Print Friendly, PDF & Email

almostadoctor app banner for android and iOS almostadoctor iPhone, iPad and android apps almostadoctor iOS app almostadoctor android app


Thalassaemias are autosomal recessive inherited disorders of haemoglobin, causing structural deficiencies in haemoglobin molecules. As such, they are a type of haemoglobinopathy.

They mainly effect individuals of asian, middle eastern or mediterranean ethnicity.

Heterozygous forms are relatively common and usually minor. Homozygous forms are rare, but cause a severe anaemia of childhood and can be fatal without treatment.

Haemoglobinopathies typically present with a microcytic hypochromic anaemia which will NOT respond to iron. In the most severe cases, thalassaemias can be fatal in utero or in the first few months of life, but most cases are of mixed genetic background and are mild.

Thalassaemia can be broadly classified into α-thalassaemia and β-thalassaemia, depending on the underlying structural haemoglobin changes. β-thalassaemia is more common.

They are also often referred to as thalassaemia major, thalassaemia intermedia and thalassaemia minor – however this classification usually refers to the severity of the disease (usually when referring to β-thalassaemia).

The vast majority of cases are of minor disease and are typically asymptomatic. The most severe forms of the disease (rare) are incompatible with life and can result in miscarriage or death of the newborn. In between these extremes is Thalassaemia major – a serious condition, which often manifests in infancy with failure to thrive, fevers and bony (including facial) deformities. It can be cured with bone marrow transplant (if available) but is usually treated with lifelong recurrent blood transfusions . These patients often become iron overloaded and as a result require iron chelation therapy, and regular cardiac and liver monitoring under the supervision of a multi-disciplinary team.


  • 1.5% of the global population are carriers of β-thalassaemia. Most prevalent in:
    • Mediterranean
    • Middle east
    • Southern China
    • Central, south and southeast Asia
  • 5% are carriers of α-thalassaemia. most prevalent in:
    • Southeast Asia
    • Africa
    • India


Haemoglobin molecules are made up of 4 “globin” chains. There are 4 types of globin chain; alpha (α), beta (β), gamma (γ) and delta (δ). Usually a haemoglobin molecule is made up of a pair of one type of globin chain (e.g. a pair of α chains) and then two other chains.

  • Most commonly, haemoglobin is made up of 2 alpha and 2 beta chains – HbA (α22)
  • Mutations in the alpha chains give rise to α-thalassaemia, and mutations in the beta chains give rise to β-thalassaemia

Over 300 mutations have been identified and the clinical severity of the disease varies widely.

  • Clinically, severe cases of thalassaemia manifest as haemolytic anaemia with splenomegaly (+/- hepatomegaly) and pallor (pale-looking) – often at birth or within the first few months of life.
  • Individuals with thalassaemia traits (either alpha or beta) are often asymptomatic
  • The clinically asymptomatic types of α-thalassaemia and β-thalassaemia produce a mild microcytosis – which often can appear like an iron-deficiency anaemia (although will often have normal iron studies). They will not respond to iron therapy.

α thalassaemia

There are two genes that code for α chains. That’s easy to understand. And then thalassaemia starts to get very complicated.

There are 6 possible genotypes. You will definitely NOT be expected to know all of these unless you are a haematologist. But, for completeness – here they are*:

Normal(a,a / a,a)No thalassaemia
α+ thalassaemia heterozygous(a,- / a,a)Clinically asymptomatic

↔ / ↓ Hb
↔ / ↓ MCV
α+ thalassaemia homozygous(a,- / a,-)
Clinically asymptomatic
↓ Hb (slightly)
αo thalassaemia heterozygous(a,a / -,-)
Clinically asymptomatic
↓ Hb (slightly)
HbH disease(a,- / -,-)
↓ Hb
↓↓ MCV
↓ ↓MCH
Bone changes
α thalassaemia major(-,- / -,-)
Usually fatal
↓↓ Hb (severe)
Severe intrauterine haemolytic anaemia

*I presume the genotype notation was first used before texting smiley faces became “a thing”!

