Pure Red Cell Aplasia 

Updated: May 27, 2021
Author: Srikanth Nagalla, MD, MS, FACP; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Pure red cell aplasia (PRCA) is an uncommon disorder in which maturation arrest occurs in the formation of erythrocytes.[1, 2] Erythroblasts are virtually absent in bone marrow; however, white blood cell and platelet production are normal. The anemia due to PRCA is usually normocytic but can be macrocytic. PRCA was first described in 1922 by Kaznelson, who recognized that this condition was a different entity from aplastic anemia, which presents as pancytopenia.[3]

The characteristics of PRCA (see Workup) include the following:

  • Severe anemia
  • Reticulocyte count < 1%
  • The presence of less than 0.5% mature erythroblasts in the bone marrow
  • Normocellular bone marrow in most cases

The etiology of PRCA is heterogeneous. A congenital form of PRCA was initially described by Joseph in 1936 and by Diamond and Blackfan in 1938. Congenital PRCA is a lifelong disorder and is associated with physical abnormalities.

PRCA can be transient and reversible. Transient erythroblastopenia of childhood (TEC) can occur after viral infections. PRCA due to medications and infections are often reversible.

In adults, most cases of chronic PRCA are idiopathic. Secondary PRCA occurs in patients with conditions such as the following:

  • Autoimmune disorders
  • Systemic lupus erythematosus
  • Hematologic malignancies
  • Solid tumors

Therapeutic approaches (see Treatment) include the following:

  • Transfusions for severe anemia with cardiorespiratory failure
  • Discontinuation of medications that could cause PRCA
  • Observation of children with PRCA, with treatment if indicated
  • Treatment of infections
  • Treatment of underlying conditions
  • Corticosteroids and immunosuppressive agents
  • Plasmapheresis or lymphocytapheresis

The life expectancy of patients with idiopathic PRCA is about 1-2 decades. The survival of patients with congenital PRCA is limited. The lifespan of patients with secondary PRCA depends on the course of the underlying disorder.

Pathophysiology

In general, pure red cell aplasia (PRCA) is due to a selective injury, often immunological, that affects the early phase of erythrocyte maturation.

Childhood

Diamond-Blackfan syndrome is a rare congenital PRCA that is usually detected at birth, or later during the first 18 months of childhood. Affected individuals usually have a macrocytic anemia. The expression of hemoglobin F and surface “I” antigen in erythrocytes is increased, indicating erythrocyte immaturity.

About one third of these patients have developmental defects, including cleft palates, macroglossia, craniofacial defects, thumb or upper limb abnormalities, cardiac defects, and urogenital malformations. Growth is often retarded.[2] A modest increased risk for leukemia and neoplasms is noted.

Diamond-Blackfan syndrome is caused by the deletion of genes for ribosomal protein RPS19 in 25% of patients, leading to defects in ribosome biogenesis. This ribosomopathy and haploinsufficiency may be responsible for impaired mRNA translation and the activation of the tumor suppressor gene TP53 in this disorder.[4, 5, 6, 7, 8, 9]  

Germ-line mutations in genes encoding components of both the small (RPS24, RPS17, RPS7, RPS10, and RPS26) and large (RPL35A, RPL5, RPL11, and RPL26) ribosomal subunits have also been described in DBA patients.[10] Mutations in the GATA1 gene has been found to cause DBA in a minority of patients.[11] Because GATA1 has been implicated in DBA, it is possible that non-RP genes may also lead to the characteristic erythroid hypoplasia.[10]

De novo cases of Diamond-Blackfan syndrome are believed to be caused by intrauterine damage to early erythroid stem cells.[12] A familial history of PRCA is evident in approximately 10% of patients.

Transient erythroblastopenia of childhood (TEC) is a self–limiting, benign disorder. A history of a recent viral infection is usually noted.[13] Parvovirus 19 infection should be ruled out.

Adults

Acquired primary (idiopathic) PRCA is the most common form of red cell aplasia in adults.

