eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Pure Red Cell Aplasia

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

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 thymomas^{[3 ]}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%.

Workup

Laboratory Studies

• Basic studies include the following:
  • CBC count
  • Platelet count
  • Differential count
  • RBC indices
  • Reticulocyte count
• Studies to rule out hemolysis include the following:
  • Lactate dehydrogenase level
  • Indirect bilirubin level
  • Serum haptoglobin level
• Studies to rule out iron overload include the following:
  • Serum iron value
  • Total iron-binding capacity
  • Serum ferritin levels
• In acute pure red cell aplasia, rule out the following:
  • Parvovirus B19 infection (Sensitive techniques utilizing immunofluorescence [IF] staining and increased viral DNA production by dot blot hybridization and quantitative PCR are reportedly effective in the detection of Parvovirus B19 infection.^{[8 ]})
  • Atypical mycoplasmal pneumonia
  • Infectious mononucleosis
  • Mumps
  • Viral hepatitis
• In acquired chronic pure red cell aplasia, rule out the following^{[4 ]}:
  • HIV infection
  • Thymoma
  • Chronic active hepatitis
  • Systemic lupus erythematosus
  • Autoimmune disorders (direct Coombs test)
  • Collagen-vascular disorders
  • Pregnancy
• For congenital pure red cell aplasia, obtain the following:
  • Fetal Hgb and erythrocyte adenine deaminase levels
  • Serum folate and vitamin B-12 levels
  • Genetic testing
  • Peripheral smear results - Can show megaloblastic changes

Imaging Studies

• Chest radiograph (posteroanterior and lateral)
• CT scan to rule out a thymoma
• MRI to rule out thymoma

Procedures

• Bone marrow aspiration and biopsy are indicated to confirm the diagnosis. This procedure may not be indicated in persons with acute pure red cell aplasia. Bone marrow biopsy may be useful to assess iron overload. A bone marrow biopsy is indicated to diagnose acute myelogenous leukemia, which can be a complication of immunotherapy.
• Obtain tissue samples via thoracotomy or mediastinoscopy to rule out thymoma.
• In some cases, obtaining a liver biopsy sample, with quantitation of iron levels, may be indicated to rule out iron overload.

Histologic Findings

Findings from bone marrow aspirates and biopsy usually reveal a selective depletion in RBC precursors. In congenital pure red cell aplasia, megaloblastosis of RBC precursors may be observed, and, occasionally, a depression in the level of megakaryocyte and WBC precursors occurs.

In acute pure red cell aplasia, bone marrow aspiration and biopsy performed during the recovery phase may yield misleading findings that suggest active erythropoiesis.

Findings from biopsy of a thymoma usually reveal that the tumor is encapsulated and contains primarily spindle cells, with or without small lymphocytes.

Treatment

Medical Care

Specific aspects of the treatment of acute, chronic acquired, and congenital forms of pure red cell aplasia are mentioned below. Common to all forms is the treatment of anemia. Adequate Hgb levels should be maintained with transfusion therapy. Folic acid and multivitamins have been recommended, but their value has not been established. High-dose immunoglobulin can be used to restore Hgb levels transiently in patients with parvovirus B19 infections and other forms of acquired pure red cell aplasia.

The decision to hospitalize patients with pure red cell aplasia or to treat them in an outpatient setting depends on their clinical status and the ability to evaluate, treat, and transfuse patients outside the hospital setting.

