Ineffective Erythropoiesis In Megaloblastic Anemia

The bone marrow is hypercellular in the megaloblastic conditions and the white cell precursor cells are large, especially the metamyelocytes. The myeloid-to-erythroid (M:E) ratio is 1:1 or 1:3, reflecting erythroid hyperplasia as you would see in the bone marrow

Figure 6.2 Normoblastic erythropoiesis with a polychro-matophilic normoblast (arrow).

Table 6.1 O Consequences of

Ineffective Erythropoiesis

Bone marrow destruction of erythroid precursors

Lack of regeneration of bone marrow elements during anemic stress

Lack of nRBCs in peripheral smear

Lack of polychromasia in peripheral smear


Intramedullary hemolysis

Increased bilirubin and LDH

responding to anemia. However, in the megaloblastic processes, there is an ineffective erythropoiesis, which means destruction in the bone marrow of red cell precursors before they even reach the peripheral circulation (Table 6.1). Megaloblastic precursor cells, especially at the polychromatophilic and basophilic states, hemolyze before their maturation cycle is completed. Orthochromic normoblasts and/or reticulocytes do not have the opportunity to be delivered from the bone marrow as they NORMALLY would in response to anemic stress. Consequently, the reticulocyte count is inappropriately low. The peripheral smear does not show polychromasia or nucleated red cells, and bilirubin and LDH are elevated. The last two clinical developments signal intramedullary hemolysis. If the erythropoiesis was effective and the bone marrow was responding to anemic stress, the peripheral smear would show evidence of a regenerative marrow process. Polychromasia and the presence of nucleated red cells would be self-evident (Table 6.2).


DNA synthesis is dependent on a key structure, thymidine triphosphate (TTP). This structure cannot be formed unless it receives a methyl group from methyl tetrahydrofolate or folic acid. Vitamin B12 is the cofactor responsible for transferring the methyl group to methyl tetrahydrofolate.1 Sufficient quantities of vitamin B12 and folic acid are key to the formation of TTP. If TTP cannot be synthesized, then it is replaced by deoxyuri-dine triphosphate (DTP). The synthesis of this component leads to nuclear fragmentation and destruction of cells and impaired cell division. For this reason, vitamin B12 and folic acid are essential elements in the DNA pathway.


Microorganisms and fungi are the main producers of vitamin B12, a group of vitamins known as cobalamins. This vitamin may also be embedded in liver, meat, fish, eggs, and dairy products. The recommended daily allowance of vitamin B12 is 2.0 pg/day with the daily diet providing approximately 5 to 30 pg/day and storage of 1 to 2 mg, in the liver. Dietary requirements will increase during pregnancy and lactation. Depletion of vitamin B12 stores takes years to develop. Folic acid, on the other hand, is readily available in green leafy vegetables, fruit, broccoli, and dairy products. The minimum daily requirement is 200 pg/day, a much higher requirement than that of vitamin B12, with body stores of 5 to 10 mg. in the liver. Folic acid is quickly depleted in a matter of months because the daily requirement is so much higher (Table 6.3). Pregnant women are encour-

Table 6.2 O Bone Marrow Response to Anemic Stress

The production of red cell precursor cells is accelerated.

The M:E ratio is adjusted to reflect erythroid hyperplasia.

Precursor cells, orthochromic normoblasts, are prematurely released from the marrow. Reticulocytes are prematurely released from the marrow.

Polychromasia is seen in the peripheral smear. nRBCs are present in the peripheral smear. If the reticulocyte count is high, then a slight macro-cytosis might develop.

Table 6.3 O Sources of Vitamin Bj and Folic Acid

Vitamin B12

• Eggs, cheese, and other dairy products Folic Acid

• Green leafy vegetables

• Dairy products

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