Red Cell Aplasia: Acquired and Congenital Disorders
Jeffrey M. Lipton
Bertil Glader
Robert T. Means, Jr.
ACQUIRED RED CELL APLASIA
Pure red cell aplasia (PRCA) is an acquired syndrome characterized by normochromic normocytic anemia, severe reticulocytopenia (reticulocyte count <1%), and an almost complete absence of erythroblasts from the bone marrow (erythroblasts <0.5%).1, 2 In contrast to aplastic anemia, in which the aplasia involves all three cell lines, in PRCA the aplasia is selective for the erythroid cell line so that patients have normal leukocyte and platelet counts.3 PRCA is a rare disorder that affects any age group and both males and females equally.
This disorder was first described by Kaznelson in 19224 and has appeared in the literature under a variety of different names, including pure aplastic anemia, erythrophthisis, chronic hypoplastic anemia, aplastic crisis, erythroblastopenia, erythrogenesis imperfecta, Blackfan-Diamond syndrome, pure red cell agenesis, and primary red cell anemia.1 Today the term PRCA is used primarily to describe this disorder in adults, although some of the causes of RBC aplasia in adults also are seen in children. Diamond-Blackfan anemia (DBA) refers to a pathophysiologically different congenital syndrome of children. Transient erythroblastopenia of childhood (TEC) describes a typically self-limited PRCA variant that occurs most commonly in infants and children and is discussed below. It must be noted, however, that DBA can present in adulthood and should be considered in the differential diagnosis of PRCA at any age.
PRCA may be primary or may be secondary to a variety of neoplastic, autoimmune, or infectious diseases (Table 39.1). Primary acquired PRCA affects individuals of any age in the absence of any underlying disorder. It may run an acute and usually self-limited course or may persist chronically as a form of refractory anemia. In adults the acute form of primary PRCA is very rare and the chronic form of this disorder predominates. Acute PRCA in adults escapes diagnosis because acute arrest of erythropoiesis of short duration does not lead to symptoms of anemia, as a result of the long lifespan of the red cells.
Etiology and Pathogenesis
PRCA may occur as a primary disorder or may develop as a hematologic complication in the course of a variety of diseases (Table 39.1). In the section that follows, differing etiologies of PRCA and their associated pathogenetic mechanisms are described. Secondary etiologies are arranged in approximate order of clinical significance or frequency.
Primary Acquired (Autoimmune) Pure Red Cell Aplasia
In primary acquired PRCA and TEC, multiple studies have indicated that the arrest of erythropoiesis is caused by the presence in the patient’s plasma of an erythropoietic inhibitor. Early studies in mice have shown that injection of patients’ plasma leads to a significant suppression of in vivo erythropoiesis as measured by 59Fe incorporation into newly formed red cells.101, 102 Evaluation of the response of patients’ marrow cells to erythropoietin by measuring heme synthesis in vitro showed that, in the presence of normal plasma, PRCA marrow responds normally to erythropoietin, but in the presence of a patient’s autologous plasma, a significant decline in heme synthesis is observed, suggesting the presence in the patient’s plasma of an inhibitor acting on erythroid cells.103, 104 In about 60% of cases, patients’ marrow cells respond to erythropoietin in a normal way by increasing the rate of heme synthesis by 2- to 9-fold and in about 40% an inhibitor of erythropoiesis can be detected in their plasma. This inhibitor has been localized to the IgG fraction, and it disappears from the plasma after remission of PRCA.103, 104, 105
The stage of erythropoiesis at which the arrest occurs has been studied by assaying PRCA marrow cells in semisolid media for erythroid progenitors. Despite a conspicuous absence of erythroblasts from the PRCA marrow, in at least 60% of patients, normal numbers of early burst-forming unit erythroid (BFU-E) and late colony-forming unit erythroid (CFU-E) erythroid progenitors can be detected, indicating that the arrest occurs at any level between CFU-E and basophilic erythroblasts. In the remainder of patients the erythroid cell compartment is affected at a stage earlier than the CFU-E, so that the CFU-E and/or BFU-E marrow pools are significantly reduced.1, 106, 107, 108 The presence of normal numbers of erythroid progenitors has been associated with a favorable outcome of immunosuppressive therapy.106, 108 The patient’s serum IgG inhibits maturation and differentiation of erythroid progenitors into erythroblasts in vitro. The inhibition is dose-dependent and is no longer present in the IgG fraction of the patient’s plasma collected after remission.105 The inhibitory effect of the IgG is specific for erythroid cells, because no effect on myeloid progenitor cell growth is detected.107, 108, 109