• Acute self-limited pure red cell aplasia
  • Discontinue offending drugs and treatment of associated infections or other illness.
  • Transfusion therapy is not usually indicated because of the self-limited nature of acute pure red cell aplasia.
  • Transfusions may be indicated in patients with hemolytic anemias who develop pure red cell aplasia.
• Acquired chronic (sustained) pure red cell aplasia^{[4 ]}
  • A strategy needs to be developed.
  • The underlying disorder (eg, thymoma, systemic lupus erythematosus [SLE], collagen-vascular disease, lymphoproliferative disorder) should be treated.
  • Corticosteroids can be effective, but a high dosage is often required, and the adverse effects frequently preclude using these agents. However, some patients respond to low doses of corticosteroids. Prednisone can induce remission in approximately 45% of cases.
  • If the underlying cause of pure red cell aplasia is immunological and the response to corticosteroids has been inadequate, the next level of treatment is with cytotoxic or immunosuppressive drugs. Cyclophosphamide, 6-mercaptopurine, azathioprine, and cyclosporine have all been used. These drugs have been effective at dosages sufficient to induce leukopenia. Some immunogenic agents can be leukemogenic.
  • As reported by Rabitsch et al in 2003, Ig-Therasorb immunoadsorption has been used to treat pure red cell aplasia resulting from ABO incompatibility.^{[9 ]}
  • In 2003, Herbert et al reported on the use of alemtuzumab (Campath-1H) to treat pure red cell aplasia refractory to corticosteroids.^{[10 ]}
  • Repeated, low doses of rituximab were reported to be successful in two patients after ABO-incompatible allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.^{[11,12 ]}
  • Autologous and nonmyeloablative allogeneic peripheral stem cell transplantation have been used and may be considered in patients who are refractory to other therapy.
  • Donor lymphocyte infusions have been used for refractory pure red cell aplasia relapsing after both autologous and nonmyeloablative allogeneic peripheral stem cell transplantation.
  • Antithymic or antilymphocyte serum has been effective. Several patients have responded to plasmapheresis or lymphocytapheresis.
  • Patients whose disease is refractory to immunosuppressive therapy may respond to danazol.
  • If patients do not respond to the above measures, transfusions most likely must be performed weekly to maintain an adequate Hgb level. Two units of blood every 2 weeks is usually sufficient, unless patients have hypersplenism, blood loss, or hemolysis. Consider iron chelation in patients with a prolonged transfusion requirement to avoid hemosiderosis.
• Congenital pure red cell aplasia
  • Treatment is complicated because this condition is a lifelong disorder, and the consequences of treatment can have devastating effects on growth and sexual maturity.
  • Transfusion is an integral modality in treating congenital pure red cell aplasia. The severity of anemia varies from patient to patient. With severe anemia, patients can have a lifelong dependency on transfusions. Two units of blood every 2 weeks are usually sufficient. Aggressive chelation using deferrioxamine (ie, desferrioxamine) infusions are critical to avoid hemosiderosis because transfusion therapy is usually started at a young age.
  • Corticosteroids are also a principal therapeutic option, and this therapy is believed to allow the abnormal stem cells in patients with congenital pure red cell aplasia to become more sensitive to growth factors. High doses of prednisone (ie, 1-2 mg/kg) are needed but should not be continued for more than 4-6 weeks. If prednisone therapy fails, a trial of high-dose methylprednisolone can be tried. Some patients respond to high-dose corticosteroid therapy and then can be maintained on low doses of these agents. The major complications of corticosteroid therapy in these patients are growth retardation, muscle weakness, and osteopenia.
  • Danazol and other androgens can be used in refractory cases, but these agents may be contraindicated in prepubertal children.

Surgical Care

Surgical care may be indicated if a thymoma is suspected or if the patient has significant hypersplenism.

• Thymectomy may be indicated for the treatment of acquired chronic pure red cell aplasia. However, the incidence of thymoma-induced pure red cell aplasia is not as common as has been reported in the past.
  • Evidence indicates that only 30% of patients with acquired pure red cell aplasia respond to thymectomy and that only 2 out of 37 patients with pure red cell aplasia have thymic enlargement.
  • While the removal of a thymoma may be helpful, the removal of a normal thymus has not been effective in treating pure red cell aplasia.
• Splenectomy is not indicated unless hypersplenism can be documented to interfere with the treatment of pure red cell aplasia.

Consultations

Consultation with a hematologist and rheumatologist may be indicated.

• Consult a hematologist to assist with the treatment of patients with hypersplenism, underlying hemolytic anemia, and underlying lymphoproliferative disorders. A hematologist should be consulted to monitor therapy, especially immunotherapy, intravenous IgG therapy, and antithymocyte globulin therapy.
• Consult a rheumatologist or a specialist in collagen-vascular diseases if rheumatoid or collagen-vascular disorders may be responsible for pure red cell aplasia.

Activity

Activity should be monitored in anemic patients and, at times, curtailed in those in whom the anemia is significant.

Medication

The goals of therapy are to restore erythroid production, to maintain Hgb at an adequate level, and to treat underlying disorders. Therapy is also designed to prevent and treat complications of therapy.

Corticosteroids

Mainstay of therapy for pure red cell aplasia (PRCA). Approximately 45% of patients with pure red cell aplasia 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 a number of potentially serious adverse effects.
Refer to references listed in bibliography for a complete list of potential contraindications. Benefits and risks should be individualized when treating PRCA.

Dosing

Adult

1-2 mg/kg PO qd for 4-6 wk, discontinue if not successful after 4 wk, taper gradually when no longer indicated

Pediatric

1-2 mg/kg PO qd, taper gradually when no longer indicated

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral, fungal, and bacterial infections; relative contraindications include peptic ulcer disease, hepatic dysfunction, connective-tissue infections, diabetes, and fungal or tubercular skin infections; osteoporosis; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur; abrupt discontinuation of prednisone treatment may cause adrenal crisis and depression, as well as relapse of PRCA

Prednisolone (Delta-Cortef, Econopred)

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

Dosing

Adult

1 g/d IV push for 3 d

Pediatric

Not established

Interactions

Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin lesions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer, diabetes, and myasthenia gravis

Immunosuppressives

Important agents for the treatment of pure red cell aplasia. Cytoxan, 6-mercaptopurine, and azathioprine are used most often. Cyclosporine reportedly not effective. Increase remission rate and may reduce corticosteroid dose needed to manage pure red cell aplasia. Typical doses for immunosuppressive agents are listed. A hematologist should be consulted to individualize doses of immunosuppressive agents to arrive at appropriate dosage.