However, PRCA can be secondary to underlying disorders. For example, autoimmune disorders (eg, type 1 diabetes, thyroiditis, rheumatoid arthritis, Sjögren syndrome) can be responsible. PRCA has been shown to be secondary to T-cell inhibition of marrow erythroid cells. PRCA can also be secondary to and is associated with the following:

  • Thymoma (1-15%)

  • Hematological malignancies (eg, B- and T-cell chronic lymphocytic leukemia)

  • T-cell large granular lymphocyte leukemia and solid tumors

  • Infections

  • Drugs

  • Pregnancy[14]

  • Systemic lupus erythematosus

  • Renal failure

  • Good syndrome (thymoma with combined B- and T-cell deficiency)

PRCA can occur following ABO-mismatched marrow transplantation.[15]

The incidence of PRCA has increased in patients with chronic renal disease who have received epoetin therapy. This has been ascribed to the generation of antiepoetin antibodies, which occurs more often with epoetin-alpha than with epoetin-beta. This complication may be avoided by using an erythropoietin-mimicking human antibody, which stimulates erythropoiesis but does not appear to induce antiepoetin antibodies and PRCA.[16, 17, 18]

Etiology

Infections such as the following can cause PRCA[19, 20, 21] :

  • HIV infection
  • Respiratory tract infections
  • Gastroenteritis
  • Primary atypical pneumonia
  • Infectious mononucleosis
  • Mumps
  • Viral hepatitis

Most cases of acute transient PRCA are caused by parvovirus B19 infection.[22, 23] Parvovirus B19 can cross the placenta in infected women and can destroy erythroid cells in the fetus and induce spontaneous abortions. Parvovirus 19 infections can persist longer in immunocompromised patients.

A partial list of medications thought to cause PRCA is as follows[24, 25] :

  • Antiepileptic medications (eg, phenytoin, carbamazepine, sodium valproate)
  • Mycophenolate
  • Azathioprine
  • Chloramphenicol
  • Thiamphenicol
  • Sulfonamides
  • Isoniazid
  • Procainamide
  • Clopidogrel [26]

Originally, thymoma was cited as the primary cause of acquired PRCA. However, subsequent studies have revealed that only a small percent of all cases of PRCA result from thymomas. Conversely, only 7% of patients with thymomas had PRCA.

Epidemiology

Pure red cell aplasia (PRCA) is an uncommon disorder. The idiopathic form is the most common type of PRCA. The incidence of transient and reversible PRCA that occurs in childhood and in adults secondary to medications and infections is probably underestimated. The reason for this underestimation is the anemia is self-limiting. Acquired secondary PRCA is not common. Diamond-Blackfan syndrome is rare.

No racial, age, or sex predilection is reported in PRCA. However, females are more likely to have autoimmune disorders.

Prognosis

Prognosis varies among the different types of pure red cell aplasia (PRCA).

Transient erythroblastopenia and other PRCA disorders in children and adults are benign with an excellent prognosis.

The prognosis of secondary PRCA depends on the course of the underlying condition, such as a thymoma or a hematological malignancy. About 30% of PRCA cases due to thymomas are reversed by thymectomy.

Most cases of PRCA are idiopathic. About 68% respond to intervention. However, relapses are common. The lifespan of these patients is about 1-2 decades.

Most patients with Diamond-Blackfan syndrome respond to corticosteroid therapy but are prone to relapses. Estimating the lifespan of patients with this disorder is difficult because it is rare.

Prognosis is also influenced by the complications of therapy, as follows:

  • Hemosiderosis can develop in multitransfused patients.
  • Corticosteroid therapy can lead to osteopenia and osteoporosis, infections and growth retardation.
  • PRCA can evolve into aplastic anemia and acute myelogenous leukemia, which have high morbidity and mortality rates.
  • The possibility exists for the transmission of infections by transfusion therapy, intravenous immunoglobulin G, and antilymphocytic serum. Infections acquired during blood product transfusions can affect prognosis.

Patient Education

The consequences of iron overload due to multiple transfusions and the possibility of the transmission of infections by transfusion therapy, intravenous immunoglobulin G, and antilymphocytic serum should be explained.

The adverse effects of corticosteroids, immunotherapy, and other aspects of management should be discussed.