The target antigen and mode of action of the IgG inhibitor of erythropoiesis has been investigated in a number of cases of primary autoimmune PRCA, but appears to be variable. As discussed above, it may target erythroid CFU-E and/or BFU-E progenitors or it may be directed against morphologically recognizable erythroblasts.110, 111 The molecule(s) on the erythroid cell membrane with which the PRCA IgG inhibitor interacts has not yet been defined. In rare cases, endogenous erythropoietin itself appears to be the target antigen.112, 113 In some cases of autoimmune hemolytic anemia, concurrent with PRCA, the antibody causing hemolysis can also suppress erythroid progenitor colony formation,75 while in other cases the two processes result from two different antibodies.76, 77
In addition to antibody-mediated PRCA, cases of PRCA have been reported in which the immunologic mechanism is T cell mediated. These cases appear to be particularly associated with thymomas.114, 115, 116, 117, 118, 119, 120, 121 There are also cases of PRCA in which no immune pathogenic mechanism or other known mechanism can be established by in vitro assays. These cases are classified as idiopathic PRCA. However, failure to demonstrate an immune mechanism does not necessarily exclude an immune pathogenesis, since the outcome of treatment seems to be the same among autoimmune and idiopathic cases.1
Transient Erythroblastopenia of Childhood
This is a common cause of acquired red cell aplasia in young children122, 123 due to a transient antibody-mediated suppression of normal erythropoiesis.124, 125 The disorder is characterized by the gradual (over weeks) development of anemia (hemoglobin level of 2 to 8 g/dl), reticulocytopenia, and a pronounced reduction of bone marrow erythroblasts. The platelet count is normal to increased. The leukocyte count is usually normal, although 20% of children
may have significant neutropenia (less than 1,000 neutrophils per dl). The disorder uniquely occurs in previously healthy young children from 6 months to 4 years of age and is seen with equal frequency in boys and girls. Occasionally cases of the disorder occur in clusters, suggesting it may be a consequence of some seasonal environmental toxin or virus. To date, however, serologic studies have failed to reveal exposure to a common virus. The natural history of TEC is that all patients recover spontaneously in a few weeks and there are no long-term hematologic sequelae. In many children with the disorder, particularly if there is evidence of recovery at the time of diagnosis, no specific therapy other than careful observation is necessary. Erythrocyte transfusions are indicated only if a child is symptomatic from the anemia, and rarely is more than one transfusion needed. Neither iron nor steroid therapy have any role in the management of this disorder. The diagnosis often is confused with that of iron deficiency anemia, although the erythrocytes in patients with TEC are normocytic (mean corpuscular volume [MCV] 70 to 85 fl, which is normal for children), whereas iron deficiency anemia is characterized by microcytosis (MCV, 50 to 70 fl). TEC also may be confused with DBA, although the latter generally presents before 6 months of age, often is associated with congenital abnormalities, and usually is characterized by macrocytic erythrocytes with many fetal-like features. (See section “Diamond-Blackfan Anemia.”)
may have significant neutropenia (less than 1,000 neutrophils per dl). The disorder uniquely occurs in previously healthy young children from 6 months to 4 years of age and is seen with equal frequency in boys and girls. Occasionally cases of the disorder occur in clusters, suggesting it may be a consequence of some seasonal environmental toxin or virus. To date, however, serologic studies have failed to reveal exposure to a common virus. The natural history of TEC is that all patients recover spontaneously in a few weeks and there are no long-term hematologic sequelae. In many children with the disorder, particularly if there is evidence of recovery at the time of diagnosis, no specific therapy other than careful observation is necessary. Erythrocyte transfusions are indicated only if a child is symptomatic from the anemia, and rarely is more than one transfusion needed. Neither iron nor steroid therapy have any role in the management of this disorder. The diagnosis often is confused with that of iron deficiency anemia, although the erythrocytes in patients with TEC are normocytic (mean corpuscular volume [MCV] 70 to 85 fl, which is normal for children), whereas iron deficiency anemia is characterized by microcytosis (MCV, 50 to 70 fl). TEC also may be confused with DBA, although the latter generally presents before 6 months of age, often is associated with congenital abnormalities, and usually is characterized by macrocytic erythrocytes with many fetal-like features. (See section “Diamond-Blackfan Anemia.”)
