Haemoglobin Disorders

Beta Thalassaemia

Beta thalassaemia is a condition caused by the lack or severe reduction of the β-globin chains of the heamoglobin molecule.

In order for an autosomal recessive disease to be transmitted, both parents must be at least heterozygotes, in order to transmit one affected gene each to their child.

In this case, the child bears a 25% possibility to get both affected genes and thus express the disease. There is also a 50% possibility that the child gets only one affected gene from one of the parents, thus becoming a heterozygote (carrier) and another 25% possibility to get no affected gene from either parents and thus be completely normal and incapable to transmit the disease any further, as explained in the following figure:

 

 

Click to read: Beta Thalassaemia, Alpha Thalassaemia and Sickle Cell Disease Educational Community booklet, p.p. 15-17. TIF Publication (2014).

There is a spectrum of clinical severity ranging from an almost normal Hb level to an anaemia which is not compatible with life, unless regular blood transfusions from healthy donors keep the person alive by providing oxygen carrying haemoglobin from the donated red cells.

Among the serious consequences in bodily function that severe anaemia can cause, if not properly treated, are:

• Apart from low vitality and poor growth, anaemia causes the heart to pump blood more intensely, aiming for more oxygen to reach the tissues. But the heart muscle also needs oxygen and poor supply will weaken the organ and eventually lead to heart failure, which is a potentially lethal condition.

• Failure to provide blood, and keep the haemoglobin level to an acceptable minimum level, which is over 9g/dl in TDT patients, also causes the body to keep producing ‘empty’ red cells, by expanding the activity of the bone marrow, both within the bone marrow cavity and in other parts of the body, such as the liver, the spleen and the lymphatic system. Masses of blood forming tissue are formed which can destroy bone structure and put pressure on several organs. This in medical terms is called extra-medullary haemopoiesis.

• One of the body’s response to anaemia is to increase the absorption of iron from the food. This is exacerbated by the iron provided by the break-down of red cells in the donated blood. This will, in all thalassaemia patients, sooner in TDT patients or later in NTDT patients, result in iron overload; The body is unable to excrete such a large amount of extra iron, and so it piles up in the tissues and organs of the body. Iron overload can cause damage to vital tissues and result in a series of complications, mainly affecting the heart, the endocrine glands and the liver.

Iron toxicity is, for these reasons, the major cause of ill-health and finally premature death in thalassaemia patients, even those that are classified initially as having milder forms of the disease. If this iron is not removed by medical intervention, it can be extremely harmful.

Managing the β-thalassaemias is achieved by a series of measures which must be provided by special services, with trained medical and nursing staff.

These measures include:

  • The backbone of treatment is blood transfusion, with a regularity that is tailored to each patient’s needs. In general transfusion should aim to keep patients’ haemoglobin levels at between 9-10.5g/dl before transfusion. Under this regime, patients will experience:

-minimal expansion in bone marrow

– normal growth and increased physical energy

– no or delayed enlargement of the spleen

  • However, chronic transfusion exposes the patient to various risks, principally to iron overload, allo-immunisation (reaction to the donated blood), and transmission of bacterial and viral infectious agents. These possible adverse reactions to donor blood are dealt with by close collaboration of clinic with the blood bank.
  • Removing excess iron through iron chelation, is the second major pillar of thalassaemia management. If there is no control of iron levels, then thalassaemia will become, sooner or later a multi-organ disorder, affecting dangerously vital organs. Chelation is based on three drugs that bind to iron and remove it from the body. These are Desferrioxamine, Deferiprone and Deferasirox. There are tests that can determine the amount of iron accumulated in specific organs, such as Serum Ferritin, Transferrin Saturation or Total iron-binding capacity (TIBC), and iron measurements by MRI. Careful and regular patient monitoring will detect early any iron loading.
  • Since vital organs can be affected quite early in life, especially in the severe TDT forms, it is necessary for each patient to examined, at least once a year, by heart specialist and an endocrinologist. A liver specialist will also be necessary, perhaps from the middle teen years. This is known as the multidisciplinary approach. Early detection and management of organ involvement has made a significant difference to patient survival and wellbeing.

Strict adherence to these measures, known as conventional treatment, has led to the good quality of life and long survival of patients, in those countries or specialised centres where this is being provided.

Bone Marrow Transplantation (BMT), also known as Haemopoietic Stem Cell Transplantation (HSCT), is a medical procedure during which stem cells (a special types of blood forming cells cells) are transferred from a healthy individual (the donor) into the blood of an individual with a blood disease such as β-thalassaemia (the recipient).

This process replaces the patients ‘faulty’ blood forming tissue with that taken from a non-thalassaemic donor. These donated stem cells will develop into mature red blood cell with normal oxygen carrying capacity. The donor, however, must be fully matched with the recipient. Matching means that the proteins of the two individuals will not react against each other, otherwise the recipient will develop antibodies against the donor proteins and reject the graft.

A good match is recognised by testing for certain proteins which are found on the surface of white cells, known as human leukocyte antigens (HLA antigens). In order to minimise any rejection, the donor’s HLA type must be the same as the recipient’s, and so the best or most likely compatible donor is a sibling of the patient. This, among the small families which characterise modern society, is not always possible – in fact only about a quarter of patients have a matched sibling donor. Using donors that are not fully matched increases the risks of rejection and complications.

Click to read: Bone Marrow Transplantation in β-thalassaemia. TIF Publication. (2018)

 

Gene therapy is a novel, revolutionary treatment that aims at curing thalassaemia by replacing the affected gene that causes the disease with a healthy one in the patient’s DNA. This approach has recently been given approval by the European Medicines Agency (EMA) and services are being set in selected European centres. The product, ZYNTEGLOTM, by BluebirdBio, is the first to be marketed, after it has undergone successful clinical trials. It is based on the introduction of a functional β-globin gene into the patient’s stem cells by means of a viral vector. (Fig.1)

 

Click to read: Gene Therapy in β-thalassaemia and other haemoglobin disorders. TIF Publication. (2019)

Explaining Gene Therapy in Thalassaemia. TIF Publication. (2020)

An Introduction to Gene Therapy for Genetic Diseases by BluebirdBio

Autologous transplants, using the patients’ own stem cells does not need HLA matching and so is potentially available to all patients and so risks are reduced. However, marrow ablation is still needed to make ‘room’ for the treated stem cells to over red cell production and so long term issues like infertility may still be a problem.

Gene editing is another new approach to genetic therapy, consisting in the ability to make highly specific changes in the DNA sequence of a living organism, essentially customizing its genetic makeup. Gene editing is performed using enzymes that have been engineered to target a specific DNA sequence, where they introduce cuts into the DNA strands, enabling the removal of existing DNA and the insertion of replacement DNA.

However, this approach has only recently entered clinical trials and not only its effectiveness is yet to be proven, but it has also brought new urgency to long-standing discussions about the ethical and social implications surrounding the genetic engineering of humans.

Another new approach to treatment is a medication called Luspatercept (REBLOZYL®). The U.S. Food and Drug Administration (FDA) has approved REBLOZYL® for the treatment of anaemia in adult patients with β-thalassaemia who require regular red blood cell (RBC) transfusions. Its main effect is to increase the interval between transfusions, so that patients with TDT need less blood.

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