Pure Red Cell Aplasia (PRCA) is a rare disorder in which there is a failure of the bone marrow to produce precursors of red blood cells (RBCs or erythrocytes) resulting in anemia.
Read more about Anemia- Causes, Symptoms, and Treatment
Read more about Bone Marrow- Structure, Composition, and Functions
The disorder may be acquired or congenital.
Acquired PRCA can occur due to unknown reasons (idiopathic) or be secondary to some other underlying disorder. The most common underlying disorders include autoimmune diseases, tumor of the thymus gland (thymoma), viral infections, or certain drugs. Congenital PRCA (Diamond Blackfan syndrome) is a rare disorder affecting children.
In PRCA, the bone marrow stops producing RBCs. However, the production of WBCs and platelets remains unaffected.
The main difference between PRCA and aplastic anemia is that, in PRCA, only the red blood cells are affected, while the white blood cells and platelets remain unaffected. In aplastic anemia, all three blood cell types are affected and reduced in number leading to pancytopenia.
Read more about Aplastic Anemia – Classification, Treatment, and Prognosis
Pure red cell aplasia is an uncommon disorder. The idiopathic form is the most common type of PRCA. PRCA occurring secondarily to medications and infections is underestimated because it is self-limiting. Diamond-Blackfan syndrome is rare.
There is no racial, age, or sex predilection for the disorder. However, females are more likely to have autoimmune disorders.
What are RBCs and Erythropoiesis?
Blood consists of following major cell types
- Red Blood Cells (RBCs) or Erythrocytes
- White blood cells (WBCs) or Leucocytes
- Platelets or Thrombocytes
RBCs give the blood its characteristic color. They contain hemoglobin—a red, iron-rich protein that binds oxygen. Their main function is to carry oxygen throughout the body.
Production of new red blood cells within the bone marrow is called erythropoiesis which is carried through the following stages.
- Hemocytoblasts: Stem cells in the bone marrow which give rise to all blood cells.
- Proerythroblasts: Differentiated stem cells formed by division and differentiation of hemocytoblasts.
- Early erythroblasts: They are also called basophilic erythroblasts. Hemoglobin synthesis begins during this stage
- Intermediate erythroblasts: Hemoglobin starts accumulating.
- Late erythroblasts: The nucleus is extruded out from the cell.
- Reticulocyte: It is the precursor of mature red blood cells. These are so named because they exhibit a net-like appearance or reticulum in their cytoplasm when stained. About 1-3% of reticulocytes are found in the blood circulation.
- Mature erythrocytes: This stage is determined by the loss of ribosomes. These cells enter the circulation.
The life span of an RBC is about 120 days in the circulation.
Erythropoietin stimulates the red marrow of the bones to form increased numbers of proerythroblasts and hasten the maturation of red blood cells.
Signs and Symptoms
PRCA does not have any specific clinical features. The patients present with general symptoms of anemia. These include weakness, fatigue, general malaise, poor concentration and shortness of breath.
Chronic anemia may result in behavioral disturbances in children and reduced scholastic performance in school-going children.
In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The patient may then have symptoms such as palpitations, angina, and heart failure.
On examination, the signs include pallor of skin, conjunctiva and nail beds.
Causes and Types of PRCA
Pure red cell aplasia is characterized by maturation arrest in the formation of erythrocytes. Erythroblasts which give rise to RBCs are almost totally absent in bone marrow.
There are two types of PRCA:
Acquired Pure Red Cell Aplasia
It is the most common type of PRCA and usually affects adults.
It is further of two types:
Primary (or idiopathic)
- Primary autoimmune PRCA (includes transient erythroblastopenia of childhood)
- Primary myelodysplastic PRCA
Secondary (to underlying disorders)
- Autoimmune disorders
- SLE
- Thyroiditis,
- Rheumatoid arthritis
- Sjögren syndrome
- Type 1 diabetes
- Thymoma
- Good syndrome (thymoma with combined B- and T-cell deficiency)
- Lymphoproliferative disorders
- Chronic lymphocytic leukemia
- T-cell large granular lymphocyte leukemia
- Hodgkin disease
- Non-Hodgkin lymphoma
- Multiple myeloma
- Other hematologic malignancies
- Chronic myeloid leukemia
- Chronic myelomonocytic leukemia
- Acute lymphocytic leukemia
- Solid tumors
- Gastric, breast, biliary, lung, thyroid cancer
- Renal cell carcinoma
- Carcinoma of an unknown primary site
- Infections
- B19 parvovirus
- Viral hepatitis
- Infectious mononucleosis
- Cytomegalovirus
- Drugs
- rhEpo-induced Epo antibody-associated PRCA
- Other drugs
- Miscellaneous conditions
- Pregnancy
- Renal failure
- Following ABO-mismatched marrow transplantation
It can be transient and reversible. PRCA which is secondary to infections or drugs is often reversible once the infection goes away or the drug is stopped. Transient erythroblastopenia of childhood (TEC) which occurs after viral infections is usually transient and self-limited.
Congenital (or Inherited) Pure Red Cell Aplasia (Diamond-Blackfan Anemia)
Diamond-Blackfan anemia is a rare congenital form of PRCA which is detected at birth or during the first two years of life. It is a life-long condition. Besides features of anemia, the patients may also have physical abnormalities or mental retardation.
Read more about Diamond-Blackfan syndrome
Investigations
Complete Blood Count
- Hemoglobin, hematocrit, RBC count: Reduced depending upon the severity
- White blood cell count and differential count: usually normal
- Platelets: usually normal
Reticulocyte Count
It is decreased.