Patients should be told to avoid medications that might cause pure red cell aplasia (PRCA).

 

Presentation

History

Presenting symptoms depend on the severity of the anemia. Some patients are virtually asymptomatic, whereas others have an uncompensated anemia, have cardiopulmonary distress, and are transfusion dependent.[1, 2, 27]

Patients with aplastic anemia, as opposed to pure red cell aplasia (PRCA), may have a history of bruising due to thrombocytopenia.[28]

Obtaining the history of medications that patients are taking is important. A history of recent infections, such as infectious mononucleosis or viral hepatitis, is important.

Patients who have an underlying hemolytic anemia can become markedly anemic if they develop PRCA. This is known as an aplastic crises and is caused by hemolysis that is ongoing while erythrocyte production is impaired. The possibility of an aplastic crisis should be considered in patients with a hemolytic anemia if reticulocyte counts are low and if they have had recent infections. In contrast, the development of anemia in PRCA in patients without hemolysis is often gradual and self-limited and, hence, not noticed.

To determine whether the patient has a secondary PRCA, ask about the possibility of pregnancy, signs of systemic lupus erythematosus (SLE), signs of a hematological malignancy, and signs of other possible disorders that can cause PRCA. A history of miscarriages might suggest SLE.

A history of autoimmune disorders such as type 1 diabetes, thyroiditis, and rheumatoid arthritis should be elicited. Dryness of eyes and mouth occurs in Sjögren syndrome.

Recognize that chronic renal failure and erythropoietin therapy, AB0-incompatible transfusion, and stem cell transplantation are associated with PRCA.

Diamond-Blackfan syndrome should be considered in a child with PRCA, retarded growth, and developmental defects.

Physical Examination

The severity of anemia and degree of compensation and cardiopulmonary distress should be assessed.

Evidence of bruising and mucocutaneous bleeding might suggest pancytopenia and aplastic anemia.

Evidence of recent infection such as a rash, nasal congestion, cough, and jaundice should be evaluated. Enlarged parotid glands might suggest mumps

Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder or infectious mononucleosis.

Evidence of an autoimmune disorder such as arthritis, type 1 diabetes, autoimmune hemolytic anemia, or thyroiditis should be assessed. Leg ulcers and splenomegaly can occur in hemolytic anemias.

A malar butterfly rash and arthritis suggests SLE.

Thymomas are rarely large enough to be detected during the physical examination.

Diamond-Blackfan syndrome is suggested by retarded growth and congenital abnormalities.

One should evaluate patients for complications of therapy such as hemosiderosis due to transfusion therapy, diabetes, and osteopenia and osteoporosis due to corticosteroid therapy, myelogenous acute leukemia due to immunotherapy, and infections due to blood product transfusions.

 

DDx

Diagnostic Considerations

The classical presentation of pure red cell aplasia (PRCA) is with a normocytic anemia and a reticulocyte count of less than 1%. Bone marrow studies reveal a normocellular marrow with an absence of erythroblasts. Maturation arrest is evidenced by the presence of more immature erythrocyte progenitors.

When the results of those laboratory studies are not consistent with classical PRCA, a workup to identify other anemias should be done. If macrocytosis or microcytosis is evident, appropriate diagnostic tests should be indicated. Examination of peripheral smears and bone marrow is important. For discussion of the workup in such cases, see Anemia.

Pearson syndrome

Pearson marrow-pancreas syndrome (PS) and congenital PRCA (Diamond-Blackfan anemia [DBA]) share several features, including the following:

  • Early onset of severe anemia
  • Variable nonhematologic manifestations
  • Sporadic genetic occurrence
  • Occasional spontaneous hematologic improvement

Consequently, patients with presumptive DBA should be tested for mitochondrial DNA (mtDNA) deletion during their initial genetic evaluation, to rule out PS.[11]

 

Workup

Laboratory Studies

The following blood tests should be obtained in suspected pure red cell aplasia (PRCA):

  • Complete blood cell count (CBC) count
  • Red blood cell (RBC) indices
  • Reticulocyte count
  • White blood cell (WBC) differential analysis of WBCs

Other studies to consider include the following:

  • Iron studies, especially iron saturation and serum ferritin levels, are used to diagnose hemosiderosis; this possibility should be considered in patients who have received multiple transfusions.
  • Serum vitamin B-12 and folate levels might be indicated in patients with macrocytosis.
  • Lactate dehydrogenase (LDH), indirect bilirubin, and serum haptoglobin levels are used to detect hemolysis.
  • Hemoglobin A 2 and hemoglobin F are used to rule out thalassemia.
  • Flow cytometry is used to diagnose hematological malignancies and T-cell disorders.

