1. The commonest inherited conditions in the world
Haemoglobinopathies
The commonest inherited conditions in the world

2. What is a haemoglobinopathy?
Haemoglobinopathies are inherited abnormalities of the blood. These are genetic diseases. 
The abnormal DNA is inherited throughout many generations and is therefore more common in well-defined ethnic groups.

3. Types of haemoglobinopathy - NB. all are genetically inherited
Qualitative
Affecting the structure and therefore maybe the function of the globin molecule
Eg. HbS, HbC, HbD Punjab, HbE, hundreds of others
Quantitative
Affecting the amount of globin molecules produced
Either alpha chain defects – alpha thalassaemias
4 genes, 2 from each parent,
Or beta chain defects – beta thalassaemias
2 genes, 1 from each parent

4. Haemoglobinopathies Thalassaemia Sickle cell disorders
Unstable haemoglobins
Abnormal O2 affinity Hbs

6. Haemoglobinopathy world distribution

7. SCD: epidemiology and genetics
There are estimated 15,000 people with SCD in the UK
Sickle cell tends to affect those of African and African-Caribbean origin, but also occurs in those from the South American and Mediterranean, Middle East and Asian countries
Carriage of Sickle cell genes (HbS S, C, D)
1 in every 10 Afro-Caribbeans
1 in every 4 West Africans
1 in every 50 Asians
1 in every 100 Northern Greeks

8. What is sickle cell disease?
Genetic mutation in b globin chain of Hb molecule (Hb S)
Homozygosity (2 identical genes) or compound heterozygosity (2 different b chain variants) produces clinical disease e.g
Hb SS
Hb SC
Hb S/bthal
Hb SD
Hb molecule becomes unstable in
Low oxygen conditions leading to formation of insoluble rigid chains
Produces vaso-occlusion (“sickling” ) and destruction of the red cell (haemolysis)

10. Diagnosing Sickle Cell HPLC
Sickle Cell Trait

11. Sickle solubility test
Only detects HbS
Precipitation of HbS in reduced state in high molarity phosphate buffer
False negatives:
Children < 6/12
HbS <20% (e.g. transfused, traits with low %S)
False positive:
Hb C Harlem, some unstable Hb
Low Hb
DOES NOT DISTINGUISH BETWEEN SCD AND S TRAIT
ALWAYS CONFIRM WITH HB SCREEN
IN EMERGENCY CONSIDER FBC AND FILM RESULTS
A = control, B = test
HbS present
Hb S not present

13. Sickle cell disease: clinical problems
Anaemia (Hb 7-9g/dl in Hb SS)
Infections
Painful crises
Stroke
Leg ulcers
Visual loss
Chronic organ damage
Kidneys, lungs, joints, heart

14. Clinical problems by age Children:
Infection
Splenic sequestration
Pain
Stroke
Adults
Chest syndrome
Chronic organ damage

15. “Crisis” Complications of SCD
Painful crisis
including chest/girdle syndrome
Anaemic crisis
Usually in childhood
Associated with Erythrovirus (Parvovirus) B19 infection
Sequestration crisis
Rapidly enlarging painful spleen/liver
Rapid fall in Hb

16. Painful crisis Commonest problem for patients
Pain is variable in severity and site and may be excruciating
Unpredictable throughout life
Often precipitated by infection, physical environment, stress, menstrual cycle
Associated with fear and anxiety
Majority of patients manage at home and only require admission for severe pain or other complications
Appropriate management in the early stages will reduce length and severity of crisis

17. Hand Foot Syndrome

19. Management of acute sickle crisis
Analgesia
stepladder approach
Treat associated infection
Fluids
Monitor for acute complications (chest syndrome, stroke, ileus)

21. Infections in SCD
Most common cause of death in children but a major problem at all ages
Due to splenic dysfunction from sickle damage
occurs from a few months of age
especially with certain bacteria eg pneumococcal sepsis : 400 x  risk
Infection may be rapidly overwhelming

22. Infection in SCD - 2 prevention: aggressive treatment of infections
education
Penicillin from 3/12 age
Pneumococcal, Hib, Meningococcal vaccines
travel prophylaxis : malaria
aggressive treatment of infections

23. Stroke in SCD Stroke neurological deficit >24 hours or
Stroke neurological deficit >24 hours or
<24 hours with a lesion on MRI / CT
11% in children with Hb SS
Risk increased x280 c.f. non sickle children
Assess risk by annual TCD screening

24. Acute sequestration crisis
Splenic
mostly < 2yrs
acute massive splenic enlargement,  Hb, shock
often associated with infection
significant mortality
requires emergency transfusion

25. Transfusion in SCD Purpose
To treat anaemia and improve oxygen carrying capacity of blood
remember SCD patients are anaemic in steady state. Hb alone is not an indication for transfusion unless very low (eg<5g/dl).
Prevent or reduce painful/vaso-occlusive or sequestration complications by lowering proportion of Hb S relative to Hb A (aim < 30% acute or < 50% in some chronic situations)

26. Emergency Transfusion
Top up
Exchange
Severe anaemia
Acute Chest Syndrome
Red cell aplasia
Acute stroke
Splenic sequestration
Acute hepatic sequestration
Severe sepsis
Acute multi organ failure
Progressive intrahepatic cholestasis

