What is pure red cell aplasia?

Red blood cells (RBC) also called erythrocytes are the most common type of cells in the blood, as they carry and deliver oxygen from the lungs to the tissues. They are produced in the bone marrow by a process called erythropoiesis. Pure red cell aplasia (PRCA) is a rare blood disorder, defined by the significant reduction or absence of erythropoiesis in the bone marrow. It is characterised by severe normocytic normochromic anaemia, a type of anaemia where the reduced red blood cells are normal in size and colour, and reticulocytopenia (abnormal decrease in the red blood precursor cells called reticulocytes).¹ Reticulocytes are immature red blood cells that mature to develop into RBCs. This syndrome can be classified as congenital or acquired types. Acquired PRCA is more common in adults.

How common is PRCA in adults?

The acquired type is the most common manifestation in adults. It is a very rare disease with an estimated incidence of 1.06 cases per million annually.²

What are the causes of acquired PRCA?

Acquired PRCA may be primary or secondary in the presence of other clinical disorders. 

Primary Acquired PRCA

Primary PRCA may be an IgG (immunoglobin G, a type of antibody found in our blood) mediated autoimmune disorder (a condition where the body’s immune system mistakenly attacks and destroys its own healthy tissues) that inhibits erythropoiesis. Myelodysplastic syndromes are a group of cancers caused by the absence of red blood cell production. They sometimes present with a morphological appearance (shape, size, structure and pattern) of PRCA causing primary myelodysplastic PRCA.

Secondary Acquired PRCA

Several clinical conditions can cause secondary acquired PRCA, they include,

• Autoimmune/Collagen disorders: 

Conditions like systemic erythematous lupus (SLE), rheumatoid arthritis, inflammatory bowel syndrome (IBD), myasthenia gravis and thymoma (malignant tumour) are autoimmune/collagen disorders associated with the destruction of red blood cell precursors in the bone marrow. These disorders produce autoantibodies against the precursor cells that interfere with erythropoiesis.

• Drug-induced PRCA  

The adverse effects of certain medications like immunosuppressants (cyclosporine, azathioprine), antiepileptic drugs like phenytoin and erythropoiesis-stimulating agents like erythropoietin can cause PRCA by suppressing erythropoiesis or by triggering immune-mediated responses.

• Viral infections

 Some viral infections caused by Epstein Barr virus, parvovirus B19, hepatitis A, B, C and E, cytomegalovirus, and human immunodeficiency virus (HIV) have been linked with the development of PRCA directly by infecting the bone marrow cells or triggering immune-associated responses. Human B19-parvovirus-associated PRCA can trigger an aplastic crisis which can lead to chronic PRCA.³  

• Bacterial infections 

Tuberculosis, Bacterial sepsis and streptococcus (group C) infection have been associated with PRCA.

Toxins and chemicals: Exposure to certain toxins, chemicals and environmental factors like benzene, pesticides and halothane can disrupt the formation of the cellular components of the blood and can lead to PRCA.

• Idiopathic

 Rarely, the cause of PRCA remains unidentified and the condition is classified as idiopathic

• Other causes 

In some cases, PRCA can be associated with lymphoproliferative cancers like leukaemia, Hodgkin’s and non-Hodgkin’s lymphoma. Pregnancy can also be associated with PRCA and mostly resolves after the birth of the child.⁴ Blood group ABO-incompatible stem cell transplantations have been commonly linked with PRCA after transplantation. Rarely, PRCA is also associated with riboflavin deficiency.

What are the signs and symptoms of acquired PRCA?

The most significant sign of PRCA is severe anaemia. Patients with PRCA may present with:

• Fatigue
• Dizziness
• Pallor (pale skin)
• Weakness
• Shortness of breath
• Chest pain
• Tachycardia (increase in heart rate)
• Palpitations (heart flutters)

In the case of secondary PRCA, the signs and symptoms could be related to the underlying clinical condition.

How is acquired PRCA diagnosed?

The diagnosis of PRCA requires a complete clinical evaluation of any relevant patient's past medical history and a thorough physical examination. Diagnostic investigations include:

• Complete blood count (CBC) 

All haematological parameters could be assessed through a CBC a, presentation with reduced red blood cell count, normal white blood cell, and platelet count could suggest PRCA. An increased erythropoietin level could support the diagnosis.

