Pure red cell aplasia

Pure red cell aplasia is the diagnosis applied to isolated anemia secondary to failure of erythropoiesis. Cardinal findings are a low hemoglobin level, reticulocytopenia, and absent or extremely infrequent erythroid precursor cells in the marrow. Historical names for pure red cell aplasia include erythroblast hypoplasia, erythroblastopenia, red cell agenesis, hypoplastic anemia, and aregenerative anemia. Aplastic anemia confers the same meaning, of course, but is applied to pancytopenia and an empty marrow . Pure red cell aplasia was first separated from aplastic anemia by Kaznelson in 1922. The association of red cell aplasia and thymoma interested physicians in the 1930s and ultimately led to laboratory studies linking pure red cell aplasia to immune mechanisms, including the early identification of antierythroid precursor cell antibodies by Krantz, and later characterization of T cells that inhibited erythropoiesis. Red cell aplasia was recognized in the 1940s as an acute and life-threatening complication of sickle cell disease and other hemolytic anemias, presaging the role of a specific virus in the etiology of both acute and chronic erythropoietic failure. Despite its infrequency, pure red cell aplasia has been a subject of much laboratory research because of its link to an immune mechanism of erythropoietic failure and as a manifestation of parvovirus B19 infection and destruction of marrow red cell progenitors. However, because of its infrequency, pure red cell aplasia has not been the subject of large or controlled clinical trials; as a result, therapeutic recommendations are based on single cases or small series.


Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: BFU-E, burst-forming unit–erythroid; CD20, a cluster differentiation expressed on the surface of all mature B cells; CFU-E, colony-forming unit–erythroid; CLL, chronic lymphocytic leukemia; Ig, immunoglobulin; IL-3, interleukin 3; LGL, large granular lymphocytic leukemia; NK, natural killer cells; RPS14, RPS19, genes for the ribosomal subunit proteins; T-cell, thymus-derived lymphocyte



 Classification of Pure Red Cell Aplasia
Fetal red cell aplasia (nonimmune hydrops fetalis)
Parvovirus B19 in utero
Inherited (Diamond-Blackfan anemia)
  RPS19 mutations (~25% of cases)
  Transient pure red cell aplasia
  Acute B19 parvovirus infection in hemolytic disease (transient aplastic crisis; ~100% of cases)
  Transient erythroblastopenia of childhood
  Chronic pure red cell aplasia
  Large granular lymphocytic leukemia
  Chronic lymphocytic leukemia
  Clonal myeloid diseases (especially 5q-syndrome)
  Persistent B19 parvovirus infection in immunodeficient host (~15% of cases)
  Collagen vascular diseases
  Post stem cell transplant
  Anti-ABO antibodies
  Drug induced
  Antierythropoietin antibodies

Inherited Pure Red Cell Aplasia (Diamond-Blackfan Anemia)

What is Inherited Pure Red Cell Aplasia ?

Anemia in infancy and early childhood associated with absent reticulocytes in the blood and erythroid precursor cells in the marrow was described by Joseph1 in 1936 as a “failure of erythropoiesis” and by Diamond and Blackfan2 in 1938 as “congenital hypoplastic anemia.” Gasser3 first reported a response of a patient to glucocorticoids in 1951, and Diamond and associates4 presented a series of treated patients. Genetic linkage studies have identified a causative mutated gene in a subset of patients with inherited red cell aplasia.5 Hundreds of cases have been reported, and many excellent reviews have been published.6–15 Although Joseph was the first to describe the disorder, the anemia invariably is referred to as either Blackfan-Diamond or Diamond-Blackfan anemia.

