Pure red cell aplasia (PRCA) is a rare, chronic blood disorder which consists of the body not producing a healthy number of red blood cells. These cells are essential to us, as they transport oxygen all around our body. In people who do not have enough red blood cells, such as PRCA patients, an insufficient amount of oxygen travels to their tissues and organs, in turn making them anaemic.¹ 

One of the possible treatments to manage the symptoms of PRCA is called erythropoietin (EPO) therapy. EPO is a hormone produced in our kidneys which are in charge of stimulating and maintaining the production of red blood cells. By administering EPO as a therapy to PRCA patients, the hope is that there will be a rise in the production of the essential red blood cells and as a result, their symptoms will be alleviated. However, this is not always the case, and in fact, sometimes EPO therapy can make the situation worse. This article will detail the causes, symptoms and diagnosis methods of PRCA, as well as the double-edged sword that EPO therapy plays in PRCA treatment.  

Understanding PRCA

The pathophysiology of PRCA

PRCA starts in the bone marrow. Bone marrow is the sponge-like centre of our bones which plays a crucial role in the production of our blood cells. Within the bone marrow, cells called erythroid precursor cells can be found. These precursor cells are a specific type of stem cell, which have the sole, important purpose of continuously producing only red blood cells (also known as erythrocytes). PRCA patients lack these erythroid precursor cells, and this results in a significant decrease in the production of erythrocytes and the delivery of oxygen around their bodies, ultimately leading to the manifestation of PRCA symptoms.¹  

What causes PRCA?

There are several different causes of PRCA:

• Genetic predisposition - Some people develop PRCA due to being genetically predisposed to the disease, due to inheriting certain harmful genes from one of their parents. An example of a group of people who are more prone to developing PRCA are those who inherit a type of anaemia called Diamond-Black anaemia. This is another rare blood disorder in which its patients have mutations in the genes responsible for helping the bone marrow produce the correct amount of blood cells. Due to these genetic changes, these patients are more likely to develop PRCA and suffer from the lack of red blood cells carrying oxygen around their bodies.²
• Blood cancers - These cancers affect how the body produces functioning blood cells. They typically start in the bone marrow, and hence can affect the development of red blood cells, leading to PRCA. Examples of types of blood cancers where PRCA commonly occurs include chronic lymphocytic leukaemia³ and granular lymphocytic leukaemia⁴ 
• Autoimmune diseases - Autoimmune diseases are conditions which are concerned with the immune system not working properly. The immune system is a group of organs and specialised cells which have the purpose of protecting the body from any harmful foreign substance such as bacteria and viruses. When someone has an autoimmune disease, their immune system is not functioning properly. Instead, its cells are attacking the body’s own healthy cells, such as bone marrow stem cells like erythroid precursors, instead of protecting them. Examples of autoimmune diseases which are linked to PRCA development include rheumatoid arthritis,⁵ systemic lupus erythematosus⁶ and Crohn’s disease⁷
• Thymomas - Also known as thymic carcinomas, these are solid tumours which occur in the thymus, and they are the most common cancer associated with PRCA. The thymus is part of the immune system, and hence, when cancer is found in the thymus, PRCA can occur in a similar manner as to how it develops in autoimmune diseases⁸ 
• Viruses - Infections from viruses can also lead to the development of PRCA. A particularly common virus associated with PRCA is the parvovirus B19, which is a virus which specifically attacks the stem cells of red blood cells found in the bone marrow.⁹ Other viral infections which can attack bone marrow stem cells and cause PRCA include hepatitis A,¹⁰ hepatitis C¹¹ and human immunodeficiency virus (HIV)¹² 
• Bacteria -  Infections from bacteria can also affect stem cells in the bone marrow and cause PRCA. A common example is tuberculosis. It is believed that this bacterial infection can lead to specialised immune cells which work to attack bone marrow cells involved in the production of red blood cells, which in turn can lead to PRCA.¹³ 

Common symptoms of PRCA

PRCA can lead to symptoms which are commonly associated with anaemia. These include:¹

• Being more tired than usual (also known as fatigue)
• Having difficulties in breathing (also known as dyspnea)
• Feeling dizzy
• Paler skin than usual
• Headaches

These symptoms all arise due to the lack of oxygen being delivered to the patient’s organs and tissues.¹

How is PRCA diagnosed? 

