Thalassemia

Research Led By; Maheerah Nisar

Writers:

Mohammad Ibrahim

Barirah Usman

Ibrahim Dar

Musfirah Naveed

Ayesha Irfan

Zahra

Thalassemia is an inherited blood disorder where the body cannot make enough healthy hemoglobin, the protein that carries oxygen. This can cause tiredness, weakness, and pale skin. The condition varies from mild to severe and is passed from parents to children through genes.

Treatments of Thalessemia include:

1. Blood transfusions

Blood transfusions are the most prominent and well-established treatment for β-thalassemia; 26,000 patients in need of transfusions are born every year.

Β-thalassemia leads to reduced production and premature disintegration of red blood cells, caused by insufficient beta globin chains, a protein that forms haemoglobin present in the red blood cell. Haemoglobin cannot carry out its function of binding with and transporting oxygen without being folded into its proper quaternary structure, which is formed using both alpha and beta globin chains.β-thalassemia is a result of an imbalance where available healthy alpha globin cannot be incorporated into usable haemoglobin because of inadequate corresponding beta globin.

The deficiency can be compensated for by relying on an external source: blood transfusion, where healthy RBCs are supplied to correct the anemia, helping maintain enough haemoglobin for optimal oxygen delivery to organs and tissues until the next transfusion. Frequency of visits depends on the clinical severity.

This genetic disease can be classified into 3 categories, which are determined by the genotype inherited from the biological parents. β-thalassemia major (BTM) patients require lifelong routine transfusions (typically every 2-4 weeks) because the donor's RBC lifespan is limited, while β-thalassemia intermedia (BTI) patients may only need occasional transfusions during stress events like pregnancy, infection or periods of rapid growth. Individuals with β-thalassemia minor (carriers), however, can function normally without any medical intervention despite having relatively smaller red blood cells.

Although it is a common and reliable therapy, there may be some complications such as an allergic reaction, where the recipient's immune system considers proteins in the donor's blood plasma as foreign, leading to mild symptoms such as rashes and flushing or severe ones like stridor, bronchospasms, or hypotension. This response can be suppressed with antihistamines and corticosteroids before initiating treatment.

Blood from non-remunerated donors is selected according to the patient's blood group. Pre-transfusion compatibility tests are conducted to ensure a haemolytic reaction does not occur when the blood groups don't match, which may cause fevers, chills, nausea and muscle pain from the immune system rejecting the blood.

Alloimmunization is a major concern for β-thalassemia major patients, as their immune system becomes oversensitive to minor antigens from repeated exposure to different blood from various donors. It learns to identify and destroy the introduced foreign cells, consequently compromising the efficiency of the therapy.

2. Iron Overload Treatment Importance of Iron chelation therapy: Excess iron in the body creates complications in Heart: Iron overload cardiomyopathy (IOC), which is a leading cause of morbidity and mortality in thalassemia patients. IOC results from the toxic effects of excess iron on cardiac myocytes, leading to oxidative stress, cellular damage, and heart dysfunction. Liver: During iron overload , excess iron builds up in the liver, causing inflammation, scarring (fibrosis), and potentially leading to cirrhosis (permanent liver damage), liver failure, and an increased risk of liver cancer (hepatocellular carcinoma) due to oxidative stress and tissue damage from the toxic iron deposits, with iron accumulation visible as granules in liver cells. Endocrine glands: Iron overload damages endocrine glands by depositing iron, causing oxidative stress and cellular dysfunction, leading to hormone deficiencies and serious issues like diabetes (pancreas), infertility (pituitary/gonads), hypothyroidism (pituitary/thyroid), growth failure (pituitary/GH), and osteoporosis (bone). Therefore Iron chelation therapy is very important inorder to avoid such complications. What is Iron chelation therapy?

Iron chelation therapy removes excess iron from the body using special drugs (chelators) that bind to iron, allowing it to be excreted via urine or feces, preventing organ damage (heart, liver, pancreas) caused by iron overload from conditions like frequent blood transfusions . The process involves administering chelating agents like deferoxamine , deferasirox , or deferiprone , either by injection (often overnight) or as oral tablets, to safely lower iron levels.

