Clinical aspects of sickle cell and thalassaemia

Dr.Beverley Robertson

Consultant Haematologist

NHS Grampian

Sickle cell and thalassaemia

Genetic disorders of haemoglobin synthesis

- Haemoglobinopathies

Who is at greatest risk of being affected?

Why do we screen for them?

Normal adult haemoglobin

Normal haemoglobin (HbA) composed of haem molecule and 4 globin chains:

- 2 alpha () chains - 4 alpha genes

- 2 beta () chains- 2 beta genes

Normal adult

- Hb A () – 97%- Hb A2 (δδ) – 2%

- Hb F (γγ) – 1%

alpha alpha

alpha alpha

gamma gamma

gamma gamma Delta Beta

Delta Beta

beta

beta

Haemoglobinopathies

Inherited abnormalities of haemoglobin synthesis

Mutations leading to structurally abnormal globin chain

- HbS (Sickle cell ), HbC, HbD, HbE, HbO Arab......

Reduced or absent globin chain production

- Thalassaemia (alpha α, Beta β, delta δ, gamma γ)

1 in 4 chance of having affected child

1 in 2 chance of being a carrier or “trait”

Autosomal Recessive Inheritance

HbAA HbAS HbAS HbSS

Areas with high prevalence of haemoglobinopathies

Sickle cell Thalassaemia

Can occur in any ethnic group

Who is at risk?

Sickling disorders

African

Afro-Caribbean

Arabic Countries

Mediterranean

Thalassaemia Syndromes

- Mediterranean

- Turkey,Greece,Cyprus

- China

- SouthEast Asia

- Middle East

- Africa

- India

- Pakistan

- Bangladesh

Sickle cell disease (HbSS)

alpha alpha

alpha alpha

gamma gamma

gamma gamma Delta Beta

Delta Beta

betaS

betaS

Sickle haemoglobin (HbS) composed of haem molecule &:

- 2 chains

- 2 (sickle) chains

Sickle cell disease

-Sickled cells block small vessels – tissue damage

-Chronic haemolysis

Blood film in sickle cell (HbSS)

Sickle cell disease

Painful Vaso-occlusive crises- Bone

- Hand-foot syndrome

- Priapism

Increased infection risk- Hyposplenism

Sequestration crises- spleen

Chronic haemolytic anaemia- Gallstones

- Aplastic crisis

Organ damage due to microinfarcts- Lungs - Liver

- Brain - Retina

- Kidneys - Heart

- Chronic leg ulcers

Sickle cell – painful crisis

Hand-foot syndrome

Sickle cell – chest crisis

Management of sickle cell disease

Life long prophylaxis- Vaccination

- Penicillin (and malarial) prophylaxis

- Folic acid

Acute Events- Hydration

- Oxygenation

- Prompt treatment of infection

- Analgaesia – Opiates,NSAIDs

Management of sickle cell disease

Blood transfusion- Episodic and chronic

- Alloimmunisation

- Iron overload

Disease modifying drugs- Hydroxycarbamide

Bone marrow transplantation

Stroke in sickle cell

5 - 10% of children

Red cell transfusion reduces risk of recurrence

Transcranial doppler (TCD) ultrasound

Increased TCD flow in children with sickle cell- Stenosis of intracranial blood vessels

Associated with increased risk of stroke

STOP trial (Adams et al. NEJM 1998)– prevention of stroke in children at high risk

Chronic transfusion therapy

Sickle cell and pregnancy

Increased frequency of painful crises

Worsening of anaemia- Folic acid

- Caution with iron

Increased risk of- Foetal growth retardation

- Intrauterine death

- Premature labour

- ?pre-eclampsia

Intensive monitoring throughout

Thalassaemias

A group of inherited disorders of Hb synthesis

Mutations or deletions - In alpha genes (alpha thalassaemia) - αα/αα- -α/αα “α+”- --/αα “α0”

- In beta genes (beta thalassaemia)

Mutations lead to reduced or absent globin chain production

Chain Imbalance – chronic haemolysis and anaemia

alpha alpha

alpha alpha

gamma gamma

gamma gamma Delta Beta

Delta Beta

beta

beta

Thalassaemias

Homozygosity - Spectrum of clinical severity

Mild hypochromic, microcytic anaemia ( eg. α+/α+)

No alpha chains (α0/α0) – Hydrops fetalis

Beta thalassaemia major – transfusion dependent

Copyright ©1997 BMJ Publishing Group Ltd.

Weatherall, D J BMJ 1997;314:1675

Beta Thalassaemia major

Beta thalassaemia major

Severe anaemia

- Present at 3-6 months of age

- Expansion of ineffective bone marrow

- Bony deformities

- Splenomegaly

- Growth retardation

Life expectancy untreated or with irregular transfusions <10 years

Copyright ©1997 BMJ Publishing Group Ltd.

Weatherall, D J BMJ 1997;314:1675

Beta thalassaemia major

“Hair on end” appearance -due to bone marrow expansion

Beta thalassaemia major - treatment

Chronic transfusion support - 4-6 weekly

- Normal growth and development

- BUT - Iron overloading

- Death in 2nd or 3rd decades due to heart/liver/endocrine failure if untreated

Beta thalassaemia major - treatment

Iron chelation therapy

- s/c desferrioxamine infusions (desferal)

- Oral deferasirox (exjade)

Good adherence to chelation – life expectancy >40 years

- Requires regular monitoring

Bone marrow transplantation-curative

Sickle cell and thalassaemias - summary

Significant impact on quality of life and life expectancy if untreated

Antenatal screening gives couples informed choices on antenatal diagnosis and continuation of pregnancy

Neonatal screening allows early intervention to reduce mortality and morbidity from these disorders