Antilymphocytic serum and high-dose IVIG must be administered by physicians with extensive experience with these agents because a number of complications exist that should be anticipated and monitored.

Androgens (danazol) may be effective in some cases of refractory pure red cell aplasia.

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.

Dosing

Adult

50-100 mg/m²/d PO or 400-1000 mg/m² PO in divided doses 4-5 d
Alternatively, 400-1800 mg/m² (30-40 mg/kg) IV in divided doses over 2-5 d; may repeat at 2- to 4-wk intervals; alternatively, administer 10-15 mg/kg IV q7-10d or 3-5 mg/kg bid

Pediatric

Administer as in adults

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; nausea and vomiting may occur; reversible hair loss may occur; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; hydration (2-3 qt of fluid daily) may prevent development of hemorrhagic cystitis; patients should be monitored for development of Cytoxan-related acute leukemia and myelodysplastic syndromes

6-Mercaptopurine (Purinethol)

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

Dosing

Adult

1.2-2.5 mg/kg/d PO or 80-100 mg/m²/d qd

Pediatric

Not established

Interactions

Toxicity increases when administered with allopurinol; hepatic toxicity increases when used in combination with doxorubicin

Contraindications

Documented hypersensitivity; severe leukopenia; thrombocytopenia; pancytopenia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Exercise caution in patients diagnosed with renal or hepatic impairment; patients on this medication have a high risk of developing pancreatitis, monitor for myelosuppression

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.

Dosing

Adult

1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d

Pediatric

Initial: 2-5 mg/kg/d PO/IV
Maintenance: 1-2 mg/kg/d PO/IV

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity; low levels of serum thiopurine methyl transferase; severe leukopenia; pancytopenia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check thiopurine methyl transferase level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated

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.

Dosing

Adult

Initial: 14-18 mg/kg/d PO q4-12h; alternatively, 5-6 mg/kg IV qd 4-12h
Maintenance: 5-15 mg/kg/d PO qd or divided bid; alternatively, 2-10 mg/kg/d IV divided q8-12h

Pediatric

Administer as in adults

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because it may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

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.

Dosing

Adult

10-20 mg/kg/d IV for 8-14 d; a test dose of 5 mcg IM should be administered and anaphylaxis monitored

Pediatric

Not established

Interactions

Unstable in acidic solutions and precipitates in dextrose solutions (package inserts describe optimal conditions)

Contraindications

Documented hypersensitivity; severe thrombocytopenia; leukopenia; aplastic anemia; anaphylaxis; should not be administered to a patient who has received varicella vaccine or another live vaccine within 3 mo

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Complications include thrombocytopenia, leukopenia, pancytopenia, eosinophilia, anemia, hemolysis, deep vein thrombosis, lymphadenopathy, CNS signs (eg, seizures, paresthesias, confusion, headache), chills and fevers, hyperglycemia, GI symptoms and signs (eg, diarrhea, nausea, vomiting), nephrotoxicity, gynecologic malignancies (eg, vaginal, cervical, endometrial), hepatotoxicity, respiratory failure, dermatological reactions, musculoskeletal symptoms (eg, back pain, arthralgias, myalgia, tremors), anaphylaxis and serum sickness, and transmission of infections (herpes simplex)

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/d but extended over 4 d are indicated in patients with fluid overload.

Dosing

Adult

Not to exceed 2 g/kg IV over 4 d

Pediatric

Not established

Interactions

Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine

Contraindications

Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies; renal insufficiency and >85% volume depletion; consider benefits versus risks of administering IVIG to patients with preexisting renal disease and minimal volume depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Danazol (Danocrine)

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

Dosing

Adult

200 mg PO bid/tid initially; if efficacious, taper dosage by 50% over 2-3 mo

Pediatric

Not established

Interactions

Decreases insulin requirements and increases effects of anticoagulants; may increase carbamazepine levels

Contraindications

Documented hypersensitivity; seizure disorders; hepatic or renal insufficiency; lactation; conditions influenced by edema; undiagnosed genital bleeding; porphyria

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in renal, hepatic, or cardiac insufficiency and seizure disorders

