eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Pure Red Cell Aplasia

Author: Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Contributor Information and Disclosures

Updated: Nov 3, 2009

Introduction

Background

Pure red cell aplasia (PRCA) describes a condition in which RBC precursors in bone marrow are nearly absent, while megakaryocytes and WBC precursors are usually present at normal levels. In 1922, Kaznelson recognized that this condition was a different entity than aplastic anemia. Pure red cell aplasia exists in several forms, and the most common form is an acute self-limited condition. Acquired pure red cell aplasia is often chronic and is associated with underlying disorders such as thymomas and autoimmune diseases. A congenital form of pure red cell aplasia was initially described by Joseph in 1936 and by Diamond-Blackfan in 1938. Congenital pure red cell aplasia is a lifelong disorder, and it is associated with physical abnormalities. Both acquired and congenital pure red cell aplasia are occasionally refractory to therapy.

Recent research

Because PRCA is one of the autoimmune diseases observed in patients with lymphoma, Hirokawa et al attempted to discern the relationship between the 2 conditions,¹ assessing the disease characteristics in 8 patients who had both of these disorders. Half of the patients were found to have B-cell lymphoma, and the rest of them had the T-cell type. In 4 patients, PRCA and lymphoma developed simultaneously; in 3 of them, PRCA developed after the appearance of lymphoma (with 2 of these patients developing anemia while their lymphoma was in remission); and in 1 patient, PRCA developed first.

Chemotherapy and/or immunosuppressive therapy proved to be effective against anemia in 7 patients, with PRCA remaining in durable remission in 4 of these individuals without the use of maintenance immunosuppressive therapy. Based on their results, the authors suggested that lymphoma-associated PRCA is linked to a heterogeneous mechanism.

Pathophysiology

Erythroid precursors in bone marrow are the primary targets in pure red cell aplasia. As a result, patients can develop a normoblastic normochromic anemia and a virtual absence of reticulocytes.

Injury to stem cells in utero is believed to be the etiology of approximately 90% of cases of congenital pure red cell aplasia (ie, Diamond-Blackfan syndrome).² This theory is based on evidence that congenital pure red cell aplasia is frequently associated with random physical abnormalities, while it is rarely familial or associated with significant chromosomal abnormalities. However, a familial history of pure red cell aplasia has been detected in approximately 10% of patients with the congenital form of pure red cell aplasia.

The acute self-limited form is secondary to virus- and drug-induced impairment of erythroid progenitor cells. The acquired chronic form of pure red cell aplasia is associated with thymomas³ and autoimmune disorders. Damage to erythroid progenitors or precursor cells appears to be immune and T-cell mediated. In both the acute and acquired chronic forms of pure red cell aplasia, the affected cells are progenitors that have differentiated from stem cells and can express erythropoietin (EPO) receptors. Thus, unlike in congenital pure red cell aplasia, stem cells are not usually the targets in the acute and acquired forms of pure red cell aplasia.

Interestingly, pure red cell aplasia can be induced by FeLV-C/Sarma, a feline retrovirus, and this has been proposed as a model system for studying pure red cell aplasia. Additionally, dogs can develop pure red cell aplasia that responds readily to immunosuppressive therapy.

Frequency

United States

Acute transient pure red cell aplasia is the most common form of pure red cell aplasia. However, its frequency has most likely been underestimated because virus- and drug-induced pure red cell aplasias are usually self-limited and patients generally do not seek medical attention. Acquired forms associated with thymomas and autoimmune disorders are relatively uncommon. Since 1936, when this disorder was originally reported, hundreds of cases of congenital pure red cell aplasia have been reported.

Mortality/Morbidity

Because most cases of pure red cell aplasia are the acute self-limited form of pure red cell aplasia, morbidity and mortality from pure red cell aplasia are not significant. The mortality rate for acquired chronic pure red cell aplasia and for congenital pure red cell aplasia is expected to be slightly greater than that for the acute form of pure red cell aplasia. Most individuals with congenital pure red cell aplasia survive to early adulthood.

