Category: HEALTH

Thalassemia Major: Causes, Symptoms and Treatment

Thalassemia is an inherited blood disorder in which the body does not make adequate amounts of hemoglobin, resulting in rapid breakdown of red blood cells. It is characterized by anemia, weakness and fatigue. This disorder has several types which vary in severity, out of which beta thalassemia major is the most common and clinically apparent type. It is diagnosed in children who have two defective genes for hemoglobin, a protein present inside red blood cells. The severity of the diagnosed type determines the management regimen, which usually involves regular blood transfusions and iron chelation therapy.[1]

Causes of Thalassemia

People get thalassemia by inheriting faulty hemoglobin genes from their parents, who may have the disorder or may be carriers. Cousin marriages are by far the leading risk factor for developing thalassemia.[2] The root cause of this disorder is mutations in the genes making the protein hemoglobin present inside red blood cells, which are responsible for oxygen transport in the body. As hemoglobin consists of two alpha and two beta globin subunits, mutations in the globin genes can reduce their production which creates an imbalance in the pairing of the globin chains. This results in early destruction of red blood cells. Commonly, beta thalassemia is more severe because only two mutated copies of beta globin gene can develop severe transfusion dependent thalassemia, but it takes at least three defective alpha globin genes to create a similar state. These more common forms are diagnosed as Beta thalassemia major

Major Symptoms

Beta Thalassemia Major often manifests a few months after birth and is characterized by anemia, lethargy, weakness, fatigue, dark urine, and a pale skin. With time, facial bone deformities, an enlarged abdomen, and an inability to do any strenuous physical activity are commonly noted. The patient may have a crew-cut appearance of the head and sometimes jaundice may occur. 


This condition requires management with regular blood transfusions and iron chelation therapy along with other supporting medicines under consultation of a hematologist.[1] Bone marrow transplant, from a close relative might end the necessity for blood transfusions, provided that cell marker genes match. The only lasting cure is stem cell transplant.[3] However, both transplant options have risks involved.

Patients also have weak immunity hence they should be timely vaccinated against prevalent infections.

In contrast, patients with thalassemia minor lead a normal life and can be easily managed with dietary restrictions on iron rich foods, timely vaccination and Vitamin B, Folic acid and calcium supplementation.

Outcome of Thalassemia

The prospects for a person with thalassemia minor are bright and most cases don’t need treatment when compared to thalassemia major. The outlook of thalassemia major has also improved drastically from earlier times, provided iron chelation is taken timely and iron deposition in the body organs, especially the heart, is averted.[2] This will lead to better quality of life for the affected ones.


As thalassemia is a genetic disorder, early diagnosis remains the mainstay for prevention. Premarital screening via Hb electrophoresis can help reduce the burden of thalassemia in a population. Cousin marriages must be averted because they lead to higher risk of inheritance of genetic disorders. Diagnosed carriers should avoid marriages with other carriers or they can opt to have offspring via in vitro fertilization with preimplantation genetic diagnosis to have children. Early diagnosis of thalassemia can also help in arranging an early bone marrow transplant to lessen the risk of iron deposition in the heart, which leads to heart failure.[2]   

Importance of premarital screening in the prevention of thalassemia in Pakistan.

With over 100,000 active patients and 5000 affected babies being born every year, thalassemia remains a common genetically inherited blood disorder in Pakistan.

The diagnosis of thalassemia is pretty simple. A Complete Blood Count (CBC), measuring the concentration of haemoglobin, size and number of Red Blood Cells is performed as an initial test, followed by Haemoglobin electrophoresis to confirm the diagnosis of this disorder. Unfortunately, the management process, including regular blood transfusions, iron chelation therapy, and consistent consultations with a haematologist, is expensive and most children do not receive the care they require.

What is premarital thalassemia screening?

Premarital thalassemia screening refers to the process of determining the presence of thalassemia carrier genes in both partners before they get married.

If both spouses are carriers, there is a considerable likelihood of the transfer of mutated genes to their offspring. Approximately, there is 25% chance of their offspring being thalassemia major, 50% chance of them being thalassemia minor (carriers of the disorder), and only 25% probability being normal.

The presence of a carrier gene in only one of the partners is considered safe as it produces progeny with a 50% chance of normal genes, and 50% of carrier genes. No thalassemia major child is born to such a couple.

Premarital screening reduces the rate of genetic disorders as prevalent as thalassemia.

The technique is seen to be 100% efficient in Cyprus where no child with thalassemia was born from 2002 to 2007 followed by a massive premarital screening


Why is premarital thalassemia screening important?

1. Helps identify asymptomatic carriers

Since it is a recessive gene disorder, thalassemia carriers are asymptomatic. In recessive gene disorders, both parents contain one mutated gene and the other normal one. One mutated gene coding for the disease is inherited by each parent.

This means that thalassemia carriers aren’t aware of the potential hazards that can happen if they mate with another carrier. Both carriers, asymptomatic, together have a considerably high probability of having children suffering from thalassemia.