A chelating drug (e.g., Deferoxamine, Deferasirox) is given to the patient. The drug circulates in the bloodstream and binds tightly to excess iron, forming a stable complex. This iron-drug complex is then removed from the body, primarily through urine or feces. By removing iron, the therapy prevents it from building up in vital organs like the heart, liver, pancreas, and endocrine glands, which can lead to severe damage, heart failure, or irregular rhythms.

3. Hydroxyurea

Hydroxyurea: Hydroxyurea is a medication taken orally in the form of a capsule or liquid form used to mitigate the effects of thalassemia by stimulating the production of fetal hemoglobin (Hbf). It does this by promoting the formation of gamma chains which are components that make up fetal hemoglobin. It typically takes up to several months in order for its effects to be established and must be consistently consumed every day. By taking these specific precautions, it can reduce the iron-overload caused by thalassemia along with the need for blood transfusions. This overall improves the red blood cell health in patients.

Decitabine :Decitabine is a chemotherapy drug administered via an l.V line which functions as a DNA methyltransferase inhibiting agent. In the case of thalassemia, decitabine works by unmasking the γ1-globin gene, located on the 11th autosomal chromosome, which boosts fetal hemoglobin (HbF) production. These elevated fetal hemoglobin levels can rebalance the overall hemoglobin composition, alleviating the complications arising from thalassemia, and improving the oxygen-carrying capacity in red blood cells. Ultimately, this results in a better all-round blood health for patients.

Luspatercept: Luspatercept is a recently developed therapeutic agent used for treating thalassemia taken in the form of an injection. It works by binding to certain growth factors that contribute to thalassemia, preventing the maturation of red blood cells and reducing the impact of the disease. This ensures that more functional red blood cells are generated allowing for a higher quality of oxygen transportation in the patient and diminishing the effects of thalassemia.

4. Gene Therapy

The CRISPR/Cas9 technique is easily programmable, fast, more powerful, and efficient at generating a mutation compared to previous gene therapy methods. Studies have shown that the genome of β-thalassemia patients can be modified using the CRISPR/Cas9 technique, and this approach might be promising for the treatment of β-thalassemia.

CRISPR-based gene therapy, removes a patient’s own blood forming stem cells and edits them to produce healthy hemoglobin before being infused again into the patient.On the other hand, transfusion-dependent beta thalassemia requires consistent red blood cell transfusions to maintain adequate hemoglobin levels.

CRISPR/Cas9 technique is approved by more than 75 countries worldwide. Pakistan is using CRISPR-Cas9 for genome editing and genomic selection in agriculture for enhancements of plant productivity. There is no clear evidence of it being introduced for the treatment of β-thalassemia for now.

5. Stem Cell Transplant

Stem cells are basic cells produced in the bone marrow, the soft, blood-forming tissue found in large bones of the human body. They develop into highly specialized cells, such as red blood cells (RBCs), which contain hemoglobin and carry oxygen to body tissues essential for growth and development. A stem cell transplant (SCT) also called bone marrow transplant (BMT) is currently the only curative treatment with long term effects for β-thalassemia major. In a stem cell transplant, the patient’s diseased bone marrow is replaced with healthy stem cells from a donor, so the body can start making normal hemoglobin.

-TYPES OF TRANSPLANT:

1) Allogeneic transplant (from another person): effective option. Effective for major thalassemia but risks like GVHD and major infections.

2) Matched sibling donor (gold standard): best option with highest success rate of 90%.

3) Matched unrelated donor: risking option. Lower success rate and higher risk.

4) Haploidentical donor (parent): unpredictable. Newer techniques with improving outcomes, but limited donor registries and high cost make it less accessible in developing countries. -WHO NEEDS IT?

1)Mainly patients with Thalassemia Major 2)Those who are transfusion-dependent 3)Best results in: Children/young patients, patients with less iron overload, patients without severe liver or heart damage.