When acquired pure red cell aplasia is associated with thymomas and autoimmune disorders, morbidity can be due to these underlying conditions. Patients with the congenital form of pure red cell aplasia can also have physical abnormalities.

Profound transfusion-dependent anemia is the most common morbidity associated with acquired chronic pure red cell aplasia and congenital pure red cell aplasia. However, the treatment of anemia in persons with pure red cell aplasia can contribute to significant morbidity, as follows:

• Transfusion therapy can lead to hemosiderosis, and the consequences of iron overload are growth retardation, delay in sexual maturity, cardiac arrhythmias, and cardiac failure. Transfusions can also transmit infections.
• Corticosteroid therapy can lead to growth retardation, osteopenia, diabetes, and other complications.
• Because of immunotherapy, a small percentage of patients can develop aplastic anemia or acute myelogenous leukemia, and both conditions have high morbidity and mortality rates.

Race

No racial predilection is observed.

Sex

Females are more likely to be affected in immunologically related pure red cell aplasia. However, the male-to-female ratio is 2:1 for pure red cell aplasia associated with thymoma.

Clinical

History

Anemia is the primary problem in pure red cell aplasia. The degree of anemia can range from subclinical to severe. Anemia in acute self-limited pure red cell aplasia is barely noticeable. Profound anemias can also occur in chronic acquired pure red cell aplasia and in congenital pure red cell aplasia. Patients with severe anemias have symptoms and signs of uncompensated anemia and present with weakness, tachycardia, and dyspnea.

• Acute self-limited pure red cell aplasia due to viral infections
  • Often, the patient has a recent history of infectious diseases such as respiratory illnesses or gastroenteritis.
  • Mumps, infectious mononucleosis, and viral hepatitis often precede the development of acute pure red cell aplasia. Symptoms ascribable to these infectious processes may predominate over those of the transient anemia.
  • Because the decrease in the hemoglobin (Hgb) level is gradual and self-limited, most cases of acute pure red cell aplasia go unnoticed.
  • In patients with acute pure red cell aplasia who have hemolytic disorders, anemia can be severe because virtually no production of erythrocytes occurs to compensate for hemolysis. This is known as an aplastic crisis. Under these conditions, patients can develop uncompensated anemia with marked weakness and dyspnea.
• Acute self-limited pure red cell aplasia due to drugs
  • Patients may have a history of taking drugs that can induce pure red cell aplasia.
  • Having taken a medication for an extended period does not rule out the possibility that the drug is responsible for the episode of acute pure red cell aplasia.
  • See Causes for a list of medications reported to cause pure red cell aplasia.
• Persistent virus- or drug-induced pure red cell aplasia
  • In some cases of acute pure red cell aplasia due to viral infections or drugs, pure red cell aplasia may persist for a prolonged period.
  • The following explanations are proposed for this chronicity:
    • Patients who are immunocompromised cannot mount an adequate defense against viral infections.
    • Some individuals have an underlying sensitivity to drugs that can induce pure red cell aplasia.
    • In other patients, an underlying subclinical disorder predisposes patients to prolonged pure red cell aplasia. The acute pure red cell aplasia superimposed on an underlying condition can be severe and prolonged.
  • A careful history should be taken to elucidate conditions that could lead to this chronicity.
• Acquired chronic (ie, sustained) pure red cell aplasia^1,4
  • This can occur in patients with underlying thymoma, lymphoproliferative disorders, systemic lupus erythematosus (SLE), autoimmune disorders, or immunocompromised states.
  • Also, as reported by Musso et al in 2004, it can occur following major ABO-incompatible myeloablative and nonmyeloablative stem cell transplantation.⁵
  • Autoimmune disorders may be associated with arthritis.
  • Thymomas are rarely large enough to be detected during the physical examination.
  • Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder or systemic lupus erythematosus.
• Congenital pure red cell aplasia
  • Some, but not all, cases of congenital pure red cell aplasia are associated with severe anemias.
  • In addition to anemia, approximately one third of patients develop physical abnormalities, most often involving the head, upper limbs, thumbs, urogenital system, or cardiovascular system. Growth retardation and unusual thumb formation can occur. However, these physical deformities are less severe than in Fanconi syndrome.
  • Anemia is not often observed during the early neonatal period, but pallor, weakness, and dyspnea attributable to the anemia develop during the first year of life.

