Thalassemia & the spleen

Thalassemia (thal-uh-SEE-me-uh) is an inherited (i.e. passed from parents to children) blood disorder affecting approximately 18.28 per 100,000 people worldwide,¹ with regional variations. It is caused by genetic mutations that disrupt the production of haemoglobin, an essential substance of red blood cells for the carriage of oxygen. Thalassemia can be categorised based on the part of haemoglobin affected (as alpha or beta thalassemia) or by the severity of the condition (as thalassemia major, intermedia or trait).²

The spleen plays a critical role in filtering old, damaged red blood cells³ and, therefore, is one of the most affected organs in thalassemia. In patients with thalassemia, the enlargement of the spleen (splenomegaly), which occurs due to a multitude of reasons, leads to various health issues and a poor prognosis. In such cases, surgical removal of the spleen (splenectomy) may be considered as a treatment option, provided certain criteria are met.⁴

This article explores the role of the spleen in thalassemia, the potential benefits and complications of splenectomy, and its role in improving patient outcomes.

How does thalassemia occur?

Each haemoglobin molecule has four subunits: two alpha-globin chains and two beta-globin chains, attached to a heme group.⁵ The information for the production of these chains is stored in genes, and mutations in these can lead to thalassemia.⁵

Alpha thalassemia occurs when mutations or deletions in the alpha-globin genes reduce the number of alpha chains which resulting in an excess of beta chains. In beta thalassemia, mutations in the beta-globin genes lead to reduced or absent beta chains, causing an excess of alpha chains.²

The excess chains precipitate inside red blood cells and result in cell damage and hemolysis.² The destruction of red blood cells leads to anaemia (low haemoglobin levels) and other clinical symptoms. 

What are the symptoms of thalassemia?

• Symptoms of anaemia
  • Excessive tiredness and weakness
  • Faintness and dizziness
  • Palpitations (fast, pounding heart)
  • Shortness of breath
  • Paleness
  • Jaundice (yellowish discolouration of skin and sclera)
• Enlarged spleen (splenomegaly)
• Poor appetite
• Bony deformities of the forehead and cheeks
• Delayed growth and puberty

The importance of the spleen in thalassemia

The spleen is a part of the lymphatic system and functions in filtering out unwanted material, including infectious particles and old red blood cells after their normal lifespan of 120 days.⁶ In thalassemia, red blood cells (RBCs) that pass through the spleen are often trapped because they are misshapen and damaged. This leads to increased premature destruction of red blood cells, and the iron released during this process tends to accumulate in the spleen, contributing to its enlargement (splenomegaly).⁷

Also, when haemoglobin levels are low, the body tries to increase red blood cell production. Blood cells are usually produced inside the spongy parts of the bone, called the bone marrow. However, in those with thalassemia patients, the bone marrow cannot meet this demand to produce red cells rapidly, and the spleen takes over blood cell production (also called extramedullary hematopoiesis), further contributing to splenomegaly.²

When the spleen is enlarged, it can store large amounts of blood and blood cells. Reduction of the number of circulating blood cells can result in a number of issues. As white blood cells are essential to fight invading infections, a decrease in their number makes thalassemic patients more vulnerable to infections (i.e. immunocompromised).⁸ Additionally, reduced red blood cells in circulation worsen anaemia, resulting in an increased need for blood transfusions.⁸

Moreover, an enlarged spleen is more susceptible to rupture, which can result in life-threatening bleeding.⁹ 

Indications for Splenectomy in Thalassemias

Splenectomy is the surgical removal of the spleen, often required for patients with thalassemia major, typically performed after the age of 5 years.⁸ With optimal management of the condition through adequate blood transfusions and iron chelation therapy, the need for splenectomy can be delayed or reduced.⁷

Indications for splenectomy in thalassemia include:⁸

• Increased blood transfusion requirements of more than 200-220 mL of red blood cells per kilogram per year
• Persistent iron overload (increased iron stores) despite optimal iron chelation therapy
• Leucopenia (low white cell count) or thrombocytopenia (low platelet count) resulting in recurrent bacterial infections or bleeding complications
• Symptomatic splenomegaly with left upper abdominal pain or early satiety

However, splenomegaly without an increased need for transfusions or splenomegaly due to inadequate transfusion therapy is generally not an indication for splenectomies.

Splenectomy: preparation and procedure

Pre-procedure considerations

After careful selection of candidates for splenectomy based on the indications discussed above, it is essential to carry out a thorough evaluation to minimise postoperative complications:¹⁰

• Blood tests - to check for the haemoglobin level and platelet number. Blood transfusions are administered to achieve a target haemoglobin and platelet count if required⁷
• Vaccinations - to reduce the risk of post-splenectomy sepsis, pneumococcal, meningococcal, influenza, and Haemophilus influenzae vaccines are given at least 2 weeks prior to the surgery¹⁰
• Ultrasound scan of the abdomen - this is performed to identify the presence of gallstones. If gallstones are present, removal of the gallbladder (cholecystectomy) will also be done at the same time⁸
• Additionally, the appendix may be removed (to prevent confusion in differentiating appendicitis and enterocolitis in the future), and liver biopsies may also be taken to evaluate iron concentration, during the procedure⁸

Surgical procedure

The two commonly used surgical techniques for total splenectomy are the open and laparoscopic approaches.⁸

Open technique:¹⁰

This involves making an incision on the left side of the abdomen just beneath the rib cage (left subcostal incision) or the middle of the abdomen (midline incision). Surgery via open technique is less time-consuming and favourable for those with larger spleens when compared to laparoscopy. This approach is beneficial when the removal of other structures (i.e. gallbladder or appendix) is attempted concurrently.