The reticulocyte count is a measure of bone marrow activity. Low count indicates that the bone marrow is not producing enough RBCs.
ESR
It is usually elevated, sometimes to high values.
Peripheral Blood Film
A small sample of blood is checked under a microscope to look for abnormalities in blood cells. Anemia is usually of normocytic type although it may be macrocytic. WBC and platelet series are usually normal.
Bone Marrow Aspiration and Biopsy
PRCA shows a normocellular marrow. (This is in contrast to aplastic anemia which shows a hypocellular marrow).
Erythropoiesis is affected. The number of erythroid precursors is markedly reduced. WBCs and platelet series are unaffected unless there is an associated secondary hematological disorder like leukemia.
Giant proerythroblasts are characteristically seen in parvovirus infection.
Image Credit: hematology.org
Bone marrow can also help in diagnosing megaloblastosis and blood cancers.
A bone marrow biopsy can also be used to detect iron overload, which occurs as a complication in patients who are given multiple blood transfusions for treatment.
Bone Marrow Culture
It can help to diagnose bacterial including mycobacterial infections.
Iron studies (serum ferritin and transferrin saturation)
To diagnose iron overload in patients who have received multiple blood transfusions.
Serum vitamin B-12 and folate levels
To rule out megaloblastic anemia in those presenting with macrocytosis.
Flow cytometry
To diagnose blood cancers
Tests to detect infections
- Serological tests
- PCR
Tests to detect autoimmune disorders
- Antinuclear antibody test
- Quantitative immunoglobulin analysis
- Direct Coombs test to detect autoimmune hemolytic anemia
- Specific tests for thyroiditis, diabetes mellitus, rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus (SLE)
Cytogenetics
This is required if the following disorders are suspected
- Primary myelodysplastic PRCA
- Lymphoproliferative disorders
- Chronic myeloid leukemia
Tests for diagnosing Diamond-Blackfan syndrome
- Adenosine deaminase determination
- Genetic testing
Liver function tests
Kidney function tests
Chest X-ray
To detect infections
Computed tomography (CT) or magnetic resonance imaging (MRI) scan
- To rule out thymoma or lymphoid neoplasms
- Appropriate imaging for congenital anomalies associated with Diamond blackfan anemia.
- MRI of the marrow of the axial skeleton can give a better assessment of bone marrow cellularity. (PRCA may have patchy areas of hypercellularity in the bone marrow; so bone marrow aspiration and biopsy may give misleading results)
The characteristic features of PRCA include the following:
- Severe anemia
- Reticulocyte count <1%
- Red blood cells may be normocytic or macrocytic
- < 0.5% mature erythroblasts in the bone marrow
- Normocellular bone marrow in most cases
Treatment for PRCA
The treatment goal is to restore red blood cell production and to treat any underlying disorder. The most common treatments are:
Treat the underlying cause
The main treatment of secondary PRCA is treating the underlying cause.
Drugs causing PRCA should be discontinued.
Parvovirus B19 infections may require treatment with high-dose intravenous immunoglobins. PRCA due to drugs or infections is usually reversible within a few months.
Hematological malignancies or solid tumors should be treated appropriately with surgery, chemotherapy or radiation.
Thymoma-associated PCRA should be treated with surgical removal of the thymoma.
Blood Transfusions
It is indicated in cases of severe anemia or those having cardio-respiratory symptoms. Patients who don’t respond to other treatments may require blood transfusions on a regular basis.
Iron chelation therapy
It is considered in patients who have had multiple blood transfusions and have evidence of iron overload.
Plasmapheresis
It can be used to remove autoantibodies in case of autoimmune associated PRCA.
Corticosteroids
They are indicated in idiopathic PRCA as well as in secondary PRCA due to autoimmune disorders. Prednisone is the most commonly used steroid. About half of the patients show a positive response within 4-6 weeks. Corticosteroids, however, can have severe side effects when given in high doses (as required for the treatment of PRCA). Also, they have to be used judiciously in children as they can cause growth retardation.
Read more about Side Effects of Corticosteroid Therapy
Immunosuppressive therapy
They also have a role in idiopathic and autoimmune PRCA if the patient is not responding to corticosteroids. Drugs used are cyclophosphamide, cyclosporine, azathioprine with or without corticosteroids. Other medicines used are anti-thymocyte globulin or rituximab.
Stem cell transplantation
Autologous and nonmyeloablative allogeneic peripheral stem cell transplantation can be carried out in patients who are not responding to other treatments.
Prognosis or Outlook
The prognosis of patients with idiopathic PRCA is poor with patients surviving for about 1-2 decades.
The prognosis of secondary PRCA depends on the underlying cause. Most of these conditions result in transient pure red cell aplasia which gets reversed once the causative factor is removed or treated.
Diamond blackfan anemia is a life long condition. With treatment, many children survive into adulthood.
References
- Young NS. Pure Red Cell Aplasia. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri MA, eds. Williams Hematology. 9th ed. New York, NY: McGraw-Hill Education; 2016. 539-48.
- Hirokawa M, Sawada K, Fujishima N, et al; PRCA Collaborative Study Group. Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group.Br J Haematol. 2015;169 (6): 879-886.
- Ruggero D, Shimamura A.Marrow failure: a window into ribosome biology. Blood.2014;124(18):2784-2792.
- Hoffman R, Benz EJ, Silberstein LE, Heslop H, Weitz J, Anastasi J. Biology of Erythropoiesis, Erythroid Differentiation, and Maturation. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Churchill Livingstone; 2013.
- Sawada K, Fujishima N, Hirokawa M. Acquired pure red cell aplasia: updated review of treatment. Br J Haematol.2008;142(4): 505-514.