Physical

The signs of anemia and its severity are the major physical findings in persons with pure red cell aplasia. Pallor and weakness are early manifestations. Evidence of a decompensated anemia (eg, dyspnea, tachycardia, incipient heart failure) occurs in those with more severe anemias. Severe anemias can be observed in patients with acute pure red cell aplasia and hemolytic disorders who develop an aplastic crisis. Specific physical findings associated with acute, acquired chronic, and congenital pure red cell aplasia are described below. Also discussed are findings related to possible complications from therapy.

• Acute self-limited pure red cell aplasia
  • Often, physical evidence of anemia is scant or borderline.
  • Evidence of a recent viral infection (eg, a rash, jaundice in viral hepatitis, splenomegaly in infectious mononucleosis, enlarged parotid glands in mumps) may be present.
  • When acute pure red cell aplasia occurs in patients with hemolytic anemias, physical evidence of the hemolytic disorder (eg, splenomegaly, leg ulcers) may be present.
• Acquired chronic (ie, sustained) pure red cell aplasia
  • In addition to evidence of anemia, patients may have physical findings of underlying thymomas, lymphoproliferative disorders, autoimmune disorders, or immunocompromised states. However, thymomas are rarely large enough to be detected during the physical examination.
  • Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder.
• Congenital chronic pure red cell aplasia (ie, Diamond-Blackfan syndrome)
  • The severity of the anemia varies among patient populations.
  • Anemia is not often recognized during the early neonatal period but is usually apparent during the first 2 years of life.
  • More than one third of patients have malformations or mental retardation.
  • Osteogenic carcinoma of the mandible, and abnormalities of the thumbs have been observed.
  • In general, these physical abnormalities are not as severe as those observed in Fanconi syndrome. Thymomas have not been found in these patients.
• Complications of therapy
  • Iron overload secondary to transfusion therapy can manifest as hyperpigmentation of the skin, arthralgias, cardiac arrhythmia, evidence of endocrinopathies, jaundice due to hepatic dysfunction, and hepatosplenomegaly.
  • Complications of corticosteroid therapy include retarded growth, diabetes, and osteopenia.
  • Complications of immunotherapy can include aplastic anemia and acute myelogenous leukemia.

