult-onset aplastic anemia. Some of these associations are very rare for example, eosinophilic fasciitis.[3][4]

Epidemiology

Accurate information regarding the epidemiology regarding the incidence of aplastic anemia is generally not available. Studies suggest the incidence is 0.6 to 6.1 cases per million population; this rate is largely based on data from retrospective reviews of death registries.[5][6]

The male-to-female ratio is approximately 1:1. Although aplastic anemia occurs in all age groups, a small peak in the incidence is observed in childhood. A second peak is found in the 20 to 25-year-old age group.

Pathophysiology

Two interrelated explanations exist for aplastic anemia: extrinsic immune-mediated suppression of hematopoietic stem cells and intrinsic abnormality of marrow progenitors.[7][8]

Damaged hematopoietic stem cells mature into self-reactive T-helper cells (T1) that release cytokines interferon-? (IFN?) and tumor necrosis factor (TNF) to propagate a cytotoxic cascade to kill and suppress other hematopoietic stem cells. The exact antigens T1 cells target are unclear, but one appears to be the glucose phosphate inositol (GPI)-linked protein on cell membranes (the mechanism behind pancytopenia in PNH). Also, the genes for apoptosis and death pathways are upregulated. Moreover, immunosuppressive therapy targeting T-cells leads to a response in two-thirds of patients with idiopathic aplastic anemia, and patients with graft-versus-host disease develop aplasia in the setting of healthy bone marrow progenitors.

In the second theory, stem cells with inherent defects lose the capacity to differentiate and proliferative. Their inability to dedifferentiate can lead to clonal evolution into hematologic neoplasms, for example, myelodysplastic syndrome. This is common in patients with Fanconi anemia. Partial defects in telomeres, the component of DNA intertwined with cell division, lead to premature hematopoietic stem cell exhaustion and marrow aplasia as well. Shortened telomeres are present in cells of half the patients with aplastic anemia.

Histopathology

Bone marrow biopsy from patients with aplastic anemia will be markedly hypocellular. Fat cells and fibrotic stroma replace normal bone marrow tissue. Stray lymphocytes and plasma cells remain, the remainder is devoid of marrow progenitors.

History and Physical

Aplastic anemia presents at any age with equal distribution among gender and race. Symptoms related to the absent cell lineage (anemia, progressive weakness, pallor, and dyspnea; neutropenia, frequent and persistent minor infections, or sudden onset febrile illness; thrombocytopenia, ecchymoses, mucosal bleeding, and petechiae). Splenomegaly is not seen, and its presence suggests an alternative diagnosis. Labs will demonstrate macrocytic normochromic anemia with reticulopodia, neutropenia, and thrombocytopenia. There must be no cytologic abnormalities as this would suggest an underlying hematologic process.

Evaluation

The diagnostic criteria for aplastic anemia are the following: the presence of bone marrow hypocellularity and  2 or more cytopenias (reticulopodia less than 1% or less than 40,000/microliter, neutropenia less than 500/microliter, or thrombocytopenia less than 20,000/microliter). The moderate disease has less than 30% bone marrow cellularity; the severe disease has less than 25% cellularity or less than 50% cellularity containing fewer than 30% hematopoietic cells, and very severe meets severe criteria plus neutropenia less than 200/µL. Aspirate of bone marrow has little yield (“dry tap”). Bone marrow biopsy is essential: it will be markedly hypocellular and devoid of marrow progenitors. Genetic testing with flow cytometry and fluorescence in situ hybridization (FISH) is useful to exclude hematologic malignancies responsible for pancytopenia. Additional testing depends on the underlying condition responsible for bone marrow failure, for example, telomerase mutation testing for dyskeratosis congenital.[9][10]

Treatment / Management

Management of aplastic anemia is directed at the underlying cause. Remove the offending agent(s), if possible. Some drugs have been discontinued in the United States due to their associations with aplastic anemia (e.g., Ticlopidine, a platelet aggregation inhibitor used as primary/secondary stroke prevention or dual antiplatelet therapy following percutaneous coronary intervention; phenylbutazone, a NSAID used as an analgesic and antipyretic). Aplastic anemia associated with pregnancy is self-limited and ends with delivery. Patients with thymoma usually have full bone marrow recovery following thymectomy.[2][11][12](B3)

For patients in whom no reversible cause is found, treatment depends on age, disease severity, donor availability, and performance status. Young patients (younger than 50 years) in good health with severe disease should undergo allogeneic hematopoietic cell transplant (HCT) before initial immunosuppressive therapy. Older patients (50 years or older) in good health and young patients without an HCT donor receive full-dose immunosuppressive therapy using eltrombopag, horse/rabbit anti-thymocyte globulin (ATG), cyclosporine A, and prednisone. This combination can be tailored to single-agent eltrombopag, ATG, or cyclosporine A for less healthy individuals. Eltrombopag is a thrombopoietin non-peptide agonist that increases platelet counts and activates intracellular signal transduction pathways to increase proliferation and differentiation of marrow progenitor cells. ATG eliminates antigen-reactive T-lymphocytes and induces hematologic responses in aplastic anemia. Cyclosporine A inhibits the production and release of interleukin-II (IL-2) and inhibits IL-2 induced activation of resting T-lymphocytes. Prednisone induces cell death of immature lymphocytes. Clinical studies are underway for alternative therapies used as second-line agents.

Supportive care includes infection prophylaxis/treatment and transfusions (leukoreduced red blood cells for Hb less than 7 mg/dL or platelets less than 10,000/microliters or less than 50,000/microliters for active blood loss). Monitor for secondary hemochromatosis and administer iron chelators as indicated. Use of growth factors such as erythropoietin or granulocyte colony-stimulating factors is not recommended because there are inadequate precursor cells to generate sufficient responses.

Survival in aplastic anemia depends largely on age, disease severity, and response to initial therapy. Those who recover following drug cessation or treatment of underlying condition have a stable clinical course, as well as those with self-limited processes. Five-year survival is greater than 75% for patients who undergo bone marrow transplant from a suitable donor. The majority of untreated patients die within one year from disease-related complications (e.g., bleeding, infections, or transformation to lymphoproliferative disorders).

Differential Diagnosis

Pancytopenia can occur due to myelophthistic syndrome, a pathologic process that replaces normal bone marrow. Etiologies are solid tumor metastases (ex. lung, breast, and prostate malignancies), lymphoid or myeloid neoplasms (ex. acute myelogenous leukemia), myelofibrosis, hemophagocytic lymphohistiocytosis, osteopetrosis, or Gaucher disease. The bone marrow biopsy will not be hypocellular and reflect the underlying disease.

Isolated failure of single hematopoietic lineage is common (ex. agranulocytosis, pure red cell aplasia). These share the same causes for aplastic anemia (ex. propylthiouracil and agranulocytosis, thymoma and pure red cell aplasia). Patients will have symptoms related to the cell line involved, not all three.

Prognosis

Survival in aplastic anemia depends largely on age, disease severity, and response to initial therapy. Those who recover following drug cessation or treatment of underlying condition have stable clinical courses, as well as those with self-limited processes. Five-year survival is >75% for patients who undergo bone marrow transplant from a suitable donor. The majority of untreated patients die within one year from disease-related complications (ex. bleeding, infections, or transformation to lymphoproliferative disorders).

Complications

The most common complications of aplastic anemia include bleeding, infections, or transformation to lymphoproliferative disorders. These are managed by surveillance and symptomatic treatment including antibiotics, chemotherapy, and/or transfusions.