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Agranulocytosis

Clinical features. Severe neutropenia with either complete absence of granulocytic precursor cells or only early myeloid precursors in marrow. Almost always associated with drug use and typically older female patient. Sore throat and fever classical.

Drug associations and mechanisms. Drugs and chemicals injure cells through reactive metabolic intermediates that covalently bind to cellular components and lead either to direct toxicity or damaging immune response. Two drugs as models of marrow damage: dipyrone.

Therapy. Early parenteral, broad spectrum antibiotics for fever or local infection most important. G-CSF and GM-CSF of uncertain value because of variable natural history.

Clinical features. Pancytopenia of the peripheral blood with bone marrow hypocellularity. Usually presents with bleeding, especially in skin and mucous membranes, or complaints.

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.

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 are patients in whom the distinction between MDS and AA is so difficult.

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 rural Thailand; similar figures for China. Disease of the young, with the peak incidence in late adolescence and early adulthood.

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 produce adequate or excessive quantities of growth factors. Recovery of hematopoiesis in a high proportion of patients with nonreplacement therapy implies that stem cells are not entirely absent in typical aplastic anemia.

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).

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.

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%.

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 platelet infusions receive them prophylactically or at the first symptom of