Tests to identify infection, including the following, are indicated:

  • Parvovirus B19 infection [29]
  • Hepatitis
  • Infectious mononucleosis

Tests to detect autoimmune disorders should include the following:

  • Antinuclear antibody test
  • C-reactive protein (CRP) level
  • Erythrocyte sedimentation rate (ESR)
  • Quantitative immunoglobulin analysis
  • Direct Coombs test to detect an autoimmune hemolytic anemia
  • Tests for thyroiditis, diabetes mellitus, rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus (SLE) might be indicated.

In addition, the following tests are helpful in diagnosing Diamond-Blackfan syndrome:

  • Hemoglobin F assay
  • “I” antigen on the surface of erythrocytes
  • Adenosine deaminase determination

Peripheral smears demonstrate a normocytic anemia in most cases of PRCA. However, macrocytic anemia occurs in Diamond-Blackfan and Good syndromes and in HIV infections. Peripheral smears can be used to screen for infectious mononucleosis, megaloblastosis, and hematological malignancies.

Bone marrow histology

Bone marrow aspiration smears in PRCA usually reveal a normocellular marrow. An absence of erythroblasts is noted, whereas more immature erythrocyte progenitors are present (maturation arrest). WBCs and platelet maturation are normal. Bone marrow can be used to evaluate iron stores and help diagnose megaloblastosis and hematological malignancies.

Imaging Studies

Uses of imaging studies include the following:

  • Positron emission tomography (PET) and computed tomography (CT) scans are used to detect thymomas.
  • Spleen size can be determined by ultrasound imaging.
  • Appropriate imaging studies are used to help diagnose and evaluate hematological malignancies.
  • Duel-energy x-ray absorptiometry scans are used to assess osteopenia and osteoporosis due to corticosteroid therapy.

Procedures

Procedures can include the following:

  • Bone marrow aspiration and biopsy
  • Appropriate biopsies to diagnose hematological malignancies.
 

Treatment

Approach Considerations

The initial treatment plan should include transfusions for patients who are severely anemic and have cardiorespiratory failure. Anemia is more severe in patients with pure red cell aplasia (PRCA) who have ongoing hemolysis (aplastic crises).

Medications that could cause PRCA should be discontinued.

Children with PRCA should be observed and not aggressively treated to avoid corticosteroid-related growth retardation. This caution is feasible since PRCA in children is often transient and reversible. However, transfusion should be administered if indicated.

Infections should be treated. High-dose intravenous immunoglobin therapy should be considered for parvovirus B19 infections.[30] PRCA due to medication or infections is usually reversible within a few months, if not earlier. However, immunotherapy may be needed to reverse erythropoiesis-stimulating agent (ESA)–related PRCA.

Underlying conditions should be treated. These conditions include a thymoma, hematological malignancies such as T-cell large granular lymphocyte leukemia,[31] solid tumors, and systemic lupus erythematosus (SLE). Surgery or gamma irradiation of the thymus should be considered in a patient with a thymoma.

PRCA considered to be idiopathic and due to autoimmunity should be initially treated with corticosteroids.[1, 2, 27] A response is expected within 4-6 weeks in about 45% of patients. Corticosteroids should be judiciously given to children to avoid growth retardation. Immunosuppressive agents have an important role. Immunosuppressive agents used in PRCA include cyclophosphamide, 6-mercaptopurine, azathioprine, and cyclosporine A. Rituximab has been reported to be effective in managing PRCA.[32, 33, 28, 34] Antithymic globulin (ATG) is another therapeutic option. Danazol has been helpful in some cases but is contraindicated in children. Plasmapheresis has been used to remove autoantibodies.