Diagnosis of PRCA is done via a physical examination to discuss symptoms, as well as various blood and imaging tests. The following tests can be used to diagnose PRCA:¹ 

• Complete blood count - Identifies the numbers of all types of cells found in the blood
• Reticulocyte count - Identifies the number of immature red blood cells (also known as reticulocytes) in the bone marrow 
• Peripheral blood smear - Identifies the numbers of red blood cells, as well as two other components of the blood known as white blood cells and platelets
• Bone marrow biopsy - This test consists of removing the marrow from inside the bone to assess its contents
• Bone marrow aspiration - Done at the same time as the biopsy, this test consists of using a thin needle to take a small amount of liquid from the bone marrow, to assess the blood cells in it
• CT scan
• Parvovirus B19 test - If the parvovirus B19 is suspected to be the cause of the PRCA, then a specific blood test will be done to determine this

For a patient to have a diagnosis of PRCA, their bone marrow must show little-to-none erythroid precursor cells. Moreover, they must have a significant decrease in their reticulocyte number.¹

EPO therapy in PRCA

EPO therapy was first assessed as a potential PRCA treatment roughly 30 years ago. This therapy involves administering the hormone to patients either through a subcutaneous injection or an intravenous infusion. 

The EPO therapy works in the following manner:¹⁴

1. In a PRCA patient, there will already be low levels of oxygen due to the lack of red blood cell production in the bone marrow. This deficiency of oxygen in the body is known as hypoxia
2. When EPO is injected, EPO will be stimulated by this hypoxia to travel to the bone marrow and promote the development of erythroid precursor cells 
3. This in turn will result in the precursor cells producing red blood cells
4. A surge in red blood cell production will allow more oxygen to be transported around the body 
5. The organs and cells getting the vital oxygen from these red blood cells they need will alleviate PRCA symptoms 

To assess whether this therapy is working effectively, the patient’s red blood cell count will be monitored, to make sure that their levels are increasing to a healthy amount.¹⁴ It is also important to monitor that the patient is not “overflowing” with red blood cells, as too many of these blood cells can lead to the development of other blood disorders. 

Promising results have been found with this therapy for patients who have PRCA associated with viral infections such as HIV¹⁵ and hepatitis C.¹⁶ These studies found that EPO therapy provided various advantages for PRCA patients:

• Many PRCA patients have to undergo regular blood transfusions to make up for the lack of red blood cells in their own blood and to alleviate their symptoms. However, with these regular transfusions comes its own set of risks, such as dyspnea and allergic reactions. EPO therapy can help reduce the number of blood transfusions they have to do
• EPO therapy can improve the quality of life of PRCA patients, as their anaemic symptoms will be significantly alleviated

Complications associated with EPO therapy

EPO therapy has not worked for all PRCA patients. In fact, in some cases, EPO administration has worsened the quality of life for some patients. Various studies have found that this therapy can result in the development of substances known as neutralising antibodies against EPO. These antibodies typically target foreign substances in the body and “neutralise” them, stopping them from having any effect.¹⁷ Hence, these antibodies being created against EPO means they will interact with the hormone being administered into the body, and will stop it from functioning. This results in no development of erythroid precursor cells and red blood cells, ultimately worsening PRCA symptoms due to the continued lack of oxygen around the body.¹⁸  

Moreover, EPO therapy itself can lead to the development of PRCA in some people. People who suffer from chronic kidney disease can also commonly be given EPO therapy as a treatment, as their natural EPO will not be produced due to their kidneys not working properly. However, administration of EPO therapy has often resulted in the development of PRCA. This is thought to occur due to the production of neutralising antibodies against EPO (described above). This type of PRCA is known as EPO-associated PRCA.¹⁸ 

How to tackle EPO-associated PRCA? 

To address EPO-associated PRCA, the following treatments can be used:¹⁹

• EPO therapy is discontinued - This is the first step taken, to prevent any further production of the neutralising antibodies. This will stop the worsening of the patient’s condition
• Immunosuppressive therapy - This type of therapy involves using medications to suppress the immune system, which neutralising antibodies are a part of. This will stop the production of such antibodies, and stop any existing ones from attacking any EPO found in the body. Examples of such immunosuppressants include the medications called Cyclosporine A and corticosteroids  

Summary

Pure red cell aplasia (PRCA) is a rare blood condition which results in the lack of red blood cells in a person’s blood, in turn leading to no oxygen being delivered to tissues and organs, making a person suffer from anaemia. PRCA can be caused by various reasons - from being genetically predisposed to it, to viral and bacterial infections, to more long-term illnesses such as certain blood cancers, thymomas, and autoimmune disorders. A treatment option to manage PRCA symptoms is known as erythropoietin (EPO) therapy, which involves administering the EPO hormone to the patient, with the hope that the hormone will stimulate the production of red blood cells. In some patients, such as those who develop PRCA due to viral infections, this therapy is successful in improving their quality of life. However, in other patients, this therapy leads to the worsening of symptoms, as their immune system can instead attack the EPO being administered to them. When this occurs, EPO therapy is not appropriate, and instead, immunotherapies are more suitable alternatives.