TABLE 39.1 CLASSIFICATION OF PURE RED CELL APLASIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Myelodysplastic Primary Pure Red Cell Aplasia
A small percentage of cases of idiopathic PRCA, usually refractory to treatment, may evolve into acute leukemia, and these cases are classified as preleukemic or myelodysplastic.1, 126 In a sense, such cases should be regarded not as part of a PRCA syndrome but rather as myelodysplastic morphologically resembling PRCA.
Parvovirus-induced Pure Red Cell Aplasia
It has been known for many years that human B19 parvovirus is responsible for the aplastic crisis seen in patients with chronic hemolytic anemia.127, 128, 129, 130, 131 It was subsequently demonstrated that B19 parvovirus can produce chronic PRCA in immunocompromised patients, such as those with HIV, posttransplantation, or on immunosuppressive drugs.45, 46, 47, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141
B19 parvovirus directly infects human erythroid progenitors by a process requiring the red cell surface P antigen (globoside).142, 143 Individuals who do not express P antigen are not susceptible to parvovirus infection.144 B19 parvovirus induces apoptosis in erythroid progenitors.145 The precise mechanism by which this occurs in unclear, but appears to involve viral nonstructural protein 1.146, 147 Hypoxia-inducible factor-1 appears to upregulate expression of viral messages in infected cells.148
Recombinant Erythropoietin-induced Immune Pure Red Cell Aplasia
As noted earlier, autoimmune PRCA caused by antibodies against endogenous Epo has been described infrequently.112, 113, 149 Beginning in the mid- to late 1990s, cases of PRCA associated with antibodies against recombinant human (rh) Epo began to appear.
These cases occurred in patients with end-stage renal disease receiving rhEpo for anemia management.99, 150, 151, 152, 153, 154, 155, 156 These cases were unusual in that more than 90% of cases involved a particular rhEpo product, it was primarily associated with subcutaneous treatment, the vast majority of cases occurred outside the United States, and there was wide nation-to-nation variation, even allowing for use of specific rhEpo products.99, 157, 158, 159, 160, 161, 162, 163, 164, 165 Eventually the process was attributed to packaging features of the rhEpo product (such as adjuvant effects of the material used in syringes).157, 166, 167, 168, 169, 170 In response to changed packaging, the problem has largely resolved.
It has been suggested that the low level immunogenicity of rhEpo might be enhanced in specific patients by the presence of Epospecific CD4+ T cells, or by HLA-DRB1*09.92, 171, 172, 173, 174
It has been suggested that the low level immunogenicity of rhEpo might be enhanced in specific patients by the presence of Epospecific CD4+ T cells, or by HLA-DRB1*09.92, 171, 172, 173, 174
Thymoma
The association between thymic neoplasms and PRCA has been known for many years.5, 6, 7, 40, 175, 176, 177, 178 PRCA may precede the development of thymoma, coexist with thymoma, or develop even years after the surgical removal of a thymoma. The incidence of PRCA among patients with thymoma was earlier estimated to be as high as 15%; however, in more recent reports the incidence was found to be close to 4%.1, 179 Approaching it from the other perspective, the presence of a thymoma among patients presenting with PRCA was initially reported to be as high as 50%, but in more recent series it was estimated to be close to 9%.1, 61, 118, 175, 180 The pathogenetic mechanism involved is uncertain but presumably related to T cell-mediated processes.118, 120, 181, 182
Lymphoproliferative Disorders
Various lymphoproliferative syndromes have been associated with severe erythroid aplasia (see Table 39.2), with chronic lymphocytic leukemia (CLL) of B cell, T cell type, or with the large granular lymphocyte (LGL) type, the last being the most frequent.8, 183 The incidence of severe erythroid aplasia among patients with CLL may be as high as 6%, with many cases missed because severe normochromic anemia and reticulocytopenia is a frequent manifestation of advanced-stage CLL and is usually attributed to the primary disease process. The development of erythroid aplasia does not affect the prognosis of CLL and in the majority of cases does not seem to be related to previous cytotoxic chemotherapy.1, 8 PRCA has been also described in association with Hodgkin12 and non-Hodgkin lymphomas,13 multiple myeloma,21 Waldenström’s macroglobulinemia,23 angioimmunoblastic lymphadenopathy,16 and Castleman’s disease.97