27. Sickle cell is a variable disorder
Majority of patients will have a history of symptoms
Severity of symptoms vary throughout a person’s life
Severity of symptoms very between individuals even with the same genetic make-up
Patients with milder disease may not present until late childhood or adult life e.g
SC disease
S/b+ thalassaemia
SS with other ameliorating factors
Newborn screening should pick up clinically significant births (UK)
Future severity of disease cannot be easily predicted for a newborn baby

28. Common misconceptions about SCD
Confined to black races
Severe anaemia needs transfusion
Patients are “drug seeking”
Pain levels are under-estimated by medical staff leading to inappropriately low analgesia
Sickle cell trait causes symptoms

29. What is Thalassaemia?
A group of inherited disorders resulting in reduced production of one or more globin chains.
this results in an imbalance of globin chains with the excess chain producing the pathological effects:
damage to red cell precursors ®ineffective erythropoeisis
damage to mature red cells ® haemolytic anaemia
Results in hypochromic, microcytic anaemia

30. Types of Thalassaemia 2 main types Alpha Thalassaemia a chains
controlled by 4 genes (2 from each parent)
Beta Thalassaemia b chains
controlled by 2 genes (1 from each parent)
a/b chain imbalance leads to haemolysis and anaemia

31. Who is at risk? Ethnic origin is critical!

32. Clinical Classification of Thalassaemia
Thalassaemia Major
Transfusion dependent
Thalassaemia intermedia
Less severe anaemia and can survive without regular blood transfusions
Thalassaemia minor or carrier
Asymptomatic carrier

33. Thalassaemia carriers in the UK - how common?
Alpha thalassaemia
Chinese
Cypriots
Beta thalassaemia
Asians
Afrocaribbeans
White British
1 in 15 to 1 in 30
1 in 50 to 1 in 300
1 in 7
1 in 10 to 1 in 30
1 in 30
1 in 50
1 in 1000
SMAC Report 1994

35. Alpha Thalassaemia phenotypes
Normal
Normal or minimal change to Hb, MCV and MCH
More marked changes. MCH<25pg
Moderately severe anaemia Hb 3-10g/dl, MCH 15-20pg
Hb Barts hydrops foetalis

36. Alpha Thalassaemia disease sates
Alpha thalassaemia major
Hb Barts hydrops fetalis
Incompatible with life
Due to inheritance of 2 copies of a0 gene
Mainly found in Chinese, S E Asian
Screening algorithm aims to pick out couples at high risk
Hb H Disease
Loss of 3 out of 4 a genes
Mild to moderate haemolytic anaemia
Majority do not need transfusion
Not specifically screened for

37. B thalassaemia Type Heterozygous Homozygous b0 b+
Thalassaemia carrier (trait)
Hb A2:>3.5%
Thalassaemia major
HbF:98%; Hb A2:2%;
no Hb A b+
Thalassaemia major/intermedia
HbF:70-80%; Hb A 10-20%; Hb A2: variable
Over 200 genetic defects producing B thalassaemia
B thalassaemia common in Mediterranean, S Asia, SE Asia but found worldwide.
Interaction with other Hb Variants possible

38. Thalassaemia clinical
Problems due to anaemia
Failure to grow and develop
Gross enlargement of liver and spleen
Skull deformities
Death in childhood/teens (if untreated)
Problems due to iron overload
Failure to grow and mature
Organ damage due to iron deposition
Cardiac
Liver
Endocrine eg diabetes, hypothyroidism, low sex hormones
Death in early adulthood due to cardiac/liver disease

40. Beta Thalassaemia Major
Age at presentation: 6-12 months
Clinical presentation with severe symptoms: failure to feed & thrive, listless, crying a lot and pale baby
Blood results:
HB 4-7 g/dl, Hb F > 90% (cord & neonatal sample)
Ferritin normal
Predictable clinical course:
Usually requires lifelong blood transfusion
Main clinical effects are due to iron overload from blood and anaemia ( if inadequately transfused)

41. Management in UK Regular blood transfusion Iron chelation treatment
infusions
oral
Specialist management of complications
Life expectancy with good treatment and good patient adherence is excellent

42. Complications of iron overload
Multi-organ failure
Endocrine organs
Growth failure
Diabetes
Thyroid failure
Gonadal failure - infertility
Cardiac
Liver

44. Desferrioxamine infusion
Given parenterally (s.c or i.v)
Short t1/2 – cont infusion
Dose-effect response
Dose limited by toxicity
Iron excreted in urine and faeces
Can reverse toxic effects

45. Thalassaemia major -life expectancy
Without regular transfusion
Less than 10 years
With regular transfusion and no/poor iron chelation
Less than 25 years
With regular transfusion and good iron chelation
??40 years, ?longer??

47. screening for Hb disorders
1. National Universal newborn screening programme
detects clinically significant sickle disorders and sickle carriers
detects most cases of Thalassaemia Major
does NOT detect thalassaemia carriers
AIM: to start supportive care and prophylactic immunisation and penicillin before 3/12 age

48. 2. National Antenatal screening programme
Hb screening cont
2. National Antenatal screening programme
Universal in areas of high prevalence eg Manchester
Selective in low prevalence areas based on FBC and ethnic origin
Partner screening offered for significant carrier states
Prenatal diagnosis (PND) offered to couples at high risk of baby with major haemoglobinopathy
AIM: to enable women to make informed choices about options available to them (e.g. continuing or terminating pregnancy)

49. Other indications for Hb Screening
Pre-pregnancy/genetic counselling
Pre-operative (sickling disorders)
In the investigation of anaemia