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