PROCEDURE

1)Comparability testing: After initial HLA compatibility is confirmed, a laboratory cross-match ensures the donor’s cells do not react with the recipient’s blood. If rejection occurs, the transplant is cancelled even if HLA matches.

2)Stem cell donation: Stem cells are typically collected from the donor’s pelvic bone but can also be obtained from the bloodstream using a needle, a less invasive method. In special cases, umbilical cord blood may be used, though the limited number of stem cells can affect transplant success.

3)Myeloablation: This pre-transplant treatment destroys the patient’s bone marrow to create space for donor cells to engraft. It is mainly achieved through chemotherapy; irradiation is rarely used and is no longer recommended for non-malignant conditions like thalassemia.

4)Transplantation: Donor stem cells are infused into the recipient’s bloodstream, similar to a blood transfusion. The cells migrate to the bone marrow, where they begin producing normal red blood cells, white blood cells, and platelets. Engraftment usually takes 2–3 weeks.

5)Cure: If successful, the donor’s stem cells with a normal β-globin gene take over the recipient’s bone marrow, producing healthy blood cells for life, effectively curing the patient of thalassemia.

-BENEFITS:

Cure from thalassemia No need for lifelong blood transfusions No iron chelation therapy afterward Replaces defective bone marrow with healthy stem cells, eliminating the disease. The bone marrow produces normal red blood cells, white cells, and platelets.

Long term survival rates especially in children with matched sibling donors.

-DRAWBACKS:

Graft-versus-host disease (GVHD) Infections (due to low immunity initially) Organ damage (from chemotherapy) Transplant failure Infertility (an important long-term issue) as Chemotherapy can affect reproductive health. Best outcomes require a matched sibling donor, which may not always be available.

6. Improving quality of Life

Effective management of beta thalassemia requires comprehensive medical care, a balanced diet with appropriate nutrient intake, mental health support, and daily condition management. Consuming a diet rich in essential nutrients while monitoring iron intake can improve overall health and energy levels (Nutrition | Northern California Comprehensive Thalassemia Center, 2024). Regular blood transfusions, iron chelation therapy, and routine medical checkups are also essential components of care (Transfusion Management of Beta (β) Thalassemia, 2023). Mental health support is critical, as ongoing treatment and lifestyle adjustments may contribute to stress, anxiety, or depression. Addressing both physical and psychological needs enables patients to maintain better health and activity levels.

7. Early Diagnosis

Early detection of beta thalassemia through effective screening methods is crucial for proper disease management and the reduction of long-term complications. Newborn screening, carrier testing, and prenatal screening allow timely intervention. They also support informed family planning. Public education and genetic counseling in high-risk groups can prevent severe cases. These measures also help ensure proper care. Emphasizing early detection, prevention, and ongoing management reduces the burden of beta thalassemia on individuals and healthcare systems.

Sources

https://www.sciencedirect.com/science/article/pii/S0268960X193009530

https://www.sciencedirect.com/science/article/pii/S0268960X23000991#:~:text=Despite%20the%20established%20genotype%2Dphenotype,trait/minor%20%5B34%5D.

https://www.ncbi.nlm.nih.gov/books/NBK614240/

https://europepmc.org/article/med/36403178

https://pmc.ncbi.nlm.nih.gov/articles/PMC6636870/#:~:text=A%20key%20driver%20of%20the,more%20than%2075%20countries%20worldwide

https://www.hematology.org/newsroom/press-releases/2025/gene-therapy-leads-to-improved-quality-of-life#:~:text=Transfusion%2Ddependent%20beta%20thalassemia%20requires,infused%20again%20into%20the%20patient

https://my.clevelandclinic.org/health/diseases/23574-beta-thalassemia

https://pmc.ncbi.nlm.nih.gov/articles/PMC3033168/

https://www.sciencedirect.com/science/article/abs/pii/S0146280624005462

https://en.wikipedia.org/wiki/Beta_thalassemia

https://my.clevelandclinic.org/health/diseases/23574-beta-thalassemia

https://rarediseases.org/rare-diseases/thalassemia-major/

https://www.nhs.uk/conditions/thalassaemia/

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