Pure Red Cell Aplasia 

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

The characteristics of PRCA include a severe anemia, a reticulocyte count of less than 1%, and the presence of less than 0.5% mature erythroblasts in the bone marrow. The bone marrow is usually normocellular.

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 is also often reversible when these medications are discontinued. PRCA due to infections is often reversible.

In adults, most cases of chronic PRCA are idiopathic, and a cause cannot be established. Secondary PRCA occurs in patients with conditions such as autoimmune disorders, thymomas, hematologic malignancies, and solid tumors.

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.

A selective injury, often immunological, is thought to affect the early phase of erythrocyte maturation.

Childhood

Diamond-Blackfan syndrome is a rare condition that is usually detected following birth and during the first 18 months of childhood. A macrocytic anemia is usually present in congenital pure red cell aplasia (PRCA). 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.

A modest increased risk for leukemia and neoplasms is noted. The syndrome is believed to be caused by intrauterine damage to early erythroid stem cells.^[3] The syndrome is currently thought to be due to the deletion of genes for ribosomal protein RPS19 that leads to defects in ribosome biogenesis.^{[4, 5]} 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.^[6] Parvovirus 19 infection should be ruled out.

Adults

Acquired primary (idiopathic) PRCA is the most common form of this disorder 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^[7]
• Systemic lupus erythematosus
• Renal failure
• Good syndrome (thymoma with combined B- and T-cell deficiency)

PRCA can occur following ABO mismatched marrow transplantation.^[8]

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 that 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.^{[9, 10, 11]}

Infections can cause pure red cell aplasia (PRCA) and include parvovirus 19 infections, HIV infection, respiratory tract infections, gastroenteritis, primary atypical pneumonia, infectious mononucleosis, mumps, and viral hepatitis.^{[12, 13, 14]} Most cases of acute transient PRCA are caused by parvovirus B19 infection.^{[15, 16]} 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^{[17, 18]} :

• Antiepileptic medications (eg, phenytoin [Dilantin], mycophenolic acid carbamazepine, sodium dipropylacetate, sodium valproate)
• Azathioprine
• Chloramphenicol
• Thiamphenicol
• Sulfonamides
• Isoniazid
• Procainamide

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

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 is secondary to medications and infections is probably underestimated. The reason for this underestimation is the anemia is self-limiting. Patients are often asymptomatic and are not aware of a temporary drop in hemoglobin. 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 varies among the different types of pure red cell aplasia (PRCA).

Transient erythroblastopenia of childhood (TEC) is a benign disorder, and the prognosis should be excellent. PRCA due to medications and infection is usually reversible, and the prognosis should be excellent.

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. Hemosiderosis can develop in multitransfused patients. Corticosteroid therapy can lead to osteopenia and osteoporosis and infections. PRCA can evolve into aplastic anemia and acute myelogenous leukemia, which have high morbidity and mortality rates. Infections acquired during blood product transfusions can also affect prognosis.