Causes

• Acute self-limited pure red cell aplasia can be caused by viral infections or certain medications.
  • Respiratory infections, gastroenteritis, primary atypical pneumonia, infectious mononucleosis, mumps, and viral hepatitis may trigger pure red cell aplasia.
  • Most cases of acute transient pure red cell aplasia are caused by parvovirus B19 infection. Parvovirus B19 can cross the placenta in infected women and can destroy erythroid cells in the fetus; in some cases, the virus can induce spontaneous abortion.
  • Most drugs believed to cause pure red cell aplasia are thought to do so by exerting a direct toxic effect on RBC precursors. The evidence for drug-induced immunological selective impairment of RBC production is controversial.
  • Probable causes include the following:
    • Antiepileptic medications (eg, phenytoin [Dilantin], carbamazepine, sodium dipropylacetate, sodium valproate)
    • Azathioprine
    • Chloramphenicol and thiamphenicol
    • Sulfonamides
    • Isoniazid
    • Procainamide
  • Possible coincidental associations include the following:
    • Nonsteroidal anti-inflammatory agents
    • Allopurinol
    • Halothane
    • D-penicillamine
    • Dapsone/pyrimethamine (Maloprim)
    • Quinidine and quinacrine
    • Gold
    • Benzene
    • Pesticides
• Acute chronic pure red cell aplasia is caused by several factors, including thymomas, autoimmune disorders, and immunocompromise.
  • Originally, thymoma was cited as the primary cause of acquired pure red cell aplasia. However, subsequent studies revealed that thymomas caused only 2 of 37 cases of pure red cell aplasia. Conversely, only 7% of patients with thymomas had pure red cell aplasia. T-cell–mediated erythroid rejection is considered the mechanism for the production of pure red cell aplasia in patients with thymomas. This is supported by evidence that a subgroup of T cells in B-cell chronic lymphocytic leukemia is responsible for pure red cell aplasia.
  • Pure red cell aplasia has been associated with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, chronic active hepatitis, collagen-vascular diseases, and chronic lymphocytic leukemia. Immunoglobulin G (IgG) antibodies in sera from many of these patients suppressed the growth of RBC precursors. Evidence indicates that in some cases, acquired chronic pure red cell aplasia can be T-cell mediated. The occurrence and role of autoimmune antibodies against EPO in persons with pure red cell aplasia have not been substantiated.
  • In patients who are immunocompromised, pure red cell aplasia may be due to persistent parvovirus B19 infections. In healthy persons, an IgG and immunoglobulin M response limits the parvovirus infection, but this response is attenuated in individuals who are immunocompromised.
• The etiology of congenital chronic pure red cell aplasia (ie, Diamond-Blackfan syndrome) is not clear.
  • Approximately 90% of cases are sporadic, and one suggestion is that the sporadic cases are caused by in utero damage to erythroid stem cells. This theory is based on evidence indicating that while Diamond-Blackfan syndrome frequently manifests with random physical abnormalities, it is rarely familial or associated with significant chromosomal abnormalities.
  • In 10% of patients, a dominant, or more rarely recessive, familial pattern has been observed. One locus on arm 19q13.2 encoding ribosomal protein S19 accounts for a quarter of patients with either the dominant or the sporadic form. Families not linked with this locus have also been described.
  • Evidence indicates that recombinant EPO can induce pure red cell aplasia in patients with chronic renal failure who had been on dialysis. Thirteen such cases were described by Casadevall et al in 2002 in the New England Journal of Medicine.⁶ Apparently, additional cases of EPO-related pure red cell aplasia have been noted, bringing the total to approximately 38. Neutralizing anti-EPO antibodies were detected in these patients and considered to be involved in the development of pure red cell aplasia.
    • The basis for pure red cell aplasia being due to EPO therapy is an enigma. Most of the cases have been reported in France and in patients undergoing renal dialysis. Pure red cell aplasia in these patients is usually severe, and it is unlikely that this would have been overlooked in the United States. Also, EPO-related pure red cell aplasia has only been observed since 1998.
    • Several possibilities should be considered. EPO used in France may have been manufactured by a different procedure than that used in the United States, and the manner of administration may be different. All patients who developed pure red cell aplasia had been treated with subcutaneous EPO. Although EPO is administered subcutaneously to cancer patients in the United States, EPO is not administered by this route to patients with chronic renal failure in the United States. Home administration of EPO is practiced in Europe but not in the United States. Patients are provided syringes with the appropriate single EPO dose that they keep refrigerated until use, and improper storage may have caused EPO degeneration.
    • Importantly, note that EPO-related appears to be a rare complication when one considers that approximately 3 million patients are treated with EPO worldwide. Nevertheless, maintain awareness of the possibility of this complication. In 2002, Casadevall et al recommended that patients receiving EPO should be tested for neutralizing anti-EPO antibodies as soon as possible after the onset of an unexplained anemia.⁶
    • Patients receiving darbepoetin alfa (Aranesp), which has a different carbohydrate structure than endogenous EPO, should be monitored closely.
    • Obviously, the administration of EPO for athletic performance should be avoided.
    • Neutralizing anti-EPO antibodies should be obtained in patients who are not responding to EPO. Following an initial rise in Hgb levels, approximately 20% of patients do not have a sustained response to EPO. Possibly, the generation of anti-EPO antibodies occurs more commonly than suspected. The development of pure red cell aplasia may represent the extreme end of the spectrum of EPO-induced immunological suppression of RBC production.
    • In 2004, Bennet et al reported that between January 1998 and April 2004, 191 cases of epoetin-associated pure red cell aplasia were reported.⁷ This occurred primarily with the Eprex brand name of epoetin alfa, and more than half of these cases were reported in France, Canada, the United Kingdom, and Spain. With appropriate procedures for storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted prevalence rate decreased by 83%.

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