  • Severe homozygous α thalassaemia is usually fatal in utero
    • Is one of the two main causes of hydrops fetalis – the other being rhesus incompatibility – which is now rarely seen.
  • α-thalasseamia carrier – refers to deletion of one α chain, and is asymptomatic
  • α-thalasseamia trait – refers to presentations with deletions of two α chains (a,- / a,-) or (a,a / -,- )
  • α-thalasseamia media – refers to HbH disease – whereby beta-haemoglobin chains replace this missing alpha-chains – and hence the predominance of HbH
    • HbH – haemoglobin H chains are an abnormal type of haemoglobin produced when a patient inherits an α+ from one parent and an αo from another
  • α-thalasseamia major – as above


Unlike in β-thalassaemia, haemoglobin electrophoresis is usually normal.

  • α-thalasseamia carrier and α-thalasseamia trait – usually undiagnosed, asymptomatic. Can be detected on genetic testing, or with an “α-β chain synthesis ratio”
  • α-thalasseamia media – HbH disease – on blood films stained with a supra vital stain, there are tell-tale inclusions in the RBCs known as Heinz Bodies

β thalassaemia

There is only a single gene that codes for the beta chain – which makes β-thalassaemia slightly easier to understand!

Normal22)No thalassaemia
β-thalassaemia trait( – / β2)
Clinically asymptomatic
↑HbA2 >4%
↓ Hb (slightly)
β-thalassaemia intermedia( – / β2) OR (β+/β+)
↓ Hb (markedly)
↓↓ MCV
↓ ↓MCH
Bone changes
May require transfusion
β-thalassaemia major(-o / -o )
↑HbF >90%
↓ Hb (markedly – severe haemolytic anaemia)
↓↓ MCV
↓ ↓MCH
Splenomegaly, hepatomegaly
Bone changes
Chronic transfusion dependency


Newborns are born with large amounts of HbF – the γ chains in HbF are slowly replaced by β chains in the first years of life. This process is highly variable. The typical presentation for β-thalassaemia is around the end of the first year of life, but it can take up to 5 years.

Defective β-chain synthesis usually results in increased alpha-chain synthesis. Excess alpha chains will precipitate in red cells and cause the red cell walls to be weakened. These fragile RBCs will subsequently be destroyed in bone marrow and the spleen. This causes a progressive splenomegaly as well as bone marrow proliferation – which results in bony deformities.

  • Homozygous disease usually presents by the age of 3 months, and if untreated can be fatal by the age of 1 year. Some may not present until as old as 5. Presenting features include:
    • Failure to thrive
    • Vomiting
    • Sleepiness
    • Irritability
    • Stunted growth
    • Fevers – due to hyper-metabolic state
  • Most neonates with β-thalassaemia major are detected on blood spot screening at birth
  • Signs and symptoms are usually absent if Hb >90 g/L


In milder cases (Hb >90 g/L) there are rarely any signs or symptoms. In more severe cases, signs can include:

  • Hepatoslpenomegaly
  • Bony deformities
    • Frontal bossing
    • Prominent facial bones
    • Dental deformities
  • Jaundice
  • Pallor
  • Cardiac flow murmur secondary to anaemia
  • Poor exercise tolerance

A child with failure to thrive and a microcytic anaemia should be strongly suspected of having a haemoglobinopathy (most commonly thalassaemia).


Thalassaemia can be a differential for any other causes of a microcytic anaemia, such as:

  • Iron deficiency anaemia
  • Anaemia of chronic disease
  • Sideroblastic anaemia

Other differentials include:

  • Acute leukaemia
  • Rhesus incompatibility



  • FBC
    • Microcytic hypochromic anaemia
    • May be confused with iron deficiency – especially β-thalassaemia
    • WCC may be elevated due to haemolysis
    • Platelets may be low due to splenomegaly
  • Iron studies
    • Increased ferritin
    • Saturation as high as 80%
  • Haemoglobin electrophoresis is diagnostic in β-thalassaemia
    • Checks for the presences of HbA2
      • Normal 1.5 – 3%
      • >3.5% is diagnostic for β-thalassaemia
  • DNA testing can be used to establish the underlying carrier status in families and parents
Iron deficiency anaemiaAnaemia of chronic diseaseβ-thalassaemiaHaemochromatosis
Serum Iron↑ or ↔
TIBC – aka Transferrin
Serum Ferritin↑ or ↔↑ or ↔↑↑
MCV↑ or ↔↑ or ↔↑↑
Investigation pathway for microcytic anaemia
Investigation pathway for microcytic anaemia



