Definition of pure red cell aplasia (PRCA)

Pure red cell aplasia (PRCA) was first described in 1922 by the Czech physician Paul Kaznelson.^1,2 As the name suggests, PRCA is characterised by lacking red blood cells (anaemia).³ The number of almost fully matured and fully matured red blood cells (reticulocytes⁴ and erythrocytes,⁵ respectively) found in the blood and the number of red blood cell precursors in the bone marrow is severely diminished. In almost all PRCAs, the few mature red blood cells that remain have a normal size (normocytic) and display the usual red colour (normochromic).^1,2 Mature red blood cells are vital as they normally carry oxygen and deliver it from the lungs to the rest of the body.⁵

Interestingly, PRCA only affects the red blood cells. The two other main groups of cells found in the blood are the white blood cells (leucocytes, cells of the immune system protecting the body against threats such as viruses and bacteria)⁶ and the platelets (thrombocytes, form blood clots at wounds to stop the bleeding)⁷ are not affected.^1,2

Types of pure red cell aplasia (PRCA)

Congenital PRCA

This type of PRCA, also referred to as Diamond-Blackfan anaemia (DBA),⁸ is slightly different to the forms of PRCA which are acquired over one’s lifetime. DBA is present from birth (congenital),⁹ and the small number of mature blood cells still present is bigger than normal (macrocytosis).¹⁰ Unfortunately, the newborn child often suffers from other health-related, sometimes serious, problems due to DBA. 

The cause of DBA is mutations in certain genes, which provide some of the building blocks for the cell's protein manufacturing machines (ribosomes).¹¹ The gene mutations lead to the construction of malfunctioning ribosomes, which ultimately results in the death of the majority of the red blood cell precursors, causing DBA.⁸

Primary PRCAs

Primary PRCAs are acquired over time (they are not present at birth), and they develop as a direct result of a biological dysfunction in the human body.¹² They are mostly found in adults but sometimes also in children. So far, two primary PRCAs have been found and characterised, namely primary autoimmune PRCA and primary myelodysplastic PRCA.¹³

1. Primary autoimmune PRCA: Autoimmunity means that the white blood cells of the immune system (leukocytes⁶) start mistakenly targeting and destroying healthy cells of the body instead of e.g. infected cells or harmful organisms such as viruses and bacteria.¹⁴ In the case of primary autoimmune PRCA, the autoimmunity specifically targets the red blood cell precursors, thereby disrupting the generation of red blood cells (erythropoiesis).¹⁵,¹⁶ Therefore, suppressing the immune system by administering specialised drugs eliminates this particular brand of PRCA^17,18
2. Primary myelodysplastic PRCA: With this PRCA, genetic mutations in certain immature red blood cell precursors in the bone marrow cause them to malfunction. These malfunctioning immature red blood cell precursors then start to engage in uncontrolled and unwanted multiplication without ever maturing. Therefore, they never become the much-needed mature red blood cells. This leaves a small number of healthy immature red blood cell precursors to try and make up for it, albeit with only very limited success¹³

Secondary PRCAs

Secondary¹² PRCAs are also defined as acquired since they take time to develop and are therefore not present at birth. They are the indirect side effects of other illnesses or conditions.¹³ The number of conditions or illnesses that indirectly give rise to secondary PRCAs is vast. Secondary PRCAs can be caused by:¹³

1. Certain autoimmune disorders whose targets are unrelated to the red blood cell precursors (e.g. systemic lupus erythematosus)¹⁴
2. Some blood cancers such as certain leukaemias and lymphomas
3. Certain infectious diseases, e.g., the Epstein-Barr virus or viral hepatitis
4. Conditions such as suboptimal stem cell transplantation or pregnancy
5. Certain drugs, e.g. some anti-seizure medicines
6. Thymoma

In this article, particular emphasis will be placed on the secondary PRCA caused by thymoma. Thymoma is the non-blood tumour type that is most commonly associated with PRCA.¹³

Thymus and T cells

As the name suggests, thymomas develop in and from the thymus.¹⁹

The thymus is a small organ located behind your breastbone. Its main task is to create a specific set of white blood cells called T lymphocytes or T cells (or T-cells).²⁰ A very important aspect of their development is testing if they can distinguish between foreign (viruses, bacteria, cancer cells, etc.) and self (healthy body cells). It is ensured that T cells only attack the foreign and not the self.²¹

T cells are an important part of the immune system, destroying virus or bacteria-infected cells and cancer cells (cytotoxic T-cells) or supporting and regulating the immune response (helper T-cells and regulatory T cells, respectively).²¹

Thymoma

Thymomas are benign (non-aggressive) tumours derived from the thymus's surface cells (epithelial cells). Being benign, thymomas tend to grow at a slow rate, and they normally do not expand beyond the thymus.¹⁹ Thymomas often cause autoimmune disorders/conditions,¹⁴ such as myasthenia gravis^22,23 and PRCA.¹³ Given that one of the important functions of the thymus is to make sure T cells know the difference between foreign threats and harmless body cells,²¹ dysregulation of this mechanism by a thymoma is likely to result in autoimmunity.¹⁴

Thymoma-associated PRCA

The secondary PRCA brought on by a thymoma is called thymoma-associated PRCA. Because it is caused by a neoplasm (tumour), a thymoma-associated PRCA qualifies as a paraneoplastic syndrome. Paraneoplastic syndromes are disorders which occur due to a tumour’s indirect influence on the body (‘unintentional’, so to speak) and not due to the tumour mass itself.²⁴

Thymoma-associated PRCA is believed to be the result of autoimmunity.^13,14 More specifically, it is hypothesised that T cells, presumably influenced by the thymoma, inhibit the maturation of red blood cell precursors in the bone marrow via an unknown mechanism.^13,25 This causes the lack of red blood cells (anaemia) and the other typical aspects of a PRCA.³ 2 - 5% of patients with a thymoma also suffer from thymoma-associated PRCA. Additionally, 7 - 20% of people with PRCA have a thymoma.^13,26

Symptoms of thymoma-associated pure red cell aplasia (PRCA)

The majority of patients do not experience any symptoms when they are made aware of their thymoma for the first time.²⁷ As soon as a thymoma starts causing problems, various symptoms may occur.