Follow-up

Further Inpatient Care

• The goals of inpatient care are to complete the workup, initiate appropriate treatments, monitor the response to therapy, and manage potential adverse effects of therapy.
  • Response to therapy: An increase in the reticulocyte count is the earliest response to therapy or evidence of a spontaneous remission. Subsequently, a rise in Hgb to levels within the reference range is expected. If a partial response occurs, consider other causes of anemia (eg, iron deficiency, blood loss, hemolysis, chronic disease).
  • Monitoring underlying and contributory conditions: Underlying hemolytic anemia can be assessed by lactate dehydrogenase, indirect bilirubin, and haptoglobin evaluations. Autoimmune disorders can be monitored by a direct Coombs test. Monitor rheumatoid arthritis, SLE, and collagen-vascular disorders using appropriate tests.
  • Complications of transfusion: Perform periodic tests to rule out hepatitis and iron overload; tests include liver function tests, serum iron values, total iron-binding capacity, and serum ferritin levels.
  • Monitoring complications of therapy: These complications are mentioned above.

Further Outpatient Care

• Outpatient care is the same as inpatient care.

Inpatient & Outpatient Medications

• See Treatment and Medication.

Deterrence/Prevention

• When medication has been implicated as the cause of acute pure red cell aplasia, medications that might cause pure red cell aplasia should be avoided.

Complications

• Effects of severe uncompensated anemia can cause myocardial dysfunction, heart failure, and failure of other organs.
• Repeated transfusions can cause hemosiderosis, cardiac failure and arrhythmias, failure of growth, and delay of sexual maturity.
• Patients who are on immunotherapy can develop an acute leukemia and aplastic anemia.

Prognosis

• Prognosis varies widely, depending on the etiology of pure red cell aplasia and on the underlying disorders and the clinical course.
  • Acute self-limited pure red cell aplasia usually has an excellent prognosis.
  • Acquired chronic pure red cell aplasia is associated with a number of complications. The morbidity depends on the underlying conditions, the response to therapy, and the complications of therapy. The mortality rate is low.
  • Congenital pure red cell aplasia is usually a lifelong disorder and is associated with a high morbidity rate due to the disorder and the treatment of the condition. Most patients survive through early adulthood, and estimating the mortality rate for this disorder has been difficult.

Patient Education

• The consequences of iron overload resulting from repeated transfusions should be explained to patients and to responsible parents if the patient is a child. This is important because hemosiderosis may cause growth failure and delayed sexual development.
• The possibility of the transmission of infections by transfusion therapy, intravenous IgG, and antilymphocytic serum should be explained.
• The diverse adverse effects of corticosteroids, immunotherapy, and other aspects of management should be explained.

Miscellaneous

Medicolegal Pitfalls

• Missing the diagnosis of pure red cell aplasia or instituting inappropriate care is subject to lawsuits. However, a few points should be considered, as follows:
  • Failure to explain the consequences of iron overload resulting from transfusions
  • Failure to explain the possibility of transmission of infections by transfusion, IVIG, and antilymphocytic therapy
  • Failure to explain the adverse effects of corticosteroids, immunotherapy, and other aspects of treatment
  • The administration of immunotherapy, IVIG, and antilymphocytic therapy without consultation and significant involvement of a physician with extensive experience with these agents

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Keywords

pure red cell aplasia, red cell aplasia, red blood cell aplasia, aplastic anemia, erythropoietin, erythropoiesis, erythropoietic, erythroblastic hypoplasia, erythroblastopenia, erythroid hypoplasia, red cell agenesis, RBC precursors, normoblastic-normochromic anemia, Diamond-Blackfan syndrome

Contributor Information and Disclosures

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
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Rodger L Bick, MD, PhD, FACP, Clinical Professor of Medicine, University of Texas Southwestern Medical Center; Director, Dallas and Pacific Thrombosis Hemostasis and Vascular Medicine Clinical Center
Rodger L Bick, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Blood Banks, American Cancer Society, American College of Angiology, American College of Physicians, American Geriatrics Society, American Heart Association, American Medical Association, American Society for Clinical Pathology, American Society of Hematology, Association of Clinical Scientists, California Medical Association, California Thoracic Society, International College of Angiology, International Society of Hematology, International Society on Thrombosis and Haemostasis, New York Academy of Sciences, and Southwest Oncology Group
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Related eMedicine topics
Bone Marrow Failure
Bone Marrow Transplantation
Hematopoietic Stem Cell Transplantation
Pure B-Cell Disorders
Thymoma

Clinical guidelines
(1) KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. (2) 2007 update of hemoglobin target . National Kidney Foundation - Disease Specific Society. 1997 (updated 2006 May; addendum released 2007 Sep). Original guideline: 145 pages; addendum: 60 pages. NGC:006019

(1) Transfusion guidelines for neonates and older children. (2) Amendments and corrections to the transfusion guidelines for neonates and older children. British Committee for Standards in Haematology - Professional Association. 2004 Feb (addendum released 2005 Dec). Original guideline: 21 pages; Addendum: 5 pages. NGC:006583


Clinical trials
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