TABLE 39.2 DRUGS AND CHEMICALS ASSOCIATED WITH PURE RED CELL APLASIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Most pathophysiologic studies have been performed in CLLassociated PRCA. PRCA appears to derive from immune suppression, but not typically through inhibitory antibodies.14 Various studies have demonstrated that in T cell CLL (including LGL type), the T lymphocytes are responsible for the suppression of erythropoiesis.11, 184, 185 The suppression is mediated by direct cell-to-cell interaction, mainly between a subset of T cells expressing receptors for the γ chain of IgG (Tγ cells) and erythroid progenitors, and it is HLA-DR restricted.184 The suppression is selective for the erythroid cells and is not detectable after remission of the PRCA.184, 185 Similar findings have been reported in B cell CLL, in which there seems to be a progressive increase in the marrow of Tγ cells, which, when they reach a critical concentration, suppress erythropoiesis and cause red cell aplasia.116, 117, 121 In LGL lymphocytosis, clonal expansion of LGLs of the γ/δ type expressing killer-cell inhibitory receptors for Class I HLA antigens has been shown to be responsible for lysis of erythroblasts, most likely related to the declining density, with eventual disappearance of HLA-I antigens in late marrow erythroid cells. However, the role of killer-cell inhibitory receptors in the pathogenesis of PRCA in large granular lymphocytosis remains unclear, since such receptors are also detectable in large granular lymphocytosis patients without PRCA.186, 187 Expansion of the marrow population of CD8+/perforin+ memory T cells has also been noted in thymomaassociated PRCA patients.188
Other Hematologic Malignancies
PRCA has been reported in association with chronic myelogenous leukemia,24, 25 chronic myelomonocytic leukemia,9 chronic eosinophilic leukemia,33 primary myelofibrosis,26, 27 essential thrombocythemia,28 and acute lymphoblastic leukemia.30, 31 Few cases have been studied in detail, but in general the course of PRCA appears to run independently of the associated disease and may reflect a coincident autoimmune disorder.24
Nonthymic Solid Tumors
There have been a number of reports of PRCA observed in patients with nonthymic, nonhematologic malignancies (see Table 39.1).
Given that these reports are rare and that the primary malignancy and PRCA typically run independent courses,1 it is likely that the association is coincidental.
Autoimmune Disorders/Collagen Vascular Disease
It should not be surprising that PRCA is a hematologic complication of various autoimmune diseases, including collagen vascular diseases, such as systemic lupus erythematosus,67, 68 rheumatoid arthritis,72 mixed connective tissue disease,73 Sjögren syndrome,6, 189 autoimmune hemolytic anemia,75, 76, 77 multiple endocrine gland insufficiency,74 autoimmune hypothyroidism,190, 191 inflammatory bowel disease,78 autoimmune liver disease,79, 80 pyoderma gangrenosum,192 and pernicious anemia.89 PRCA may occur prior to, during, or after the onset of these disorders. When investigated in detail, cases of PRCA associated with autoimmune or collagen vascular diseases are typically found to be mediated by antibodies which inhibit erythropoiesis.193, 194
ABO-incompatible Stem Cell Transplantation
PRCA may occur as a consequence of ABO-incompatible bone marrow or stem cell transplantation.93, 94, 195, 196, 197 In one series, this complication occurred in 26% of ABO-incompatible transplants and was most common in circumstances where a blood group O recipient was transplanted from a blood group A donor.197 Erythroid precursors express surface blood group antibodies, and anti-A or anti-B isoagglutinins from recipient plasma cells are the etiologic agents.94 There is a 60% to 70% frequency of spontaneous recovery, but the remainder may developed sustained PRCA requiring treatment.197
Pure Red Cell Aplasia with Infections Other Than Parvovirus
Acute, self-limited PRCA may develop in the course of various infections.1, 51, 53, 55, 60, 62, 64, 199, 200 Viral hepatitis and infectious mononucleosis in particular have been reported many times in association with PRCA. In general, PRCA remits with treatment or the resolution of the underlying infection. Studies on the pathogenesis of PRCA in the course of viral hepatitis, infectious mononucleosis, and HTLV-1 infection have suggested that the suppression of erythropoiesis is mediated by cytotoxic T lymphocytes.
