Hypoplastic and Aplastic Anemias

Paul L. Martin

HYPOPLASTIC ANEMIAS

The hypoplastic anemias (i.e., pure erythrocyte anemias, aregenerative anemias) constitute an uncommon group of congenital or acquired blood disorders characterized by anemia, reticulocytopenia, and a paucity of erythroid precursors in otherwise normal cellular bone marrow. Unlike the aplastic anemias (i.e., pancytopenias), the other formed elements of the blood usually are present in normal or increased numbers.

Pathophysiology

An understanding of the pathophysiology of the hypoplastic anemias requires a brief review of cellular aspects of erythropoiesis. Insight into the understanding of the nature and interactions of erythropoietic primordial cells has been possible because of the development of techniques for in vitro culture of bone marrow in media such as plasma clots, methylcellulose, and agar. Early committed erythroid progenitor cells can be inferred by their ability to form colonies of erythroid cells using these techniques. Two classes of progenitor cells have been identified: so-called colony-forming units, erythroid (CFUs-E), which give rise to compact colonies containing 10 to 100 hemoglobinized erythroid cells after 48 hours of culture; and more primitive erythroid progenitor cells, designated as burst-forming units, erythroid (BFUs-E), recognized by their capacity to form large colonies containing as many as 30,000 erythroid cells after 7 to 9 days of culture. Colony formation by CFUs-E requires the presence of erythropoietin, the glycoprotein hormone that regulates erythrocyte formation in the intact animal. BFU-E development does not require the presence of erythropoietin. BFUs-E and CFUs-E are present in small numbers in the normal bone marrow and morphologically resemble mature lymphocytes.

The next phases of erythrocyte development are represented by cells that can be morphologically identified as belonging to the erythroid series. These include the pronormoblast and the basophilic, polychromatophilic, and acidophilic normoblasts. In the latter stages of maturation of the erythrocyte, nuclear condensation and extrusion occur, resulting in the reticulocyte and finally the mature erythrocyte.

The hypoplastic anemias are a heterogenous group; both congenital and acquired varieties are recognized (Box 292.1). Factors that contribute to hypoplastic anemia are listed in Box 292.2.

Congenital Hypoplastic Anemia

At the 1938 meeting of the American Pediatric Society, Diamond and Blackfan described four children with severe aregenerative anemia that developed during the first year of life and required regular transfusions for survival. Only approximately 300 cases of congenital hypoplastic anemia (CHA) have been described in the literature, but many more cases have been recognized.

A familial recurrence in some families suggests that genetic factors may be operative occasionally but, in most cases, no inherited pattern is evident. Approximately 25% of the patients have physical abnormalities of various kinds, including short stature and facial, cardiac, and renal abnormalities. A subset of patients has thumbs with three rather than the usual two phalanges (i.e., Wranne syndrome).

Clinical Presentation

Anemia at or shortly after birth is the presenting manifestation of CHA. Approximately one-fourth of the patients are pale at birth. Sixty-five percent are anemic by 6 months of age, and almost all are anemic by 1 year of age. CHA described in older infants, particularly those reported before 1970, must be viewed with some skepticism because the cases may have represented transient erythroblastopenia of childhood.

Laboratory Findings

At the time of diagnosis, hemoglobin levels may be as low as 2.5 g/dL. The erythrocytes are macrocytic and have biochemical properties of fetal erythrocyte (i.e., increased levels of fetal hemoglobin for the patient’s age, presence of the i erythrocyte antigen, and increased levels of age-dependent erythrocyte enzymes such as glucose-6-phosphate dehydrogenase [G6PD]). These findings may be of limited diagnostic value in early infancy when fetal cells are still present.

The reticulocyte count is characteristically very low, even in the presence of severe anemia. The remainder of the peripheral blood count is usually normal, although elevated platelet counts and modest neutropenia have been found occasionally.

Serum bilirubin levels are normal. Serum iron levels usually are elevated with increased transferrin saturation. Plasma and urinary levels of erythropoietin are elevated.

BOX 292.2. List of Drugs, Infections, and Environmental Toxins that Can Contribute to Hypoplastic Anemia or Other Blood Dyscrasias

Medications Antibiotics

Sulfonamides

Chloramphenicol

Ganciclovir

Cidofovir

Thyroid Mediations

Propylthiouracil

Methimazole

Anticonvulsants

Dilantin

Carbamazepine

Valproic acid

Other

Phenothiazines

Indomethacin

Quinidine

Infections

Parvovirus

Cytomegalovirus

Epstein-Barr virus

Hepatitis B

Hepatitis C

Human herpesvirus-6

Insecticides

Chlordane

DDT

Lindane

Organophosphates

Organic Solvents

Benzene

Toluene

Carbon tetrachloride

Radiation

Accidental

Environmental-radon

Therapeutic

In most patients with CHA, erythrocyte adenine deaminase levels are elevated two to three times higher than normal values. However, elevations also have been seen in some cases of acute leukemia, and the enzyme elevation may be an indicator of disordered erythropoiesis rather than a specific marker for CHA.

The most important diagnostic features are found in the bone marrow. The marrow in patients with CHA is normally cellular with normal numbers of megakaryocytes, lymphocytes, and myeloid precursors. However, erythrocyte precursors at every level of development are absent or markedly reduced. The proportion of myeloid-to-erythroid precursors in the bone marrow (M:E ratio), normally 3:1, is markedly increased (10:1 to 200:1). In some patients, a few primitive pronormoblasts can be recognized, but no more mature erythroid precursors are seen. Bone marrow erythroid cultures consistently have few BFUs-E and CFUs-E.

Therapy

The degree of anemia is often so profound at presentation that erythrocyte transfusions are necessary. Approximately 10% to 20% of patients are refractory to therapy and continue to require regular transfusions. Transfusions with packed, leukocytepoor erythrocytes are given to maintain a hemoglobin level compatible with normal activity and comfort, usually more than 8 g/dL.

When chronic transfusion therapy is necessary, transfusional hemosiderosis inevitably occurs. Serum ferritin levels should be monitored periodically, and chelation therapy should be begun when evidence exists of tissue iron overload (see Chapter 290, Hemoglobinopathies and Thalassemias).

The use of adrenocorticotropic hormone and corticosteroids in CHA was suggested as early as 1949, but it was not until 1961 that a relatively large number of corticosteroid-treated patients were reported. Between 60% and 70% of patients respond to corticosteroid therapy. The mechanism of corticosteroid action may involve an enhancement of the effect of erythropoietin on CFU-E proliferation and maturation. Corticosteroids, such as prednisone, are administered at an initial dose of 2 mg/kg. Response is heralded by the appearance of erythropoietic precursors in the bone marrow within 1 to 2 weeks, followed by reticulocytosis and an increase in the hemoglobin level. The full dose of prednisone is continued until the hemoglobin attains a normal level. The dose can then be gradually decreased until a minimal effective dose is attained, which is often as little as 0.5 to 1.0 mg/day. In many instances, corticosteroids can be administered on alternate-day schedules that further decrease corticosteroid side effects. Some patients do not respond to the usual dose of corticosteroids and should be given a trial with larger doses (4 to 6 mg/kg). Approximately 20% to 30% of these children are nonresponsive to corticosteroids and require regular blood transfusions.

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