Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + DEFINITION Download Section PDF Listen +++ ++ 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). + CLASSIFICATION Download Section PDF Listen +++ ++ See Table 4–1. ++Table Graphic Jump LocationTABLE 4–1CLASSIFICATION OF PURE ERYTHROID APLASIAView Table||Download (.pdf) TABLE 4–1 CLASSIFICATION OF PURE ERYTHROID APLASIA Fetal Red Cell Aplasia (non-immune hydrops fetalis, parvovirus 19 infection in utero) Inherited Blackfan-Diamond disease (RPS19 mutations in 25% of cases) Acquired Transient pure red cell aplasia Transient erythroblastopenia of childhood Acute parvovirus B19 infection in the setting of underlying hemolytic anemia Chronic pure red cell aplasia Red cell aplasia in association with another disease (see Table 4–3) + ACUTE RED CELL APLASIA Download Section PDF Listen +++ ++ 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. ++Table Graphic Jump LocationTABLE 4–2SOME DRUGS ASSOCIATED WITH THE DEVELOPMENT OF ERYTHROID APLASTIC CRISISView Table||Download (.pdf) TABLE 4–2 SOME DRUGS ASSOCIATED WITH THE DEVELOPMENT OF ERYTHROID APLASTIC CRISIS Generic Name Alpha-Methyldopa (Aldomet) Azathioprine Aztreonam Sulfobromophthalein sodium (bromsulphthalein) Carbamazepine Cephalothin Chloramphenicol Chlorpropamide Co-trimoxazole D-Penicillamine Diphenylhydantoin Fenoprofen Lindane (gamma benzene hexachloride) Gold Indomethacin Isoniazid Dapsone Methazolamide Pentachlorophenol Procainamide Rifampicin Sulfasalazine Thiamphenicol Valproic acid +++ 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. + INHERITED PURE RED CELL APLASIA Download Section PDF Listen +++ ++ 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. + ACQUIRED CHRONIC PURE RED CELL APLASIA Download Section PDF Listen +++ ++ 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. ++Table Graphic Jump LocationTABLE 4–3SOME DISEASES ASSOCIATED WITH OCCURRENCE OF PURE RED CELL APLASIAView Table||Download (.pdf) TABLE 4–3 SOME DISEASES ASSOCIATED WITH OCCURRENCE OF PURE RED CELL APLASIA Immune disorders Myasthenia gravis Autoimmune polyglandular syndrome Autoimmune hemolytic anemia Acquired hypogammaglobulinemia Anti-erythropoietin antibodies Collagen vascular diseases Systemic lupus erythematosus Rheumatoid arthritis Clonal lymphoid disorders Chronic lymphocytic leukemia Large granular lymphocytic leukemia Hodgkin lymphoma Thymoma Persistent B19 parvovirus in immune deficient individuals Posthematopoietic stem cell transplantation (anti-ABO antibodies) Drug-induced (see Table 4–2) Pregnancy 5q-syndrome (myelodysplasia) +++ 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). ++ For a more detailed discussion, see Neal S. Young: Pure Red Cell Aplasia, Chap. 35, p. 485 in Williams Hematology, 8th ed.