Haemoglobinopathies
The commonest inherited conditions in the world
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.
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
Haemoglobinopathies
• Thalassaemia
• Sickle cell disorders
• Unstable haemoglobins
• Abnormal O2 affinity Hbs
Haemoglobinopathy world distribution
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
What is sickle cell disease?
•Genetic mutation in globin chain of Hb molecule (Hb S)
•Homozygosity (2 identical genes) or compound heterozygosity (2 different 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)
Diagnosing Sickle CellHPLC
• Sickle Cell Trait
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
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
Clinical problems by age
Children:Infection
Splenic sequestration
Pain
Stroke
AdultsPain
Infection
Chest syndrome
Chronic organ damage
“Crisis” Complications of SCD
• Painful crisis– including chest/girdle syndrome
• Anaemic crisis – Usually in childhood– Associated with Erythrovirus (Parvovirus) B19 infection
• Sequestration crisis– Usually in childhood– Rapidly enlarging painful spleen/liver– Rapid fall in Hb
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
Hand Foot Syndrome
Management of acute sickle crisis
• Analgesia – stepladder approach
• Treat associated infection
• Fluids
• Monitor for acute complications (chest syndrome, stroke, ileus)
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
Infection in SCD - 2
• prevention:– education– Penicillin from 3/12 age– Pneumococcal, Hib, Meningococcal vaccines– travel prophylaxis : malaria
• aggressive treatment of infections
Stroke in SCD 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
Acute sequestration crisis
• Splenic– mostly < 2yrs– acute massive splenic enlargement, Hb,
shock– often associated with infection– significant mortality– requires emergency transfusion
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)
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
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/+ 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
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
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 anaemiaResults in hypochromic, microcytic anaemia
Types of Thalassaemia
2 main types
• Alpha Thalassaemia chains– controlled by 4 genes (2 from each parent)
• Beta Thalassaemia chains– controlled by 2 genes (1 from each parent)
chain imbalance leads to haemolysis and anaemia
Who is at risk?Ethnic origin is critical!
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
Thalassaemia carriers in the UK- how common?
• Alpha thalassaemia– Chinese– Cypriots
• Beta thalassaemia– Cypriots– Asians– Chinese– 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
Alpha Thalassaemia phenotypes
PhenotypeNormal
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
Alpha Thalassaemia disease sates
• Alpha thalassaemia major– Hb Barts hydrops fetalis– Incompatible with life – Due to inheritance of 2 copies of 0 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 genes– Mild to moderate haemolytic anaemia– Majority do not need transfusion
• Not specifically screened for
thalassaemiaType Heterozygous Homozygous
0 Thalassaemia carrier (trait)
Hb A2:>3.5%
Thalassaemia major
HbF:98%; Hb A2:2%;
no Hb A
+ Thalassaemia carrier (trait)
Hb A2:>3.5%
Thalassaemia major/intermedia
HbF:70-80%; Hb A 10-20%; Hb A2: variable
Over 200 genetic defects producing thalassaemia thalassaemia common in Mediterranean, S Asia, SE
Asia but found worldwide. Interaction with other Hb Variants possible
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
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)
Management in UK
• Regular blood transfusion
• Iron chelation treatment– infusions – oral
• Specialist management of complicationsLife expectancy with good treatment and good patient
adherence is excellent
Complications of iron overload
• Multi-organ failure– Endocrine organs
• Growth failure• Diabetes• Thyroid failure• Gonadal failure - infertility
– Cardiac– Liver
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
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??
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
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)
Other indications for Hb Screening
3. Pre-pregnancy/genetic counselling
4. Pre-operative (sickling disorders)
5. In the investigation of anaemia