aplasia from parvovirus B12 as discussed above) An aplastic crisis should be suspected in a patient with a known hemolytic anemia who develops increasing pallor and anemia associated with a reticulocyte count depressed in relation to its normally elevated baseline The differential diagnosis of underlying hemolytic conditions that result in red cell destruction is presented below Membrane Disorders The degree of pallor associated with anemia caused by erythrocyte membrane abnormalities depends on the hemoglobin level Hereditary spherocytosis, the most common of the membrane disorders, is usually characterized by wellcompensated chronic hemolysis Therefore, the anemia becomes clinically apparent only when the hemolysis is exacerbated by intercurrent infection In rare instances, patients with hereditary spherocytosis may develop significant anemia, jaundice, and pallor in the newborn period Moderate or severe anemia is less common in the other membrane disorders, such as hereditary elliptocytosis and hereditary stomatocytosis The anemia of these erythrocyte membrane disorders is accompanied by reticulocytosis A direct antiglobulin (Coombs) test will be negative Red cell morphology usually permits the diagnosis to be made from the peripheral smear A family history of anemia, splenomegaly, splenectomy, or cholecystectomy may be helpful as some of these disorders are inherited Infantile pyknocytosis is a hemolytic anemia seen during the first few months of life and is characterized by distorted and contracted erythrocytes and burr cells The disorder may be associated with pallor and hyperbilirubinemia Spontaneous recovery usually occurs by months of age Enzyme Disorders Erythrocyte enzymatic defects, such as pyruvate kinase deficiency and certain variants of glucose-6-phosphate dehydrogenase (G6PD) deficiency, may be associated with pallor due to increased red blood cell destruction G6PD deficiency is the most common human enzyme defect to cause anemia, with predominance in people of Middle Eastern, South Asian, and African descent This regional distribution is likely explained by the protection that G6PD deficiency confers against malaria In G6PD deficiency, pallor may be accentuated by acute hemolytic crises after exposure to oxidant stress (e.g., naphthalene-containing mothballs, antimalarials, sulfonamides, aspirin, methylene blue, or acidosis) Although alterations in red cell morphology are sometimes found in these enzyme disorders, assays of specific enzymes or substrates are required for definitive diagnosis