  • X-ray may show bony changes
    • Skull – “hair on end” deformity
    • Maxilla – overbite and overgrowth
    • Long bones and ribs – may be flat or show other deformities
    • CXR – enlarged heart, signs of heart failure
  • CT / MRI
    • Can be used to assess the liver in patient on chelation therapy

Other potential investigations

  • ECG and Echo – to monitor cardiac function
  • Liver biopsy – to assess iron deposition and the degree of haemochromatosis
  • Bone marrow biopsy – may be needed to confirm diagnosis
  • HLA typing – in cases where bone marrow transplant is considered
  • Monitor of chelation therapy
    • Eye tests
    • Hearing tests
    • Renal function


The aim of treatment is to prevent Hb falling below 95 g/L. Many patients will require life-long blood transfusions, although bone marrow transplant (stem cell transplant) is curative, and likely to have better outcome when performed at an earlier age.

  • Blood transfusion prolongs survival but causes iron overload. Aim for Hb >95g/L. Consider using ‘leucocyte poor’ blood to prevention sensitisation – especially if future bone marrow transplant is an option
  • Indications for transfusion include:
    • Growth impairment
    • Skeletal deformity
  • Iron overload usually occurs as a result of multiple transfusions, but can occur without transfusion. Iron deposits widely in various organs in the body, causing fibrosis and organ failure. It can be treated with chelation
    • Patient still often suffer from restricted growth, and endocrine disorders secondary to iron overload, such as diabetes, thyroid disorders and adrenal and pituitary disorders
      • Diabetes is common
      • Be wary that HbA1c is not a reliable indictor of diabetic control due to the reduced lifespan of RBCs in thalassaemia
    • Hepatitis B and C risk is increase due to multiple transfusions
    • Be wary of ever giving iron supplementation to any thalassaemia patient – unless there is proven iron deficiency
    • Chelation therapy typically with desferrioxamine
      • Dose is variable
      • Not available orally
      • Newer oral agents are now available such as deferasirox and deferiprone
  • Overall life-expectancy is reduced
  • Consider splenectomy if there is marked hypersplenism – be wary of risks of asplenism (life-threatening infections, VTE, pulmonary hypertension)
  • Bone marrow transplant is curative
    • Best outcome if done at earlier age
    • There have been recent cases of subsequent embryo selection by parents to produce a child with compatible but disease free bone marrow – the ethical and legal issues around this are still being debated.
  • Offer genetic counselling to all patients with all variants of thalassaemia
  • Lifestyle factors:
    • Avoid foods rich in iron
    • Vitamins C+E, folic acid may be beneficial
    • Drinking tea and coffee frequently can reduce the absorption of iron


α thalassaemia

  • Excellent if only a carrier
  • HbH disease has variable prognosis. Most survive into adulthood, but some suffer many complications
  • Hydrops fetalis is incompatible with life

β thalassaemia

  • Thalassaemia minor causes an asymptomatic microcytic anaemia with no effect on mortality or morbidity
  • Thalassaemia major carries an 80% mortality in the first 5 years of life
  • Patients who require transfusions have substantially reduced life expectancy
    • Without chelation – often will not survive teenage years
    • Chelation therapy has improve life-spans
  • Stem-cell transplant (bone marrow transplant) is associated with 85-90% survival after 15 years



  • Thalassaemia –
  • Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
  • Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

Read more about our sources

Related Articles

Dr Tom Leach

Dr Tom Leach MBChB DCH EMCert(ACEM) FRACGP currently works as a GP and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University, and is studying for a Masters of Sports Medicine at the University of Queensland. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009. Read full bio

Leave a Reply