Chapter 4: Pure Red Cell Aplasia

• Pure red cell aplasia describes anemia caused by an isolated depletion of erythroblasts characterized by severe reticulocytopenia and absent or markedly diminished marrow erythroid progenitors (erythroblasts).

• See Table 4–1.

• May result from transient marrow erythroblastopenia, which occurs in both children and adults. It is most common in the first several years of life.

• Seen most often in patients with a hemolytic disorder, such as hereditary spherocytosis or sickle cell anemia, when a transient severe reduction in erythropoiesis causes a rapid fall in hemoglobin level—called an (erythroid) aplastic crisis.

• May also be seen in patients who are hematologically normal.

• True prevalence is unknown, and it is assumed that many mild cases are not detected.

Etiology

• Most patients with aplastic crises are infected with B19 parvovirus, but occasionally another viral infection may be responsible.

• IgG inhibitors of erythroid colony formation in vitro have been found in some patients with a condition called transient erythroblastopenia of childhood.

• Drugs may induce aplastic crises, either by an immunologic mechanism or by direct toxicity. Commonly implicated drugs are listed in Table 4–2.

Clinical Features

• Frequently, the patient has had a recent febrile illness, often with upper respiratory symptoms, gastrointestinal symptoms, or headache.

• Listlessness, increasing pallor, and tachycardia are characteristic.

• Usually no other significant changes are found on physical examination.

Laboratory Features

• Evidence of an underlying hematologic disorder, such as hereditary spherocytosis or sickle cell anemia, may be present.

• Anemia and reticulocytopenia are characteristic. They are often severe.

• Granulocyte and platelet counts are usually normal.

• Erythroid cells are depleted in the marrow early in the illness, but reappear just before recovery; thus, if the marrow is tested during recovery, the erythroblastopenia may be missed.

• Reticulocytosis is the first sign of recovery, and some nucleated red cells may appear in the blood.

• Serum iron levels are high and serum iron-binding capacity is saturated during the aplastic phase because of markedly decreased iron utilization for erythropoiesis. Serum iron levels fall during recovery.

Differential Diagnosis

• Reduction in hemoglobin level with reticulocytopenia distinguishes red cell aplasia from acute bleeding in which reticulocyte count is mildly elevated and bleeding often apparent.

• Absence of involvement of neutrophils, monocytes, and platelets differentiates these disorders from aplastic anemia.

• Transient erythroblastopenia of childhood is differentiated from chronic forms of red cell aplasia by rapid recovery (days to weeks).

Therapy, Course, and Prognosis

• Discontinuation of potentially offending drugs when possible. Restitution of hematopoiesis may follow rapidly.

• Treatment of any associated illnesses.

• Maintenance of hemoglobin level by transfusion, as necessary.

• Recovery occurs spontaneously in days or weeks as neutralizing antibodies to B19 parvovirus ensues unless a chronic immunodeficiency state is present.

• A form of pure red cell aplasia occurring early in childhood. Also known as the Diamond-Blackfan syndrome.

• Familial occurrence. Usually autosomal dominant or occasionally autosomal recessive inheritance if familial pattern. Sporadic cases are most frequent.

• A disease of abnormal ribosomal biogenesis. Mutations involve the RPS19 gene in about 25 percent of cases; several other genes that regulate ribosome assembly have been implicated.

• The pathophysiology that leads to an isolated failure of erythropoiesis from ribosomal assembly abnormalities is unclear.

Clinical Features

• One-third of patients are diagnosed at birth or in the early neonatal period, but the disease may appear at any time into adulthood.

• Physical abnormalities occur in one-third of patients (e.g., craniofacial dysmorphism, short stature, abnormalities of the thumb, web-neck and urogenital and cardiac abnormalities).

• Onset in infancy with pallor, listlessness, poor appetite, failure to thrive.

• May progress to severe anemia, with cardiac failure, dyspnea, and hepatosplenomegaly.

• Signs of iron overload or glucocorticoid excess may develop after treatment with transfusions or prednisone, respectively.

Laboratory Features

• Normocytic, occasionally macrocytic, normochromic anemia.

• Leukocyte count is normal or slightly decreased. Neutropenia may develop over several years.

• Absolute severe reticulocytopenia in all cases.

• Platelet count is normal or mildly increased.

• Marrow is cellular but with marked erythroid hypoplasia. The few erythroid cells present may have megaloblastic changes. Other marrow cells are normal.

• Serum iron levels are elevated, and transferrin saturation is increased.

• In most cases, the fetal hemoglobin level is elevated, the density of i antigen on the erythrocyte surface is increased, and erythrocyte adenosine deaminase activity is elevated.

• Erythropoietin levels are elevated.

Differential Diagnosis

• Reticulocytopenia and the absence of erythroblasts in an otherwise normal marrow are characteristic of this disorder.

• Acute red cell aplasia is characterized by sudden onset and prompt resolution and is not characterized by dysmorphic physical findings.