Laparoscopic technique:¹⁰

This requires only a few small incisions to introduce ports for the surgical instruments. It has a number of advantages, with fewer complications during and immediately after surgery, such as reduced blood loss, shorter hospital stay, faster recovery, less pain, and better cosmetic effects. 

In some centres partial splenectomy, which involves the removal of only a part of the spleen with the aim of preserving some tissue for immune function, is offered. However, the long-term outcomes of this procedure remain unclear.⁸

Outcomes of splenectomy: benefits and complications

Benefits of splenectomy in thalassemia

Following splenectomy, patients with thalassemia experience benefits which include,¹¹

• Rise in red blood cell count, haemoglobin level and hematocrit (percentage of red cells), white cell and platelet counts
• Reduced need for iron chelation therapy 
• Alleviate symptoms of hypersplenism, such as abdominal pain and poor appetite
• Eliminated the risk of splenic rupture
• Reduction in the frequency of blood transfusions and therefore subsequent complications
• Reduction in hospital visits, improved school and work attendance, and performance

Complications of splenectomy in thalassemia

Splenectomy can result in complications that can occur during surgery or later on.¹⁰

Complications that may occur during surgery include:

• Bleeding due to damage to blood vessels supplying the spleen 
• Splenic rupture
• Damage to the surrounding organs, such as the stomach, colon, and pancreas

Complications after surgery include:

• Infections (Overwhelming Post-Splenectomy Infections - OPSI)
  • This is the most feared complication, which often occurs due to infections caused by encapsulated organisms such as Streptococcus pneumoniae (in 75% of patients), Haemophilus influenzae, and Neisseria meningitidis¹⁰ 
  • The risk is highest in children under 2 years of age and in the first 4 years following the surgery⁸ 
  • Sudden onset of fever and chills can quickly progress into multi-organ failure¹⁰
  • Vaccination against common bacteria 2 weeks before surgery, followed by periodic vaccinations, and prophylactic antibiotics, helps mitigate this risk¹⁰
• Venous thromboembolism (VTE) -
  • Patients with thalassemia have an inherent tendency to form blood clots and experience a postoperative rise in platelets (thrombocytosis). Both these factors can lead to abnormal blood clot formation in veins. Low-dose aspirin and anticoagulants are used to manage this risk⁸
• Abscess formation within the abdomen
• Pancreatitis(inflammation of the pancreas)
• Abdominal wall hernias at sites of incision
• Cancer

Alternative management strategies

Splenectomies carry significant long-term consequences¹⁰ and therefore, much attention has been given to other methods of management of splenomegaly. These are based either on medical management or interventional radiological procedures.

Medical management¹²

The goal is to prevent the occurrence of splenomegaly and hypersplenism by suppressing red cell production in the spleen. 

This is achieved by:

• Optimum blood transfusion to maintain adequate pre-transfusion haemoglobin levels (>9g/dL) and iron chelation therapy
• Hydroxyurea to decrease red cell production in the spleen¹³

Splenic artery embolization¹²

A coil or other device is used to occlude the splenic artery or its branches to reduce its size. Compared to surgery, this procedure is less invasive however, it has not gained wide popularity.   

What does the future hold?

Scientific advancements in the past decades, with attention to personalised medicine, have provided the opportunity for patients with thalassemia to be treated with life-changing therapeutic modalities.

• In 2024, the US Food and Drug Administration (FDA) gave the green light to a potentially curative, single-dose gene therapy, Casgevy. It is formulated with gene-editing CRISPR technology and works by editing a gene in the bone marrow stem cells such that they are able to make functional hemoglobin¹⁴
• Clinical trials are also underway to test new drugs to cure anaemia by improving red cell health and function. One such drug, Mitapivat, currently used in patients with a different type of hemolytic anaemia called pyruvate kinase deficiency, is in phase 3 trials in thalassemia patients¹⁵
• Scientists have also begun researching the manufacture of drugs that imitate hormones (i.e. hepcidin) within the body that may control and therefore limit iron uptake in thalassemic patients¹⁶

All of these new breakthroughs would make the patient not require future blood transfusions, other medical managements, let alone splenectomy.

Summary

• Thalassemia is an inherited condition resulting in abnormal haemoglobin production (anaemia)
• Spleen plays a crucial role in the disruption of old and damaged red cells and, therefore, is at the centre of the pathogenesis of clinical features of thalassemia
• Splenectomy is a treatment option in a selected population of patients who experience higher blood transfusion requirements, persistent iron overload, reduced white blood cells and platelets, and symptoms due to the enlarged spleen
• An open or laparoscopic approach for splenectomy can be taken depending on the individual circumstances
• Splenectomy results in improved haemoglobin levels, reduced iron loads and fewer symptoms due to hypersplenism while also reducing the need for frequent blood transfusions
• Post-splenectomy sepsis caused by encapsulated bacteria is the most dreaded complication, but can be prevented by pre-surgical and post-surgical periodic vaccination and antibiotic prophylaxis
• Optimum medical management with blood transfusions and splenic artery embolisation can be performed in place of splenectomy
• Novel gene therapies and compounds are under investigation as treatments for thalassemia, which might completely take away the place of splenectomy as a therapeutic option