2. Antenatal screening is sophisticated

Some parents choose to screen their genetics after a baby is conceived. Antenatal screening of thalassemia takes place within 19 weeks of pregnancy, through a blood test.

A positive result indicating that the mother is a thalassemia carrier is followed by paternal screening. In most cases when both parents are carriers, a further diagnostic test is suggested to confirm the presence of disease in the fetus.

1% of all diagnostic tests result in miscarriage. If the tests indicate that the fetus has thalassemia, an abortion is suggested.

Since the antenatal screening of thalassemia is sophisticated, and abortion is considered unethical by many, it is better to screen for thalassemia before marriage. It is much easier and more cost-effective compared to antenatal screening

3. Consanguineous marriages are common

Pakistan has one of the highest rates of cousin marriages in the world. With 49.6% of all women marrying their first cousins and 8.3% to their second cousins, the risk of birth defects in children is doubled.

Both parents share the same family history in consanguineous marriages, so the probability of recessive genes expressed in offspring increases. According to a 2004 study, 40.6% of beta-thalassemia cases are the outcome of cousin marriages.

In such circumstances, the need for premarital screening can not be stressed enough. The high prevalence of thalassemia in Pakistan can only be mitigated if potential spouses are screened for the disease, and provided genetic counseling if found to be carriers.

A mass awareness campaign and a subsequent screening premarital screening program can save Pakistan from such alarmingly high statistics of thalassemia patients.

The Need of Iron Chelation Therapy for Thalassemia Patients.

Iron chelation is a medical procedure used for the treatment of iron overload caused by excessive transfusions, or from birth1. Iron chelation therapy has been found to improve some symptoms of thalassemia.

Iron Chelation Therapy

This can be achieved by administering a chemical substance which binds to the iron and removes it from the body. Symptoms like fatigue, anemia and growth failure show improvement after administration/initiation of Iron chelation therapy. The most common form of chelation therapy is deferoxamine (DFO; a synthetic dimer of 2-picolinic acid). DFO works by binding to ferric ions (Fe3+), which are usually bound to transferrin and other proteins in blood plasma or stored in tissues like liver cells. The following paper will further discuss the use of Iron Chelation as a treatment method for thalassemia patients.

Necessity of Iron Chelation Therapy

Iron chelation therapy is a crucial part of management for those with thalassemia having excessive iron accumulation due to increased breakdown of red blood cells and frequent blood transfusions. It has been available since the 1960s, when it was first used to treat patients with thalassemia major and later those with thalassemia minor.


Causes of Iron Overload

Iron overload, whether hereditary or acquired, can be caused by a variety of factors, including frequent transfusions, iron usage (typically as a supplement), and chronic hepatitis. Hereditary hemochromatosis (all types), African iron overload, sickle cell disease, major beta-thalassemia, sideroblastic anemia, enzyme deficiency (pyruvate kinase, G6PD), and rare transport protein disorders (Atransferrinemia, Aceruloplasminemia) are among the genetic disorders that cause iron overload2. The patient’s small intestine absorbs a lot of iron, which builds up in the liver, pancreas, and some regions of the brain, impairing important activities.  Due to the generation of free radicals as a result of iron overload, significant complications such as mental retardation and early neurological illnesses (Alzheimer’s, multiple sclerosis, Huntington’s disease) might occur. 71% mortality in cardiac disease due to iron accumulation in myocardium is a significant complication of iron overload in beta-thalassemia. In order to avoid such serious complications, it is essential to suppress LPI (Labile Plasma Iron) and remove excess iron. Thus, the best selection for treatment of iron overload is iron chelation therapy.

Administration of Iron Chelation Therapy

Each transfusion unit includes approximately 250 milligrams of iron2. The body can only excrete a small quantity of iron per day, roughly one milligram, which is sloughed off in the skin via sweat. As a result, extra iron becomes trapped in important organ tissues such as the anterior pituitary, heart, liver, pancreas, and joints. When iron levels reach dangerous levels, disorders like diabetes, cirrhosis, osteoarthritis, heart attack, and hormone imbalances can occur. Hormone abnormalities can cause hypothyroidism, hypogonadism, infertility, impotence, and sterility. Chronic weariness, mood changes, and memory loss are all possible signs. Excess iron, if not handled, can lead to organ failure and death. In general, significant iron loading of the liver can be detected after about six months of monthly transfusions, while cardiac loading takes about eight to ten years3. Iron accumulation in liver is proportional to the duration of iron overload. In contrast, iron deposition on heart has a delayed but abrupt onset.

Advantages of Iron Chelation Therapy

Chelation treatment attempts to balance the rate of iron build up from blood transfusions by boosting iron excretion in urine and/or faeces using chelators4 . If chelation is delayed or insufficient, it will be essential to eliminate iron at a rate greater than this. Excess removal of iron can also damage the tissues therefore it is important to be cautious about the patient’s iron levels before starting chelation. To avoid toxicity from over-chelation, iron chelation therapy in patients is usually recommended at a serum.


  1. Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions
  2.  Iron Reduction: Chelation Therapy
  3. Treating Thalassemia: Chelation
  4.  IRON OVERLOAD AND CHELATION – Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT)