The chances that myelodysplastic syndrome (MDS) with pure red cell aplasia (PRCA) will occur is rare but never zero. These prominent haematologic disorders, characterised by the abnormal maturation and production of red blood cells,  cause anaemia and other complications. At times, symptoms overlap or co-exist together, usually when PRCA presents itself as a secondary complication of MDS. This article aims to provide a comprehensive review of the two conditions: their pathogenesis, clinical manifestations, diagnostic approaches, and potential management strategies. 

Introduction

Anaemia

Anaemia is a condition in which the number of red blood cells (RBCs) within an individual’s blood displays a decline (sometimes sharp) in volume and proportion of packed RBC and haemoglobin.¹ The critical functions of RBCs are to facilitate the spread of oxygen from the lungs to different bodily tissues and to bring back impure carbon dioxide to be released by the lungs. Haemoglobin transports these gases within the blood. A decrease in RBCs in the blood makes this transport inefficient and reduces the body’s ability to perform efficient gas exchange. There are various subtypes of anaemia: haemolytic, aplastic, iron- or vitamin-deficiency, microcytic, or normocytic normochromic, just to name a few. 

What is pure red cell aplasia?

Pure red cell aplasia is characterised by the onset of normocytic normochromic anaemia with a marked reduction in bone marrow erythroid precursors (cells that develop into RBCs) and severe reticulocytopenia (decreased RBC precursor cells).¹ A congenital – present since birth – form of PRCA known as Diamond-Blackfan anaemia disrupts the production of red blood cells and affects the bone marrow. Primary acquired PRCA is an autoimmune disorder that disrupts the differentiation of erythroid precursors. Myelodysplastic primary acquired PRCA is a less common presentation of myelodysplastic syndrome presenting with erythroid hypoplasia, a decrease in erythroid precursor cells.²

How do myelodysplastic syndromes correlate with PRCA?

Myelodysplastic syndromes are a category of blood cancers originating in the bone marrow, where blood cells do not mature properly, leading to the inability to form healthy blood cells. Several blood disorders are classified in this syndrome, mainly characterised by the immature or improper maturation of haematopoietic stem cells and ineffective haematopoiesis in the bone marrow. There is an increased risk of this condition further progressing to acute myeloid leukaemia.³

In most instances, PRCA usually arises because of immune-mediated suppression of erythroid progenitors.² There have been a few reports of PRCA occurring concurrently with MDS, although it is unclear if PRCA is a manifestation of bone marrow clonal changes or originates from an autoimmune source.⁴

Pathogenesis

Pathogenesis of PRCA

PRCA can be classified as congenital or acquired based on the underlying mechanism and timing.⁵

Congenital

• Diamond-Blackfan anaemia (DBA): Caused by a translocation mutation between chromosome X and 19This condition affects the ribosomal genes, and most (55 - 60%) cases are sporadic and not inherited
• Parvovirus B19 infection: Parvovirus B19  has an affinity for progenitor erythroid cells and increases the concentration of the virus in the blood. This halts the process of RBC production and leads to a transient aplastic crisis causing anaemia^6,7
• Transient erythroblastopenia of childhood (TEC): This is not very well understood; it is usually due to infection with Parvovirus B19. The virus is not always the cause of TEC in children, but both T-cell and IgG (humoral)-mediated mechanisms seem to play a role in the development of TEC⁵

Acquired

• Autoimmune disorders: Often, patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), autoimmune haemolytic anaemia, myasthenia gravis, and other autoimmune disorders display PRCA-like pathophysiology due to immune-mediated erythropoietic failure⁵.
• Erythropoietin (EPO) associated antibodies: Around 2011, there was a change in the formulation of a particular epoetin alfa product given to patients undergoing renal dialysis. There was a strong link between the antibodies generated when the EPO was given and the onset of PRCA in an individual. After a change in formulation, cases of EPO-associated antibody PRCA have become rarer⁵.
• Persistent Parvovirus B19 infection: Patients with a compromised immune system, either due to chemotherapy or immunosuppressive drugs, cannot mount an antibody response when infected with Parvovirus B19. This immunodeficiency leads to persistent infection and is considered to be toxic During pregnancy, PRCA can even prove fatal to foetuses in the mid-trimester due to transmission of the virus from the mother⁵.

Pathogenesis of MDS

MDS is a broad category of syndromes and can occur due to various mutations and abnormalities⁸. Some of these causes include:

• Anaemia:  Improperly formed RBCs originate from malformed haematopoietic stem cells. These mature into defective cells and undergo apoptosis during differentiation. This “ineffective hematopoiesis” is noted in patients with MDS and is typically present with underlying peripheral cytopenia.⁹ Most individuals afflicted with MDS display thrombocytopenia (low platelets), leukopenia with anaemia (low white blood cells and RBCs), or pancytopenia (low blood counts in all cells)
• Genetic mutations: Mutations in RNA splicing factors –-- i.e. SRSF2, U2AF1, SF3B1 –--play an important role in the pathogenesis of MDS and are one of the most common reasons for the development of MDS. Dysregulations in genes such as DNMT3A or TET2, associated with DNA methylation, can also be associated with MDS⁸
• Chromosomal abnormalities: Almost 50% of the patients express abnormalities in their chromosomes, including a deletion or loss of chromosome 7 or a loss of chromosome 5 when paired with a missing chromosome 7. A deletion of chromosome 5q - termed as 5q syndrome - is characterised by the occurrence of macrocytic anaemia⁸

Clinical manifestations

PRCA^5,9

• Onset of aplastic anaemia
• Fatigue
• Tinnitus
• Palpitations
• Dizziness
• Viral infections
• History of thymoma or thyroid cancer
• MDS

MDS³

• Fatigue
• Anaemia
• Bruising 
• Infections 
• Dizziness and weakness
• Cognitive impairment
• Angina
• Loss of appetite

In PRCA, other symptoms such as elevation in serum erythropoietin levels, reticulocytopenia, and absent or reduced erythroid precursors may be diagnosed from a bone marrow examination.

How are PRCA and MDS diagnosed?

There are no particular signs associated with PRCA. The most common way to detect it is via a full blood count followed by an examination of the bone marrow to test for the absence or depletion of erythroblasts. 

A skin exam can be performed to check for any erythema (reddened skin), infection in adults, or a rash in children associated with a parvovirus B19 infection. A systematic full-body exam should check for spleen, liver, or lymph node swelling. Although these symptoms do not provide a definite diagnosis of PRCA,  they can narrow down the differential diagnosis.⁵

A complete blood count should be performed if MDS is suspected. This can detect the type of anaemia or if another blood disorder is present. Following the standard blood count, a blood smear for dysplasia can be used to identify abnormalities within red and white blood cells as well as platelets. A bone marrow aspirate tests the marrow cell count and provides further cytological material for evaluation. Genetic testing for any genetic, morphological, or chromosomal abnormalities can be used to review the patient's unique genetic code. 

What are the treatment options?

In order to manage PRCA, the following treatments are usually used: immunosuppressive therapy (typically corticosteroids including prednisone), immunomodulatory agents, or intravenous immunoglobulin. Since bone marrow differentiation is abnormal and immunity is suppressed, immune system complications are common. Therefore, steroids are the first treatment choice for PRCA.^5,11

When managing MDS, erythropoiesis-stimulating agents, hypomethylating agents (which enhance cell maturation), and red blood cell transfusions are recommended. In some cases, an allogeneic stem cell transplant may be recommended for eligible patients,  especially in the case of AML development.³

Summary

To conclude, recent studies have shown there could be a potential link between PRCA and MDS. In rare cases, PRCA develops as a secondary complication of MDS. Much of the clinical and diagnostic testing is shared between these two distinct diagnoses, suggesting there is a shared connection. Early and adequate treatment is necessary to prevent worst-case scenarios such as AML.³

FAQs

1. What is the difference between aplastic anaemia and pure red cell aplasia?

Both disorders of haematopoiesis,  pure red cell aplasia (PRCA) and aplastic anaemia, differ in their underlying pathophysiology and clinical features. Aplastic anaemia is characterised by a failure of the bone marrow to produce an adequate number of all blood cell types, resulting in pancytopenia (low levels of red blood cells, white blood cells, and platelets). In contrast, PRCA is characterised by a specific red blood cell production deficiency in the bone marrow, leading to severe anaemia, while other blood cell types remain relatively unaffected.⁵

2. What is myelodysplastic syndrome associated with?

Myelodysplastic syndrome (MDS) is associated with abnormalities in the bone marrow, where the production of normal blood cells is disrupted. This can lead to low levels of red blood cells, white blood cells, and platelets in the bloodstream. MDS is often characterised by ineffective hematopoiesis (impaired blood cell production), resulting in cytopenias and an increased risk of developing acute myeloid leukaemia (AML).³

3. What is the difference between aplastic anaemia and myelodysplastic syndrome?

Disorders of the bone marrow, such as myelodysplastic syndrome (MDS) and  aplastic anaemia, differ in underlying causes and clinical manifestations. Aplastic anaemia is a failure of the bone marrow to produce adequate blood cells, leading to pancytopenia (low levels of red blood cells, white blood cells, and platelets). In contrast, MDS is characterised by dysplastic changes in the bone marrow and impaired production of blood cells, which results in cytopenias and an increased risk of leukaemia.³

4. What type of anaemia is associated with myelodysplastic syndrome?

Myelodysplastic syndrome (MDS) is associated with various types of anaemia, macrocytic, normocytic, and microcytic. The specific type of anaemia observed in MDS may vary depending on the underlying pathology and the stage of the disease.³

5. What is pure red cell aplasia associated with?

Pure red cell aplasia (PRCA) is a specific red blood cell production deficiency in the bone marrow, leading to severe anaemia. PRCA can be a primary condition or secondary to other underlying disorders, such as autoimmune diseases, viral infections (e.g., parvovirus B19), or exposure to certain medications or toxins.

6. What is the life expectancy of someone with pure red cell aplasia?

The life expectancy of individuals with pure red cell aplasia (PRCA) can vary depending on multiple factors, including the underlying cause, severity, treatment response, and other comorbidities. Occasionally, PRCA may respond well to treatment or resolve entirely, allowing individuals to lead relatively normal lives. However, complications such as severe anaemia and associated health problems may shorten life expectancy in severe or refractory cases.⁵