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  • Disorders caused by impaired synthesis of DNA.

  • Prototype is pernicious anemia, a deficiency of vitamin B12 (cobalamin) caused by lack of intrinsic factor, required for its absorption.

  • Characteristics are megaloblastic cells, typically present in the erythroid series as large cells with immature-appearing nuclei but with increasing hemoglobinization of the cytoplasm—often referred to as nuclear-cytoplasmic asynchrony.

  • Megaloblastic granulocytic cells have large size, giant band neutrophils are a feature in the marrow and hypersegmented neutrophils in the marrow and blood. Megakaryocytes may be abnormally large with nuclear abnormalities.

  • Other rapidly dividing tissue cells, such as intestinal epithelium and uterine cervical epithelium may also show cytologic abnormalities. A uterine cervical smear when megaloblastic cytopoiesis is present may be strikingly dysplastic.


  • Table 8–1 lists causes of megaloblastic anemia.

  • Underlying defect is impaired DNA synthesis because of failure of conversion of dUMP to dTMP.

  • Intramedullary destruction of red cell precursors (ineffective erythropoiesis) is a major feature of megaloblastic anemia. Ineffective granulopoiesis and thrombopoiesis are also present and can result in neutropenia and thrombocytopenia. Ineffective hematopoiesis is characterized by marked hyperplasia of precursor cells (hypercellular marrow) but exaggerated apoptosis of late precursors, which results in blood cytopenias.

  • Mild hemolysis also occurs; the red cell life span is reduced by about 40 percent.



  • Anemia develops gradually and patients can adapt to very low hemoglobin levels. Eventually, as it progresses, the presenting symptoms are those of anemia with weakness, palpitation, fatigue, light-headedness, and shortness of breath.

  • May present initially with neurologic manifestations without anemia.

  • Folic acid deficiency and cobalamin deficiency have indistinguishable blood and marrow changes (megaloblastosis), but the former deficiency is not associated with neuropathology and ...

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