• Peripheral blood smear 

A peripheral blood smear could help identify the characteristic abnormalities including reticulocytopenia (reduced reticulocyte count) and erythroblastopenia (absence of erythroblasts). The reticulocyte count is always <1 % in cases of PRCA.⁵ 

• Bone marrow examination 

An examination of the bone marrow morphology is required to confirm the diagnosis of PRCA and rule out any other causes of anaemia. In PRCA, the bone marrow aspiration and biopsy could reveal a marked significant decrease or absence of erythroid precursor cells.

• Serological tests 

They are performed to detect any underlying auto-immune or viral infections. Tests such as an anti-nuclear antibody (ANA), anti-double-stranded DNA antibodies (anti-ds-DNA), HIV testing and parvovirus B19 serology may be considered based on the specific clinical suspicion.

What are the treatment options for patients with acquired PRCA?

The main aim of treatment in PRCA is to alleviate symptoms and restore red blood cell production. However, the precise treatment is to address and treat the underlying cause. Some of the treatment options include:

• Immunosuppressive therapy

 Most patients with PRCA require immunosuppressive therapy, especially in the case of auto-immune mediated acquired PRCA.  Immunosuppressive therapy suppresses the destruction of the erythroid precursor cells in the bone marrow required for the production of red blood cells. Corticosteroids like prednisolone are administered as the first line of treatment, they suppress autoantibody production and hence restore erythropoiesis. Cyclosporine, a calcineurin inhibitor drug is often used in combination with corticosteroids in case of refractory (not responding to any treatment) autoimmune PRCA. A drug called anti-thymocyte globulin is used in severe cases.

• Blood transfusion 

It plays a major role in managing symptomatic anaemia and alleviating symptoms associated with PRCA. It is preferable to long-term therapy of high-dose corticosteroids especially in refractory cases. A transfusion of packed red cells (PRBCs) provides immediate relief to anaemia-related symptoms and ensures adequate oxygenation. Precautions should be taken in case of frequent transfusions to prevent complications like iron overload and alloimmunization (immune response to foreign antigens.

• Haematopoietic stem cell transplantation (HSCT) 

 Allogenic haematopoietic stem cell transplantation may be considered in select cases of PRCA, particularly in severe or refractory cases and in patients with transfusion dependence. HSCT provides durable haemopoietic recovery and long-term remission by replacing the aberrant hematopoietic stem cells with healthy donor cells. However, HSCT is associated with significant risks like graft vs. host disease (GVHD) and transplantation-related mortality, so it requires careful patient selection and consideration of all alternate therapies.

• Treatment of underlying cause 

Autoimmune conditions like systemic erythematous lupus, and rheumatoid arthritis associated with PRCA are treated with immunosuppressive drugs. Viral infections are treated with anti-viral agents and bacterial infections with antibiotics. Thymoma-associated PRCA is treated with thymectomy (surgical removal of thymomas). Discontinuation of drugs in medication-induced PRCA and switching to alternative medications with low hematologic toxicity is necessary. Avoidance of toxin and chemical exposure in toxin/chemical-related PRCA is essential by implementing safety regulations and lifestyle modifications.

• Supportive care

It is necessary to have supportive care measures to manage acquired PRCA and optimise patient outcomes. Nutrition support measures to ensure adequate nutrition, hydration and iron supplementation are significant in supporting erythropoiesis and preventing nutritional disorders. Alleviating symptoms like fatigue, weakness and chest pain through appropriate pharmacological or non-pharmacological interventions can improve the patient's quality of life. Monitoring and surveillance measures with regular monitoring of haemoglobin count, reticulocyte count, and iron status are necessary to assess treatment response, detect complications and adjust the treatment accordingly.

What is the prognosis for PRCA?

In a Japanese study, the long-term follow-up results concluded the following insights on the prognosis of acquired PRCA.⁶  Patients with acquired PRCA have a good response to immunosuppressive therapy. However, they had a shorter lifespan compared to the general population. Cyclosporine administration was necessary to prevent relapses. The most common cause of death in acquired PRCA was due to infections and organ failure.

Summary

Pure red cell aplasia in adults is a very rare haematological condition, characterised by severe normocytic normochromic anaemia and the absence or selective deficiency of erythroid precursors in the bone marrow. While this condition can be challenging to diagnose and manage, early recognition and appropriate treatment are essential for improving outcomes and alleviating symptoms in patients. By understanding the causes, symptoms, diagnosis, and treatment options for PRCA, healthcare providers can provide a strategic treatment plan and support to patients with PRCA. Continued research into the underlying mechanisms of PRCA and the development of new targeted therapies can advance the management of this rare disorder.