1. Clinical aspects of sickle cell and thalassaemia Dr.Beverley Robertson Consultant Haematologist NHS Grampian

2. Sickle cell and thalassaemia  Genetic disorders of haemoglobin synthesis -Haemoglobinopathies  Who is at greatest risk of being affected?  Why do we screen for them?

3. 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 gamma Delta Beta beta

4. 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)

5. 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

6. Areas with high prevalence of haemoglobinopathies Sickle cell Thalassaemia Can occur in any ethnic group

7. 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

8. Sickle cell disease (HbSS) alpha gamma Delta Beta betaS  Sickle haemoglobin (HbS) composed of haem molecule &: -2  chains -2  (sickle) chains

9. Sickle cell disease - Sickled cells block small vessels – tissue damage -Chronic haemolysis

10. Blood film in sickle cell (HbSS)

11. 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

12. Sickle cell – painful crisis Hand-foot syndrome

13. Sickle cell – chest crisis

14. 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

15. Management of sickle cell disease  Blood transfusion -Episodic and chronic -Alloimmunisation -Iron overload  Disease modifying drugs -Hydroxycarbamide  Bone marrow transplantation

16. 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

17. 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

18. Thalassaemias  A group of inherited disorders of Hb synthesis  Mutations or deletions -In alpha genes (alpha thalassaemia) - αα/αα - -α/αα “α + ” - --/αα “α 0 ” -In beta genes (beta thalassaemia)  Mutations lead to reduced or absent globin chain production  Chain Imbalance – chronic haemolysis and anaemia alpha gamma Delta Beta beta

19. Thalassaemias  Homozygosity - Spectrum of clinical severity  Mild hypochromic, microcytic anaemia ( eg. α + /α + )  No alpha chains (α 0 /α 0 ) – Hydrops fetalis  Beta thalassaemia major – transfusion dependent

20. Copyright ©1997 BMJ Publishing Group Ltd. Weatherall, D J BMJ 1997;314:1675 Beta Thalassaemia major

21. 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

22. 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

23. Beta thalassaemia major - treatment  Chronic transfusion support - 4-6 weekly -Normal growth and development -BUT - Iron overloading -Death in 2 nd or 3 rd decades due to heart/liver/endocrine failure if untreated

24. 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

25. 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