Cause of Inherited Pure Red Cell Aplasia

An annual incidence of 5 cases per 1 million livebirths has been estimated from registry data.16 Well-characterized pedigrees are consistent with an autosomal dominant or, less often, recessive inheritance pattern. Sporadic cases are seen most frequently. Retrospective studies may reveal subtle hematologic or biochemical lesions, or an abnormal gene, in an affected parent or another relative without clinical anemia.17

Genetic studies have led to the characterization of Diamond-Blackfan anemia as a disease of ribosomal biogenesis.18–20 Linkage analyses of several dozen European families mapped to a site on chromosome 19q1321 and the finding of a translocation in one individual allowed cloning of the RPS19 gene, which encodes a protein involved in ribosome assembly.5 Most mutations are whole-gene deletions, translocations, or truncations; this pattern suggests a mechanism of haploinsufficiency, and RPS19 behaves as a dominant gene.22 Disruption of both copies of the gene in the mouse prevents implantation.23 RPS19 mutations occur in approximately 25 percent of patients with inherited red cell aplasia,22,24 but mutations subsequently have been identified in other ribosomal biogenesis genes in Diamond-Blackfan anemia (RPS24, RPS7, RPS17, RPL35A, RPL11, RPL5) in fewer cases.22,25 RNA-interference experiments have implicated RPS14 in one of the myelodysplastic syndromes characterized by loss of 5q.26

Precisely how defects in ribosomal protein genes cause constitutional red cell aplasia is uncertain. Historically, Diamond-Blackfan anemia has been characterized by diminished erythroid progenitor cell numbers (colony-forming unit–erythroid [CFU-E] and burst-forming unit–erythroid [BFU-E]).27,28 In cell-culture analyses, early, relatively erythropoietin-independent erythropoiesis is normal; the major defect is in the late stage of erythropoietin-dependent erythroid cell expansion and maturation.29 A defect in late erythroid differentiation is compatible with the classic findings of macrocytosis and increased hemoglobin F expression. Granulopoiesis in the granulocyte-macrophage colony-forming unit assay and the earlier hematopoietic progenitors as measured in vitro by long-term culture-initiating cell assay (an assay for an early multipotential hematopoietic progenitor) frequently are abnormal but to a lesser degree than CFU-E and BFU-E formation.30 RPS19 is expressed ubiquitously, and the apparently specific role of RSP19 in red cell development has not been elucidated.20 In tissue-culture experiments, silencing of RPS19 profoundly affects erythropoietic differentiation and, to lesser degrees, myelopoiesis.31,32 In a zebrafish model, deficiency of rps19 in early embryogenesis caused a decrease in erythrocytes and also physical anomalies.33

Despite responsiveness of patients to glucocorticoids, there is little evidence of an immune mechanism, cellular or humoral, underlying inherited red cell aplasia.

Symptoms of Inherited Pure Red Cell Aplasia

Approximately one-third of patients are diagnosed at birth or within a few weeks of delivery, and almost all are identified within the first year of life.7 Considerable variations are noted with regard to severity of phenotype, ranging from hydrops fetalis34,35 to presentation in adulthood, when diagnosis is inferred from associated physical anomalies.36 No sex predominance exists. Increased rates of prematurity in patients and of miscarriages in families have been inferred from collected cases.9 Symptoms of anemia in early childhood include pallor, apathy, poor appetite, and “failure to thrive.” Physical anomalies occur in approximately one-third of cases; most frequent is craniofacial dysmorphism. The classic appearance described by Cathie37 is “tow-colored hair, snub nose, wide-set eyes, thick upper lips, and an intelligent expression.” Malformations of the thumbs and short stature are followed in frequency of occurence by abnormalities of the urogenital system, web neck, and skeletal and cardiac defects.7,12,16 These physical anomalies are less prevalent than the abnormalities seen in Fanconi anemia.

Laboratory Features  of Inherited Pure Red Cell Aplasia

The degree of anemia is highly variable at diagnosis. Erythrocytes may be macrocytic or normocytic. Reticulocytopenia is profound. The marrow, which usually is devoid of erythroid precursors, may show small numbers of megaloblastoid early erythroid cells with apparent “maturation arrest.” Platelets are normal or elevated. Leukocytes may be normal or slightly decreased at presentation. Neutrophils often decline with age, and in adult survivors neutropenia occasionally is severe enough to predispose to fatal infection.38

Erythrocyte adenosine deaminase level is elevated in approximately 75 percent of patients but also may be increased in other aregenerative anemias of childhood.39 Serum erythropoietin level, serum iron level, and total iron-binding capacity are high. Ferritin levels increase after multiple transfusions, and patients develop iron overload if they are not treated with iron chelators.