Symptoms due to the tumour mass of the thymoma can include:^19,27

• Persistent cough
• Swelling in face and neck
• Difficulty swallowing
• Pressure or pain in your chest
• Difficulty breathing/being short of breath
• Swelling in arms and hands

Symptoms due to the PRCA may include:²⁸

• Extreme exhaustion
• Dizziness
• Headaches
• Difficulty breathing
• Chest pain that keeps appearing and disappearing (angina)²⁹
• Unusually pale skin
• Hearing unexplainable noises in your ear, often synchronised with your heartbeat (pulsatile tinnitus)³⁰

Since a thymoma can also give rise to other conditions and paraneoplastic syndromes²⁴ aside from PRCA, a myriad of other symptoms are possible as well.¹⁹

Diagnosis of thymoma-associated pure red cell aplasia (PRCA)

PRCA diagnosis

If a PRCA is suspected, the first step is to draw some of the patient’s blood and look for an extremely low number of reticulocytes (almost fully mature red blood cells)⁴, paired with a normal number of white blood cells and platelets (the typical characteristics of PRCA). Discovering these in the patient’s blood makes a PRCA diagnosis very likely.¹³

Next, some other illnesses will need to be ruled out. These illnesses are unlikely to cause these PRCA typical blood counts, but they are checked for anyway as a precaution.¹³

After ruling out these other illnesses, the final step is collecting and examining some of the patient’s bone marrow. Finding an almost complete or complete lack of red blood cell precursors in the bone marrow confirms that the patient has PRCA. The only thing left to be determined is what causes it.¹³

Thymoma diagnosis

A thymoma might be responsible for the diagnosed PRCA, so the healthcare professionals are likely going to look for one just in case. A CT scan of the chest is the most common procedure used to check for a thymoma. Finding a thymoma in combination with PRCA will confirm the thymoma-associated PRCA diagnosis.¹³

A CT scan involves taking a great number of X-ray images from different angles. A computer then uses these images to construct a detailed 3D image of blood vessels, bones and soft tissue (a thymoma, for example, if one is present). In some cases, a dye (contrasting medium) might have to be injected into the patient or drunk by the patient to provide a clearer image.³¹

It is worth pointing out that in some cases, the thymoma may be found first, and in other cases, the thymoma-associated PRCA can appear years after the thymoma diagnosis.³²

Treatment of thymoma-associated pure red cell aplasia (PRCA)

The standard treatment for thymoma-associated PRCA is thymectomy (complete surgical removal of the thymus and thymoma)³³ followed by immunosuppression.³⁴ In this case, this refers to using drugs to deliberately suppress the immune system. The thymectomy ideally takes care of the thymoma. At the same time, the main target of the immunosuppression is the autoimmune¹⁴ T cells, which are believed to cause PRCA by inhibiting the maturation of the red blood cell precursors in the bone marrow.^13,25

For thymoma-associated PRCA, the immunosuppressant³⁵ of choice is cyclosporine because it excels at stopping autoimmune PRCA. Cyclosporine is sometimes used with other immunosuppressants (e.g. corticosteroids) to increase the probability of success even further. In the instances where cyclosporine is not effective (cyclosporine refractory),³⁶ or cannot be tolerated due to kidney problems (cyclosporine intolerant), other immunosuppressants or other drugs will need to be used.¹³

Prognosis of thymoma-associated PRCA

Patients treated for this condition with cyclosporine are extremely likely to get rid of their PRCA for good. In contrast, when treated with other immunosuppressants/drugs, the PRCA can return after a while.³⁷

Since thymoma-associated PRCA is relatively rare,³² it is very difficult to accurately estimate how long patients with this illness tend to live after receiving their diagnosis. One study suggests many people live for around 12 more years after diagnosis.³⁷

FAQ’s

Is pure red cell aplasia associated with thymoma?

The disorder is called thymoma-associated pure red cell aplasia (PRCA). About 7 - 20% of patients with PRCA have a thymoma. Furthermore, 2 - 5% of people with a thymoma are afflicted by thymoma-associated PRCA. 

What is the most common tumour associated with pure red cell aplasia?

In the past, the thymoma was believed to be the most common tumour associated with pure red cell aplasia (PRCA). Later on, that turned out to be false. Despite that, a significant number of people have both a thymoma and PRCA.

How does thymoma cause anaemia?

It is hypothesised that the thymoma causes certain immune cells called T cells to inhibit the maturation of the red blood cell precursors in the bone marrow. This results in a lack of mature red blood cells (anaemia). 

How do you treat thymoma and pure red cell aplasia?

When combined, it is called a thymoma-associated pure red cell aplasia (PRCA). In that case, the thymoma plus the rest of the thymus are surgically removed (= thymectomy), and the patient is given medication which suppresses the immune system to treat the PRCA.

Summary

Pure red cell aplasia (PRCA) is identified by the lack of oxygen-carrying red blood cells paired with normal numbers of white blood cells and platelets. PRCA can have numerous causes. One of them is a tumour of the thymus called thymoma, making it a thymoma-associated PRCA. Both the thymoma and the PRCA can have their own set of symptoms. The recommended treatment is the removal of the thymus and thymoma and suppression of the immune system using cyclosporine.