There are a number of reports of successful control of refractory/relapsed PRCA with sirolimus. However, multi-center and large-scale randomized controlled trials are needed to establish the efficacy of this treatment.[35, 36, 37, 38]

Several patients have responded to plasmapheresis or lymphocytapheresis.[39]

Autologous and nonmyeloablative allogeneic peripheral stem cell transplantation have been used, especially in patients whose disease is refractory to therapy.[40]

Iron chelation should be considered in patients who have had multiple transfusions and have evidence of iron overload.

Surgical Care

Thymectomy might be indicated in patients with a thymoma. However, the procedure should not be performed in patients with a normal-sized thymus. About 30% of patients with thymomas respond to thymectomy.

Although not effective in most cases, splenectomy might be helpful in refractory cases. Splenectomy is indicated to manage pure red cell aplasia (PRCA) complicated by hypersplenism.

Consultations

Consultations with a hematologist and rheumatologist are indicated. A hematologist should be consulted for the diagnosis and management of pure red cell aplasia (PRCA). A rheumatologist should be consulted in patients with autoimmune disorders.

Activity

Activity might be limited in anemic patients.

 

Medication

Medication Summary

The goals of therapy for pure red cell aplasia (PRCA) are to restore erythroid production, to maintain hemoglobin at an adequate level, and to treat underlying disorders. Therapy is also designed to prevent and treat complications of therapy.

Corticosteroids

Class Summary

Corticosteroids are the mainstay of therapy for pure red cell aplasia (PRCA). Approximately 45% of patients with PRCA respond to corticosteroids.

Prednisone (Sterapred)

Useful in acquired PRCA because they can modify the body's immune response. In congenital PRCA, corticosteroids are believed to allow abnormal stem cells to become more sensitive to growth factors. Have an anti-inflammatory effect, a profound effect on metabolism, and numerous potentially serious adverse effects.

Benefits and risks should be individualized when treating PRCA.

Prednisolone (Delta-Cortef, Econopred)

High-dose treatment is an option if no response to prednisone occurs.

Immunosuppressives

Class Summary

Immunosuppressive therapy can be effective, especially when PRCA is thought to be due to autoimmunity or idiopathic. Cyclophosphamide 6-mercaptopurine, azathioprine, cyclosporin A, and rituximab have been used. Typical doses for immunosuppressive agents are listed below. A hematologist should be consulted to individualize doses of immunosuppressive agents. Other options include antithymic globulin (ATG) and high-dose intravenous immunoglobulin G. Danazol may be effective in some cases of refractory PRCA but is contraindicated in children.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

6-Mercaptopurine (Purinethol)

Purine analog that inhibits DNA and RNA synthesis, causing cell proliferation to arrest.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs.

For children and adults, base dosing on ideal body weight.

Antithymocyte globulin (Thymoglobulin)

Purified concentrated gamma-globulin (primarily monomeric IgG) from hyperimmune horses immunized with human thymic lymphocytes. Mechanism of action is thought to be its effect on lymphocytes responsible in part for cell-mediated immunity and lymphocytes involved in cell immunity.

A hematologist or another physician with extensive experience must be involved in administration and monitoring because of the many complications and adverse effects of this therapy.

Intravenous immune globulin (Gamimune, Gammagard, Sandoglobulin, Gammar-P)

A hematologist or a physician experienced in administering this agent should be consulted because anaphylaxis, renal failure, transmission of infections, and aseptic meningitis are potential complications. Experience in selecting patients who can tolerate IVIG, dosage, monitoring for adverse effects, and managing complications of therapy is mandatory. Consider the expense of this therapy.

Mechanism is not fully established. Has been reported that IVIG neutralizes autoantibodies. Down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; and blocks complement cascade.

Total dose is administered IV but is graduated with low doses initially to monitor for anaphylaxis and other complications. Therefore, doses mentioned in package insert should be followed. Lower dosages per day but extended over 4 d are indicated in patients with fluid overload.

Danazol (Danocrine)

Reduces autoimmune responses. Used to treat pure red cell aplasia.