Differential Diagnosis of Inherited Pure Red Cell Aplasia

The characteristic triad consists of the clinical diagnostic features of anemia, reticulocytopenia, and a paucity or absence of erythroid precursors in the marrow. These findings may by supplemented by increased activity of red cell adenosine deaminase and ribosomal gene mutation analysis. Fanconi anemia can be excluded by cytogenetic analyses under clastogenic stress and determination of Fanconi anemia gene mutations (see Chap. 34). Transient erythroblastopenia of childhood, which unusually occurs in the first year of life, is characterized by spontaneous recovery. When presentation occurs at older ages, the distinction between inherited and acquired aplastic anemia is somewhat arbitrary11 because the hematologic features are similar. A positive family history, physical anomalies, and characteristic cytogenetic, enzymatic, or genetic findings strongly indicate an inherited disorder.

Treatment Therapy, Course, and Prognosis of Inherited Pure Red Cell Aplasia

Untreated inherited pure red cell aplasia is fatal; death results from severe anemia and congestive heart failure. Transfusions, glucocorticoids, and allogeneic stem cell transplantation are of proven efficacy. Predictors of a response to glucocorticoids include older age at presentation, a family history, and a normal platelet count. Younger age at presentation and premature birth correlate with continued red cell transfusion dependence.40 Supportive care consists of red cell transfusions. Injury to visceral organs from iron overload has been a major cause of death in the past. To avoid transfusional hemosiderosis, chelation should be initiated early (see Chap. 42). Red cell transfusions should be leukocyte depleted to avoid alloimmunization (see Chap. 140). Erythrocytes are administered with the goal of eliminating symptoms and permitting normal growth and sexual development, usually achieved by maintaining hemoglobin levels between 7 and 9 g/dL (70–90 g/L).

Glucocorticoids are effective in many patients.41 Although the mechanism of action of glucocorticoids in this disease is not understood, their toxicities are substantial, and a response is not predictable. Once the diagnosis is established, prednisone is administered at 2 mg/kg daily in three or four divided doses.8,9,42 A reticulocyte response is seen in the majority of patients 1 to 4 weeks later, followed by a rise in hemoglobin level. Once the hemoglobin level reaches 9 to 10 g/dL (90–100 g/L), very slow reduction of the glucocorticoid dose is undertaken by decreasing the number of daily doses. When a single daily dose is achieved, an alternate-day schedule is adopted. In general, severe anemia can be avoided with continued glucocorticoid administration. The maintenance dose may be low (1–2 mg/day). Some patients may tolerate complete withdrawal of prednisone, but relapse is frequent and most responders become glucocorticoid dependent. A variety of patterns of response have been described, ranging from prompt recovery and apparent cure to refractoriness after years of responsiveness.9 Conversely, a second trial of glucocorticoids years after an apparent therapeutic failure may be successful. In a series of 76 patients followed for the long term, 59 were treated with prednisone; 31 initially responded, and 2 of the 25 who initially failed later responded.8 Glucocorticoid responsiveness is strongly associated with better survival, and patients who require low doses of prednisone, or those few who spontaneously remit, may have normal life expectancies. Long-term use of high-dose prednisone results in significant toxicity, including some combination of growth retardation, cushingoid facies, buffalo hump, osteoporosis, aseptic necrosis of the hip and fractures, diabetes, hypertension, and cataracts. Red cell transfusions with iron chelation may be preferable to such an outcome.