Therapy, Course, and Prognosis

• Transfusions relieve symptoms of anemia but can lead to iron overload. Iron chelation therapy should be initiated promptly (see Chap. 19).

• Glucocorticoid therapy may be beneficial, although its mechanism of action is unclear.

• Glucocorticoid therapy should be initiated with prednisone at a daily dose of 1 to 2 mg/kg per day, orally, in two divided doses, than once each day, than once every other day, if feasible. A response is usually seen within 4 weeks. Initial dose is reduced very slowly to a maintenance level when the hemoglobin concentration exceeds 90 g/L. The goal is to get to low, alternate day therapy. Withdrawal of glucocorticoids is often, but not always, accompanied by relapse. Therapy should be continued for 4 to 6 weeks if no response occurs sooner. A trial of high doses of methylprednisolone may then be considered.

• Continuous glucocorticoid therapy is often required, and severe side effects frequently develop (e.g., Cushing syndrome). Long-term transfusions with iron chelation may be preferable to long-term higher dose glucocorticoids and resultant side effects.

• Allogeneic hematopoietic stem cell transplantation from a histocompatible sibling has been used but usually late in the disease. Timing is a function of balancing the serious side effects of therapy against the risk of stem cell transplantation.

• High-dose methylprednisolone, immunosuppressive agents, and IL-3 have been reported to ameliorate the disease but are not standard therapies.

• Most deaths are a result of therapeutic complications, such as chronic iron-overload, hypercorticism, or unsuccessful stem cell transplantation.

• Patients have developed acute myelogenous leukemia at a higher rate than expected.

• An uncommon disorder of adults characterized by markedly diminished red cell production.

• May be associated with thymoma, but the true prevalence of this combination is unknown, and it appears to be less common than believed previously.

• May also be found in association with other diseases, such as chronic lymphocytic leukemia or large granular lymphocytic leukemia. See Table 4–3.

• An antibody or cellular immune mechanism is believed responsible in about one-half of patients. Persistent B19 parvovirus infection may be responsible in some immunocompromised patients.

Clinical Features

• Pallor, lassitude, and other signs and symptoms of anemia are usual.

• Side effects of multiple transfusions and prolonged glucocorticoid therapy can lead to additional clinical findings.

• May occur in the absence of an underlying disease.

• Coexisting immune (e.g., systemic lupus erythematosus) or clonal lymphoid disorder (chronic lymphocytic leukemia) is frequent.

Laboratory Features

• Blood shows normochromic, normocytic or macrocytic anemia with severe reticulocytopenia and a normal leukocyte and platelet count.

• The marrow is normocellular, with normal granulocytes and megakaryocytes, but with severe erythroid hypoplasia or aplasia.

• The serum iron level is elevated, and the iron-binding capacity almost fully saturated.

• The disorder is frequently associated with serum antibodies, such as antinuclear antibodies, cold and warm hemagglutinins, and heterophile antibodies.

• Thymic enlargement, if present, may be detected as an anterior mediastinal mass on routine chest films. If not, computed tomography may be required to determine if a thymoma is present (uncommon, perhaps 5% to 10% of patients).

Differential Diagnosis

• The disorder is suggested by evidence of isolated marked erythroid hypoplasia. In some cases, nuclear abnormalities in myeloid and platelet precursors may raise the possibility of a myelodysplastic syndrome.

Therapy, Course, and Prognosis

• Red cell transfusion can be used to prevent or treat symptoms of anemia, but iron overload is a predictable complication, and acquired red cell antibodies often make it difficult to obtain compatible blood and this diminishes the effectiveness of transfusion. Two units of red cells every 2 weeks may keep nadir hemoglobin above 70 g/L. Higher nadir may be required if comorbidities exist.

• Erythropoietin administration is sometimes of benefit.

• Thymectomy should be considered if thymic enlargement (thymoma) is present or evidence of invasiveness.

• Glucocorticoids may be effective in low doses for long-term maintenance, but often large doses are required for protracted periods, with consequent severe side effects.

• Cyclosporine has been used successfully.

• Daclizumab, a monoclonal antibody against the IL-2 receptor, has been effective in a significant proportion of cases.

• Immunosuppressive drugs, such as cyclophosphamide, 6-mercaptopurine, fludarabine, or cladrabine may induce a partial or very good response, obviating a transfusion requirement.

• Intravenous gamma globulin has also been effective and may eradicate B19 parvovirus infection in some patients.

• Antithymocyte and antilymphocyte sera have also been used successfully.

• Plasmapheresis may be helpful.

• With current therapy, about 50 percent of patients enter remission.

• The very low incidence of acquired red cell aplasia has made clinical trials difficult, so therapy is based on sequential trials of agents.

• Median survival of patients with idiopathic disease is greater than 10 years and a normal life expectancy can be achieved. Common causes of death have been iron overload (now decreased in frequency by good iron chelator options) and glucocorticoid-induced hemorrhage or infection (now decreased in frequency by alternative therapeutic options).