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1-year-old Ruby presents with pallor and faltering growth. She is of Asian origin and has a family history of thalassaemia. Her blood tests show a microcytic anaemia. What do you do next?

An infographic depicting the ins and outs of thalassaemia

Thalassaemias are inherited blood disorders that can cause anaemia.

Usually, haemoglobin, comprised of four globin chains and a haem group, carry oxygen around the body. Thalassaemias impair haemoglobin synthesis by specifically affecting globin chain production.

Affected individuals make less haemoglobin but also experience chronic haemolysis due to the damaging effects of unbalanced globin chains within erythrocytes. This leads to symptoms such as pallor, jaundice, fatigue and breathlessness. In addition, signs of extramedullary haemopoiesis may also develop, such as hepatosplenomegaly or bony deformities such as frontal bossing and maxillary bone hypertrophy.

The blood disorder is commonly seen in Mediterranean, Middle Eastern or Asian populations. Approximately 5% of the world’s population has a thalassaemia variant allele, with the global birth rate of symptomatic cases estimated to be 2.4 per 1000 births. This article will focus on the two most common types of thalassaemia: alpha and beta.

Normal haemoglobin production

Globin chain types, and the derivative haemoglobins they produce, change significantly from embryonic to adult life. At birth, babies have high amounts of haemoglobin F (HbF – “F for fetal”), composed of two alpha and two gamma chains. After birth, the production of beta chains increases while gamma chains naturally decrease. This leads to a reduction of HbF and an increase in haemoglobin A (HbA – “A for adult”), which is composed of two alpha and two beta chains and is the primary adult haemoglobin subtype. A typical adult’s haemoglobin subtype percentages are around 95% HbA, with the two minor haemoglobins accounting for the remaining 5% (HbA2 2-3.5%, HbF <2%). For reference, HbA2 is composed of two alpha and two delta chains.


Alpha thalassaemia is most prevalent in Southern China, Malaysia and Thailand.

We usually have four alpha globin genes (αα/αα). Alpha thalassaemia occurs when one or more alpha genes that produce the alpha chains are deleted or mutated. As alpha chain production reaches adult levels early in fetal life, these defects are evident at birth. Alpha thalassaemia is classified according to genotype. There are four types:

Alpha thalassaemia silent carrier

ONE alpha gene affected (-α/αα)
These people are carriers and have no symptoms.

Alpha thalassaemia minor (or alpha thalassaemia trait)

TWO alpha genes affected (-α/-α) or (–/αα)
These people are usually asymptomatic but have microcytosis and occasionally very mild anaemia.

Haemoglobin H disease:

THREE alpha genes affected (–/-α)
Individuals are symptomatic, with chronic haemolysis and microcytic anaemia. On examination, they may have jaundice or splenomegaly. Most require no regular treatment, but some may require either occasional or regular blood transfusions. Regular transfusions may ease symptoms but carry the risk of iron overload, resulting in a need for chelation therapy and ongoing monitoring with serum ferritin and Ferriscan imaging.

The condition is named for one of the abnormal haemoglobins produced (HbH – a beta chain tetramer). However, it also produces another abnormal haemoglobin, Hb Barts (a gamma chain tetramer).

Alpha thalassaemia major

FOUR alpha genes affected (–/–)
In most cases, babies with this genotype will die before or shortly after birth. Most infants are stillborn with hydrops fetalis; the only haemoglobins produced are HbH and Hb Barts. Children who do not die ante- or perinatally will require regular blood transfusions to survive. The only potential cure is an allogeneic bone marrow transplant, although gene therapy is under study.


Beta thalassaemia is the most common form and is highly prevalent in Africa. An average human has two beta globin genes (ß/ß). Defective ß genes may be annotated as “ß0”, meaning no beta chain is produced, or “ß+”, representing some beta chain is produced. Beta thalassaemia is classified according to clinical significance, unlike alpha thalassaemia, which is organised by genotype. There are three main types of beta thalassaemia:

Beta thalassaemia minor (or beta thalassaemia trait)

Near normal quantities of beta chains are produced. One beta gene is affected (ß / ß0 or ß/ ß+). These individuals are usually asymptomatic and live an everyday life. However, they are microcytic and often show mild anaemia.

Beta thalassaemia intermedia

Some beta chains are produced. The usual genotype is two abnormal beta genes, either ß+ / ß+ or ß+ / ß0. Microcytic anaemia is universal, but these individuals are often asymptomatic. Therefore, they may need blood transfusions occasionally.

Beta thalassaemia major

Minimal or no beta chains are produced.2 beta globin genes affected (ß0 / ß0, ß0 / ß+, or some ß+ / ß+). These individuals have severe microcytic hypochromic anaemia and will need regular blood transfusions. In addition, they require monitoring for iron overload and usually chelation therapy. The only curative treatment historically has been an allogeneic bone marrow transplant, although experts are looking at gene therapy as an option.

Ruby is symptomatic of anaemia with pallor, lethargy, breathlessness, tachycardia, and growth failure. With her complete blood count results, haemoglobin studies (HPLC / electrophoresis) are sent. Iron studies are also sent to exclude an iron deficiency contributing to her microcytic anaemia.

How to distinguish alpha and beta thalassaemia at birth

It’s all in the globin chain graph

Babies with alpha thalassaemia have microcytic cells at birth and may also be anaemic, as their alpha chain production is low in fetal life. Babies with HbH disease or alpha thalassaemia major have a relative excess of gamma chains at birth, which form tetramers (Hb Barts). An increasing relative excess of beta chains develops through life, creating tetramers (HbH). Hb Barts and HbH are poor carriers of oxygen and cause haemolysis. Haemoglobin studies can show diagnostic features of the more severe alpha thalassaemia state from birth, and DNA testing can confirm the presence and types of alpha gene deletions.

Babies with beta thalassaemia may not have microcytic cells until later infancy due to the presence of normal quantities of normal HbF, which is the predominant foetal haemoglobin, and low amounts of HbA. Microcytosis typically emerges by around six months as the progressive switch to beta chain production is made, and gamma chain production is downregulated. As HbF production declines, is not replaced by normal beta chain production, so the MCV drops and Hb decreases. Therefore, delaying haemoglobin studies at or after six months of age can reliably confirm beta thalassaemia states with an elevated HbF and HbA2 >3.5%. DNA testing is not required for beta thalassaemia but is technically possible and performed in select cases.

Ruby’s haemoglobin studies demonstrate no HbA, a raised HbF and elevated HbA2, meaning that Ruby has beta thalassaemia major. Her parents are counselled for the need for regular red blood cell transfusions to treat her anaemia and support her growth. Patients will eventually require iron chelation therapy. This may mean oral deferasirox or deferiprone. Her social and family history is explored, and genetic counselling is offered for future family planning in the future. 


Angastiniotis M, Modell B, Englezos P, Boulyjenkov V. Prevention and control of haemoglobinopathies. Bulletin of the World Health Organization. 1995;73(3):375.

Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. ASH Education Program Book. 2009;2009(1):26-34.

Rund D, Rachmilewitz E. β-Thalassemia. New England Journal of Medicine. 2005 Sep 15;353(11):1135-46.

Vichinsky EP. Changing patterns of thalassemia worldwide. Annals of the New York Academy of Sciences. 2005 Nov;1054(1):18-24.


  • Jessica Wong is a paediatric trainee in Perth, Western Australia. She is interested in adolescent medicine and haematology. Her favourite cartoon character is Winnie the Pooh.

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  • Carly George is a paediatric clinical and laboratory haematologist in Perth, Western Australia. She enjoys teaching and going to the beach but lately spends most of her free time obeying her toddler’s commands.

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