Bone marrow transplant for Inherited Pure Red Cell Aplasia

Allogeneic stem cell marrow transplantation, when successful, is curative (see Chap. 21), but the procedure has not been widely applied to children responding to medical measures. The median life expectancy of patients requiring transfusions and iron chelation is 30 to 40 years. A less favorable outcome is related to poor compliance and resulting cardiac and hepatic disease from iron overload.8 Because of the morbidity and mortality associated with allogeneic stem cell transplant, most patients have been transplanted late in their disease course, after large numbers of transfusions, accumulation of heavy iron loads, and alloimmunization. Despite the poor predictive factors, 15 of 19 patients of the first published series of cases survived 5 months to many years post transplantation.12 Comparable survival rates have been reported from European43 and Japanese registries.44 Stem cell transplantation from unrelated stem cell donors or use of cord blood stem cells43,44 has been less successful. Recurrent red cell aplasia despite full engraftment was reported in one child after transplantation.42,45

Other therapies have not gained wide acceptance despite promising pilot studies, including interleukin (IL)-3,46 high-dose methylprednisolone,47 cyclosporine and other immunosuppressive agents,48,49 and prolactin induction by metoclopropamide.50

With better survival, the risk of late development of leukemia has become apparent.20 Four of 76 patients followed at Children’s Hospital in Boston died of acute myelogenous leukemia, with a calculated relative risk of greater than 200 times expected.8

Gene transfer in vitro has functionally corrected cells defective in RSP19 (gene encoding ribosomal protein51). In animal models, corrected cells show improved erythropoiesis and a survival advantage in vivo,52 offering the possibility of gene therapy.

Acquired Pure Red Cell Aplasia

Definition and History of Acquired Pure Red Cell Aplasia

Acquired pure red cell aplasia is an uncommon cause of anemia that occurs principally in older adults. The blood counts and marrow appearance are indistinguishable from the picture of Diamond-Blackfan anemia—that is, anemia, severe reticulocytopenia, and absent marrow erythroid precursor cells. The nosologic origins of acquired pure red cell aplasia are obscure. Early descriptions are intermixed with those of aplastic anemia (in retrospect, a poor term for generalized marrow failure). Kaznelson95 is credited with the first case report in 1922. Early distinction of the two syndromes was stimulated by the relationship of red cell aplasia to thymoma. Although red cell aplasia shares with aplastic anemia an immune pathophysiology and responsiveness to immunosuppressive therapies, the absence of involvement of neutrophils, monocytes, and platelets makes the diagnostic distinction evident. Many of the diverse clinical associations (Table 35–1) are consistent with an immune-mediated pathophysiology. The mechanism of red cell failure is best understood for T-cell–mediated autoimmune destruction and persistent B19 parvovirus infection.

Cause Etiology and Pathogenesis   of Acquired Pure Red Cell Aplasia

Immune-Mediated Erythropoietic Failure

Clinical and laboratory evidence supports both antibody and cellular mechanisms of inhibition of erythropoiesis. Red cell aplasia is associated with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, autoimmune hemolytic anemia, acquired hypoimmunoglobulinemia, autoimmune polyglandular syndrome, and especially thymoma, and with lymphoproliferative processes, such as chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma, in which immune dysregulation is common. Serum inhibitors can be detected in the laboratory. Krantz and colleagues showed that immunoglobulin fractions from the patient’s blood inhibited heme synthesis and red cell progenitor assays in vitro.96 Antibodies that inhibit BFU-E and CFU-E colony formation are present frequently in patients with red cell aplasia. A pathophysiologic role can be inferred, first from the response of patients to favorable response to directed at antibodies, such as plasmapheresis and monoclonal antibody to CD20 (an antigen present on B cells), and second from decreased or absent plasma antibody in recovered patients. Antibodies may be involved in the red cell aplasia of pregnancy.97

Autoantibodies to erythropoietin rarely have caused this disease.98,99 More frequently, red cell aplasia secondary to antibodies is elicited by administration of recombinant erythropoietin to patients undergoing renal dialysis (see Chap. 36).100–104 Anemia can be profound, and some patients remain transfusion dependent despite discontinuation of hormone therapy. Glycosylation of recombinant erythropoietin is different from the native molecule, but antibodies are directed against conformational epitopes of the protein and not to the sugar moieties; erythropoietin immunogenicity is associated with human leukocyte antigen (HLA) specificities.105 The second example of antibodies of known specificity causing red cell aplasia occurs after hematopoietic stem cell transplantation using donors mismatched at a major ABO locus, which can lead to delayed donor erythroid engraftment or late erythropoietic failure.106–109 In most cases of red cell aplasia, however, the target antigen(s) are not known.

Red cell aplasia also might be associated with lymphoproliferative disease. In one survey of patients with red cell aplasia, 6 percent were found to have CLL and 7 percent large granular lymphocytic leukemia (LGL).111,112 In another series of 47 red cell aplasia patients, four had CLL and nine had LGL.113 There might be many reasons for this association, some of which likely stem from the pathophysiology and/or treatment of the underlying lymphoproliferative disease, such as leukemia- and/or treatment-associated inhibition of erythropoiesis, disruption of the marrow microenvironment, and/or dysregulation of the adaptive immune system leading to pathologic erythroid-directed autoimmunity (see Chaps. 94 and 96).

In some cases, T cells might contribute to erythropoietic failure.110 Flow cytometric and molecular methods can sometimes detect clonal T-cell expansion in patients with normal numbers of circulating lymphocytes.114,115 Lymphocytes from patients with idiopathic pure red cell aplasia,116–119 or red cell aplasia associated with CLL,120,121 LGL,122–124 thymoma,125 other lymphoid malignancies,126,127 Epstein-Barr virus infection,128 and human T-cell leukemia virus 1 infection129 suppressed erythropoiesis in colony assays. Several mechanisms of cell killing have been suggested.14,112 Moreover, in some cases, T cells can recognize and kill and/or inhibit erythropoietic progenitor cells in a HLA-class I restricted manner as a result of expression of particular á T-cell receptors that recognize erythroid-specific peptide antigens (see Chap. 78).130 In another case of chronic red cell aplasia associated with LGL, erythropoiesis was inhibited by non–HLA-restricted T cells that lysed CFU-E. These T cells downregulated class I HLA antigens, making them susceptible to recognition and lysis by the patients’ own natural killer (NK) cells (see Chap. 79).14

Persistent B19 Parvovirus Infection

B19 parvovirus specifically infects and is toxic to erythroid progenitor cells. Parvovirus infection normally is terminated by the humoral immune response within 1 to 2 weeks of infection. Linear neutralizing epitopes are localized to a relatively small region of the capsid protein.131 In the absence of an effective antibody response, infection persists and causes pure red cell aplasia.59,131 Erythropoietic failure may be the only evidence of parvoviral infection. Persistence of B19 parvovirus infection may occur in the setting of immunodeficiency, most commonly caused by chemotherapeutic and immunosuppressive drugs,132 human immunodeficiency virus 1 infection,133 and occasionally with Nezelof syndrome’s subtle immunologic abnormalities.134 Parvovirus at one time may have accounted for approximately 15 percent of severe anemia in patients with acquired immunodeficiency syndrome,135 but highly effective antiretroviral drug regimens have reduced its role.136,137 Persistent B19 parvovirus infection can occur in the fetus exposed during the midtrimester of pregnancy. The infection can cause hydrops fetalis as a result of viral cytotoxicity for erythroid progenitors in the fetal liver and death of the newborn as a result of severe anemia and congestive heart failure.59 In rare instances, parvovirus infected or hydropic infants rescued by red cell transfusion show congenital red cell aplasia or dyserythropoietic anemia.35

Intrinsic Cellular Defects Leading to Failed Red Blood Cell Production

Red cell aplasia can be the first or the major manifestation of myelodysplasia.138 Discrete genetic defects can lead to failure of erythropoiesis. Activating point mutations in N-RAS (an oncogene in the RAS group) occur in some cases of myelodysplastic syndrome.139,140 Mutant N-RAS in vitro can induce a proliferative defect in erythroid progenitor cells.141


Idiosyncratic drug reactions account for a far smaller proportion of red cell aplasia than of agranulocytosis (see Chap. 65). Case reports have implicated various agents, such as diphenylhydantoin, sulfa and sulfonamide drugs, azathioprine, allopurinol, isoniazid, procainamide, ticlopidine, ribavirin, and penicillamine. Causality is impossible to assign from case reports. As with nonsteroidal antiinflammatory drugs, gold, and colchicine, the underlying rheumatic syndrome may be the etiologic link.

Symptoms of Acquired Pure Red Cell Aplasia

Symptomatic anemia in the older patient may manifest as pallor, fatigue, lassitude, pulsatile tinnitus, and anginal chest pain. Iatrogenic Cushing syndrome and the physical stigmata of secondary hemochromatosis are seen in patients after prolonged glucocorticoid administration and long-term red cell transfusion therapy. Concomitant diseases include CLL and lymphomas, collagen vascular disorders, myasthenia gravis, especially in the setting of thymoma, and some cancers. Red cell aplasia also may complicate pregnancy. Persistent B19 parvovirus infection should be suspected in the anemic cancer patient after stem cell transplantation, in patients treated with immunosuppressive drugs, in patients with AIDS, and in patients with a family or personal history suggestive of inherited immune disorder. Other viral infections have been implicated in pure red cell aplasia, including infectious mononucleosis and, in some patients, hepatitis (an unknown agent in seronegative hepatitis).

Laboratory Features  of Acquired Pure Red Cell Aplasia

Anemia is either normocytic or macrocytic, reticulocytopenia is profound, and white cell and platelet counts are normal. The marrow has absent or very few erythroid precursor cells but normal granulopoiesis and megakaryopoiesis. Iron saturation and ferritin level frequently are elevated and rise further after repeated red cell transfusions. Erythroid colony assays may predict responsiveness to immunosuppressive treatment. The presence of marrow or blood BFU-E and CFU-E correlates with hematologic improvement,116,142,143 but these tests are not generally available.

A thymoma should be sought by chest imaging, including computed tomographic scan. The association of thymoma and pure red cell aplasia has been emphasized but is uncommon. One experienced investigator found thymoma in only 2 of 37 patients,144 and other series reported a low incidence.110,113 The thymomas usually are encapsulated and have a spindle cell histology. In one series, 10 of 56 cases were considered malignant because of their locally infiltrating character145; therefore, the tumors should be surgically excised, if feasible.

Patients with lymphocytosis, lymphadenopathy, and/or unusual lymphocyte morphology on the blood film should undergo evaluation for an associated lymphoproliferative diseases, such as CLL (see Chap. 94) or LGL (see Chap. 96).

Persistent parvovirus infection can be difficult to diagnose. Giant pronormoblasts scattered on the marrow film are characteristic of the condition (Fig. 35–1), but such typical cells may not be observed. Marrow morphologies that are dysplastic or suggestive of leukemia also have been described. Serum antibodies specific to the virus are absent or only IgM is positive. Parvovirus DNA should be present in high concentrations in the blood and readily measured by molecular techniques.

Differential Diagnosis  of Acquired Pure Red Cell Aplasia

Distinction between inherited and acquired red cell aplasia may be impossible in the younger patient. Rarely, pure red cell aplasia is difficult to distinguish from more generalized marrow failure if other blood counts are borderline. A dysmorphic marrow smear and abnormal chromosomes point to myelodysplasia as responsible for isolated anemia and reticulocytopenia. B19 parvovirus infection should always be suspected and searched for in any immunosuppressed individual who is anemic because the infection can be treated.

