Pure Red Cell Aplasia - Causes, Management, and Prognosis

Introduction

Pure red cell aplasia (PRCA) is a rare disorder secondary to red blood cell (RBC) formation failure. Anemia occurs due to the absence of red blood cell precursors. Unique immune mechanisms characterize red blood cell destruction in PRCA. Hence, PRCA is a subject of research. Intact platelets and white blood cell (WBC) precursors are found in the peripheral blood. PRCA is yet to be evaluated on a large scale due to its rarity.

How Is Pure Red Cell Aplasia Caused?

Pure red cell aplasia is inherited or acquired.

1. Congenital: PRCA is present in a patient from birth.

• Diamond Blackfan Anemia (DBA)- Congenital PRCA occurs mainly in occasional cases (55 to 60 percent). It is followed by an autosomal dominant inheritance pattern (40 to 50 percent).

2. Acquired:

• Auto-Immune Disorders: Systemic lupus erythematosus (SLE), rheumatoid arthritis, myasthenia gravis, auto-immune hemolytic anemia, and inflammatory bowel disease are some examples. Laboratory evidence indicates antibody and cell-mediated inhibition mechanisms of RBC formation.

• Viral Infections: The transient aplastic crisis occurs when the Parvovirus B19 concentration in blood is very high. The virus has an affinity for the precursor RBC cells because of their P antigen. The P antigen acts as a receptor for the virus entry into the cell. Other viruses are human immunodeficiency virus (HIV), T-cell leukemia-lymphoma virus, Epstein-Barr virus (EBV), hepatitis A, B, C, and E, and cytomegalovirus (CMV).

• Drugs: Phenytoin, sulfonamide drugs, Azathioprine, Allopurinol, Isoniazid, Procainamide, Ticlopidine, Ribavirin, and Penicillamine can cause PRCA.

• Lymphoproliferative Disorders: Lymphoproliferative disorders cause uncontrolled lymphocyte (a type of WBC) production. Examples are chronic lymphocytic leukemia (CLL), Hodgkin disease, Non-Hodgkin lymphoma (NHL), and multiple myeloma.

• Solid Tumors: Various cancers precipitate PRCA, such as thymoma (thymus cell tumor, strongly associated), breast, biliary, gastric (stomach), lung, thyroid, and renal cell cancer.

• ABO-Incompatible Stem Cell Transplant: Blood group matching is pertinent before a stem cell transplant. A mismatched ABO blood group leads to the development of target-specific antibodies. It leads to delayed engraftment of the RBC precursors. Engraftment means when the transplanted stem cells form new WBCs, platelets, and RBCs in the recipient. It can later lead to PRCA.

How Common Is Pure Red Cell Aplasia?

Acquired aplastic anemia affects males and females equally. However, most cases affect teenagers, elderly children, and young adults. The incidence of new cases of aplastic anemia in Europe and Israel per year is two cases per one million people. The incidence rate is two to three times higher in Asia.

What Are the Microscopic Features of Pure Red Cell Aplasia?

The peripheral blood smear (PBS) demonstrates normocytic normochromic anemia with reticulocytopenia (decrease in immature RBCs). Normocytic normochromic anemia exhibits the same size RBCs (normocytic) and a normal red color (normochromic). The WBC and platelet counts are normal. The bone marrow histological picture depends on the cause of PRCA. A complete absence or near absence of erythroblasts (less than one percent) is characteristic of auto-immune PRCA. Lymphoid aggregates, along with plasmacytosis (increased plasma cells) and lymphocytes (chronic immune cells), represent an inflammatory reaction.

How Is Pure Red Cell Aplasia Diagnosed?

An acquired aplastic anemia diagnosis is suspected when a patient has decreased levels of all three blood cell types. A diagnosis is confirmed by a thorough clinical examination, patient history, and investigations. These include:

• Complete Blood Count (CBC): CBC shows red blood and white blood cell count and platelets. Anemia and a normal white blood cell count, platelet count, and markedly reduced reticulocyte count support PRCA.

• PBS: A PBS (peripheral blood smear) determines the PRCA cause.

• Bone Marrow Biopsy: A bone marrow biopsy removes a small bone marrow specimen. It is mostly done from the hip or pelvis. Then, it is studied under a microscope. In acquired aplastic anemia, the sample will show a complete lack of cells. The PRCA diagnosis is based on the absence of erythroblasts (parent RBCs) from normal bone marrow. Additional tests may be necessary to rule out leukemia. Further, the tests can determine an inherited or genetic cause.

• Parvovirus Studies: In patients with positive bone marrow examination for PRCA, B19 Parvovirus testing should be done. Polymerase chain reaction (PCR) for peripheral blood is the test of choice.

• Cellular Immunology: After the bone marrow examination, cellular immunology of cytogenetics must be performed. Cytogenetics evaluates cellular immunity. A positive bone marrow test for PRCA further indicates abnormal cytogenetics.

• Computed Tomography (CT): A mass in the thymus in a patient with PRCA may be a thymoma. Hence, a chest CT scan rules out thymoma. A chest CT scan is mandatory in every PRCA patient to rule out an associated thymoma or lymphoid malignancy.

How Is Pure Red Cell Aplasia Treated?

1. Inherited PRCA:

• Corticosteroids: DBA is treated with Prednisone (corticosteroid). The initial therapy is at 2 milligrams/ kilograms (mg/kg) thrice or four times daily. However, long-term steroid use can cause toxicity, growth retardation, hypertension, diabetes, and cataract.

• Hematopoietic Stem Cell Transplantation (HSCT): It is used in patients unresponsive to glucocorticoids.

• Red Cell Transfusions: Long-term red cell transfusion is preferred to the chronic use of steroids.

2. Acquired PRCA:

• Immune-Mediated PRCA: Cyclosporine is the first choice of treatment, with a response rate of about 75 percent. It is effective in patients in whom other treatments have failed. The starting dose is 6 mg/kg daily. Cytotoxic agents are used in patients refractory to Cyclosporine. Cyclophosphamide is the most employed cytotoxic agent compared to other drugs. Cyclophosphamide treatment should not extend beyond six months due to a high risk of secondary malignancy. Tacrolimus provides effective immunosuppression. Hence, it is useful in PRCA. Intravenous immunoglobulins (Iv IGs), plasma exchange, and allogeneic stem cell transplant are other treatments for immune-mediated PRCA.

• Thymoma-Associated PRCA: Thymoma resection is mandatory in patients with thymoma-associated PRCA.

• B19 Parvovirus-Associated PRCA: B19 Parvovirus-associated PRCA is an indication for intravenous immunoglobulins as a specific and highly effective therapy.

What Are the Complications of Pure Red Cell Aplasia?

Children with DBA are predisposed to cancer. PRCA patients who receive chronic transfusions develop iron overload and related toxicities. Immunosuppressive therapy with Cyclosporine or chronic steroid therapy predisposes patients to myelosuppression. The use of corticosteroids can cause multiple adverse events. Chronic anemia in children can lead to growth retardation and poor mental development. Severe anemia can also increase the risk of cardiac failure. This is true in patients with pre-existing heart disease and older patients. In pregnancy, it can lead to premature labor and an abnormally low birth weight. Finally, anemia can cause low energy, fatigue, and a poor quality of life.

Conclusion

It is vital to maintain a broad outlook on the disease. A thorough investigation starts with a good history, a physical exam, and appropriate clinical and genetic tests to determine the etiology. Moreover, nurses, transfusion medicine specialists, hematology specialists, and geneticists should work in close harmony for the same reason.