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Aplastic Anemia

Aplastic anemia usually presents with bleeding, especially in skin and mucous membranes, or complaints due to anemia. Mortality secondary to infection, especially fungi like Aspergillosis.

Survival a function of blood counts. Severe disease defined by satisfaction of 2 of 3 peripheral blood criteria: 1. absolute neutrophil count <500/:L, 2. platelets <20,000/:L, and 3. reticulocytes <1%. Neutrophils <200/:L defines "super-severe" category. High mortality of "untreated" severe aplastic anemia: <10-20% survival at one year with

Differential diagnosis. In secondary cases underlying illness usually obvious from history and physical examination. Distinguish especially:

Constitutional aplastic anemia (Fanconi's anemia) in adults.

Myelodysplasia may be hypocellular in about 20% of cases.

Chromosomal analysis of bone marrow cells is almost always normal in aplastic anemia, myelodysplasia is associated with the 5q- deletion and other cytogenetic abnormalities. There

Paroxysmal nocturnal hemoglobinuria. PNH/AA.

Acute lymphocytic leukemia in children and acute myelogenous leukemia in the elderly can occasionally present with pancytopenia and marrow hypocellularity.

Myelofibrosis has a characteristic blood picture, marrow is dry tap (rather than watery, as in aplastic anemia), and hepatosplenomegaly is common.

Large granular lymphocytosis. Marrow usually cellular, diagnose by flow cytometry.

Epidemiology. About 2/million (10-20-fold less common that acute myelogenous leukemia). More prevalent in the Orient: in Bangkok the incidence is 4/million and higher in

Pathogenesis. Hematopoiesis. Markedly reduced in all cases: by precursors visible on aspirate, high fat content on magnetic resonance imaging of spine, low CD34 cells by immunophenotyping, and functional assays of late progenitors and surrogate tests for stem cells show very few clonogenic cells. Adherent cells support long term bone marrow cultures and

Autoimmunity. Blood and marrow cells from patients suppress normal hematopoietic colony formation in vitro. Elevated activated cytotoxic lymphocytes in blood (CD8+, HLA-DR+, IL-2R+), produce y-interferon, lymphotoxin, and IL-2 (TH1 cytokines), which inhibit hematopoiesis in vitro. v-interferon messenger RNA detected by gene amplification specifically in marrow of aplastic anemia, and present also on intracellular cytokine staining of blood and

Chemicals and drugs. Benzene clearly associated with aplastic anemia. Many other chemicals and drugs anecdotally linked to marrow failure. From epidemiologic studies, probably only about 25% of Western cases likely to have a drug etiology. Most important associations with the nonsteroidal anti-inflammatory drugs, antithyroid drugs, penicillamine, allopurinol, and

Viruses. Parvovirus directly infects and kills erythroid progenitor cells, a cause of pure red cell aplasia but not aplastic anemia. Hepatitis associated with aplastic anemia in about 5% of cases: serologically, most cases non A non B non C. Defective marrow function common in patients

Therapy. Supportive therapy: blood product transfusion and antibiotics. About a third of patients refractory to platelets even after only a few transfusions; patients who respond to

Most important in avoiding death from infection in neutropenic setting: low threshold for prompt institution of broad spectrum, parenteral antibiotics and addition of antifungal drugs in persistently febrile cases. Aspergillus a major cause of death in this 

Definitive treatment either bone marrow transplantation or immunosuppression. In comparative studies no difference in long-term survival between transplantation and immunosuppression, but some subgroups may benefit from one treatment or other.

Immunosuppression. Antithymocyte globulin (ATG) commercial preparation in the United States. Recommend 40 mg/kg/day x 4 days as most convenient. About 50% hematological response rate, usually apparent at 2-3 months. Failures can respond to cyclosporin, orally at 12 mg (adults)-15 mg (children) /kg/d for 3-6 months. ATG plus cyclosporin higher initial response rate, about 70% and now standard in severe disease. High dose cyclophosphamide may also be effective and avoid frequent late problems of need for further treatment and development of

Stem cell transplantation. Usually genotypically identical sibling donor marrow, cures aplastic anemia, but death can occur as a result of complications of the procedure. Long-term survival in cooperative groups with younger patients at about 65%, but single center studies as high as

Hematopoietic growth factors. GM-CSF, G-CSF, IL-3, and erythropoietin all used in uncontrolled trials. Granulocytes most responsive. Do not cure disease and probably do