Therapy, Course, and Prognosis

Treatment  of Acquired Pure Red Cell Aplasia

Transfusion Therapy

As with inherited red cell aplasia, transfusions and iron chelation are basic to management.146 In an adult, one unit of packed erythrocytes per week can replace marrow erythropoiesis, which for convenience usually is transfused as two units every 2 weeks. The goal of preventing symptoms of anemia is achievable in most patients if the nadir hemoglobin is greater than 7 g/dL (70 g/L). A goal greater than 9 g/dL (90 g/L) may be preferable in patients with cardiac or pulmonary disease and in older patients. Even refractory pure red cell aplasia is consistent with a prolonged and perhaps even normal life expectancy, and iron chelation therapy can be initiated based on the ferritin level (see Chap. 42).


Immunosuppressive agents are used to treat disease with suspected immune origin. Response is likely in the majority of patients, but sequential treatment with a variety of agents often is required. Some patients, however, remain refractory to treatment.110,146–148 Typically, prednisone 1 to 2 mg/kg per day is given first, and about half of patients improve. A 1- to 2-month trial can be associated with significant toxicity and evidence of Cushing syndrome. Higher response rates have been cited for cyclosporine, and some investigators advocate using this drug first.48,149–153 Cytotoxic agents, especially azathioprine and cyclophosphamide,154 can be beneficial but are not the first choice because of their mutagenic and leukemogenic properties. These drugs may be preferred for red cell aplasia associated with large granular lymphocytic leukemia, in which cytoreduction is required.114,155,156 Acquired pure red cell aplasia often responds to antithymocyte globulin.116,143,157 More specific monoclonal antibodies have less toxicity than does antilymphocyte globulin and can be administered without hospitalization.158 Daclizumab, a monoclonal antibody directed against the interleukin-2 receptor, is effective in approximately 40 percent of patients.159 Success has been reported also using rituximab (anti-CD20 monoclonal antibody)160–162 and alemtuzumab (anti-CD52 [antigen on B lymphocytes]).163,164 Some patients with resistant disease also respond to fludarabine and cladribine.165,166 Plasmapheresis167,168 has produced long-lasting improvement in a few patients, presumably by removing pathogenic antibodies.167 The absence of randomized trials and even case series of adequate sample size makes the extrapolation of case reports to quantitative estimates of response problematic for many of these therapies.146 In cases of red cell aplasia associated with a lymphoproliferative disease, such as CLL or LGL, the therapy should be directed at, or in consideration of, the underlying leukemia/lymphoma (see Chaps. 94, 96, and 97).

A thymoma should be excised to prevent local spread of a malignant tumor, but thymectomy does not necessarily improve marrow function.145 Red cell aplasia can follow thymectomy. Cyclosporine appears the most effective drug to treat pure red cell aplasia associated with thymoma.169 Red cell aplasia is rarely an indication for stem cell transplantation because the anemia usually can be managed with less drastic approaches. Unresponsive patients have been cured by infusion of allogeneic stem cells after cyclophosphamide conditioning.170,171

Other Therapies

Despite early favorable case reports, androgens, erythropoietin, and splenectomy are not routinely used to treat pure red cell aplasia.

Immunoglobulins for Persistent B19 Parvovirus Infection

Persistent parvovirus infection results from the inability of the host to mount an effective humoral immune response. It can be effectively treated in almost all cases by administration of commercial immunoglobulins, an excellent source of neutralizing antibodies present in a large proportion of the normal population. Infusion of immunoglobulins at 0.4 g/kg per day for 5 to 10 days should produce brisk reticulocytosis and restore a hemoglobin level appropriate for the patient. A single course may be adequate to cure long-standing red cell aplasia resulting from an underlying inherited immunodeficiency syndrome,172 but patients with acquired immunodeficiency syndrome may not show complete clearance of parvovirus from the circulation and may relapse, requiring retreatment133 or maintenance immunoglobulin injections (Fig. 35–2).133,173 Patients suffering from persistent B19 parvovirus infection do not have typical manifestations of a viral infection, such as fever. In these patients, immunoglobulin infusions can induce fifth disease symptoms of variable severity, including cutaneous eruptions and arthritis. Older case reports of red cell aplasia responsive to immunoglobulin infusions likely represent treatment of patients with previously unrecognized parvovirus infection


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