Drugs and Chemicals
Many drugs and chemicals have been reported as causes of PRCA38, 92, 139, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226 (Table 39.2). Drug-induced PRCA is usually an acute disorder that remits soon after discontinuation of the drug or cessation of exposure to the chemical. It may appear after the first exposure to the drug or a significant time after its initiation. In most instances, the association of a drug with PRCA is circumstantial and is based on the evidence that PRCA remits after discontinuation of the drug.1, 227 Diphenylhydantoin, azathioprine, chlorpropamide, and isoniazid have been repeatedly implicated as causes of PRCA, and in certain instances their association with PRCA has been proven by recurrence of anemia upon reinstitution of therapy.1
Different drugs cause erythroid aplasia through different mechanisms. Studies on direct drug effects on erythroid cell growth in vitro may be confusing because many drugs may have nonspecific effects on hematopoietic colony formation in vitro. IgG inhibitors of erythropoiesis have been shown for diphenylhydantoin and rifampicin.206, 228 Isoniazid and procainamide appear to use a different mechanism.229, 230
Pregnancy
Miscellaneous Disorders
Clinical Presentation
There are no clinical features or physical findings characteristic of PRCA other than the signs and symptoms of anemia. Since a complete arrest of erythropoiesis would cause a decline of red cell mass of roughly 1% a day, so the development of anemia in PRCA is gradual, allowing for physiologic compensation which would mitigate symptomatology for any given degree of anemia. In secondary cases, physical findings related to the underlying disease may be present. Patients with chronic PRCA requiring transfusion support may have findings suggesting iron overload.
Laboratory Evaluation
Peripheral Blood Counts
In acquired PRCA the erythrocytes are normochromic and normocytic. There is a complete absence of polychromatophilic red cells on the smear, and the reticulocyte count is between 0% and 1%. A reticulocyte count >1% should raise serious doubt about the correctness of the diagnosis. The white cell count and the differential count are usually normal. Occasionally, mild leukopenia, lymphocytosis, and/or eosinophilia may be present. The platelet count is usually normal. Mild thrombocytopenia of 100,000 to 150,000 platelets/µl is occasionally seen, and some patients may have a mild reactive thrombocytosis. When present, these abnormalities typically reflect a state of immune activation.
Bone Marrow
The hallmark of PRCA is the absence of erythroblasts from an otherwise normal marrow. The cellularity of the marrow is normal or slightly increased. Markedly increased cellularity with elimination of fat spaces should lead away from the diagnosis of PRCA. In typical cases the erythroblasts are either totally absent, or they constitute <1% on the marrow differential count (Fig. 39.1A). In a small number of cases, a few proerythroblasts and/or basophilic erythroblasts may be seen, not exceeding 5% of the differential count.1, 231 The presence of large proerythroblasts (“giant pronormoblasts”) with vacuolated cytoplasm and pseudopodia formation may raise the suspicion of an active B19 parvovirus infection but are not diagnostic.232, 233, 234
In some cases a phase of ineffective erythropoiesis characterized by erythroid hyperplasia with maturation arrest at the stage of proerythroblasts or basophilic erythroblasts in the marrow and reticulocytopenia in the blood may precede the development of PRCA, develop during the course of PRCA, or appear after partial response to treatment and before the return of erythropoiesis to normal.235, 236 While this morphologic picture in the absence of dysplastic changes in other lineages or cytogenetic abnormalities should raise suspicion of PRCA, bone marrow examination would need to be repeated at a later time to confirm the diagnosis.
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