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Flashcards in Haematology Haemoglobinopthies Deck (103):
1

Main Haemoglobin in adults

The main Hb in adults is HbA

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Structure

Consists of 4 protein globin chains (2α and 2β)
Each protein globin chain is centered around a heme group. Each heme group consists of a porphyrin ring with an iron atom at the centre.

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Function

Crucial function in O2 and Co2 transport

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Fetal Haemoglobin

2α and 2γ

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Haemoglobin A2

2α and 2δ (small amounts in the body)

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The gene that encodes the globin proteins

On Chromosome 11 and 16
Proteins produced from both Chr are needed to make normal Hb (usually 2 α globins combine with 2 non α globins)
→ Chromosome 16 have 2 α genes (Maternal + Paternal = 4)
→ There are 2 β genes in total. One on each chromosome 11 (one from each parent)

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Change of structure during development

By the 12th week embryonic haemoglobin is replaced by foetal haemoglobin (HbF)
HbF is slowly replced after birth by the adult haemoglobins (HbA and HbA2)

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Adult haemoglobin

Hb-A
Hb-A2

α2 β2
α2 δ2

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Fetal haemoglobin and globin structure

Hb-F
α2 γ2

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Embryonic

haemoglobin and structure

Hb-Gower 1
Hb-Gower 2
Hb-Portland
Ζ2ε2
α2ε2
ζ2γ2

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Haemaglobinopathies →

• Inherited genetic defects of globin
• Sickling disorders and thalassaemias are the most clinically important
• Mutations of the α globin genes affect both foetal and adult life
• Β globin mutations are only manifest after birth when HbA replaces HbF

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Thalassemia: Definition

Reduced or absent synthesis of one or more of the globin chains of adult haemoglobin.
Imbalance in gobin chain synthesis

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Thalassemia: Types

Alpha thalassaemia
Beta thalassaemia

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Thalassemia: Alpha thalassaemia usually caused by

Gene deletion;

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Thalassemia: Beta thalassaemia usually caused by

Mutation

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Thalassemia: Results in

Microcytic (Small)
Hypochromic anaemia’s of varying severity (Pale)

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Thalassemia: Demographic

Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma.

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Beta Types of Genetic Defects

βo – nothing works
β+ - reduced synthesis
S – sickle cell
C (D, E, O) – a haemoglobin variant

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Beta Inheritance

Autosomal recessive – carriers are asymptomatic, but may mild abnormalities in blood tests.

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βo

A null absent gene

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β+

Reduced protein synthesis (to a variable degree)

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Beta thal trait

One healthy β and one βo – can still make HbA

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Beta thalassemia major

2 βo you cant make HbA (Both mum and dad are at least carriers)

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Clinical types of Beta thalassemia

Beta thalassemia trait – asymptomatic, normal life span
Beta thalassemia intermedia – Variable phenotype and life span
Beta thalassemia major – Early death if untreated

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β/ β

Normal

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βo/ β

β – thal trait

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βo/ βo

Homozygous β – thal (thal major)
No HbA. Transfusion dependence from 3-4/12

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βo/ β+

Compound heterozygote
Variable. Maybe thal intermedia

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Β-thal trait =

= Thalassemia indices + Increased HbA2 (increased HbF =in 50%)

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Beta Normal Inheritance

When both globin genes of each parent are functioning normally, than all the children will carry functioning genes and none will have the thalassaemia trait.

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Inheritance One Parent is a carrier of β-thalassaemia

When on parent carries a β-thalassemia gene, then each child will have a 50:50 chance (1:2) of also being a carrier (or have the trait, or be heterozygote or have thalassemia minor)

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Inheritance If both parents have βo trait children

• 25% children will have β thal major
• 50% will be carriers
• 25% will be unaffected

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Beta Thalassaemia Major: Description

Complete absence of HbA
Excess alpha chains accumulate and damage red cells

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Beta Thalassaemia Major: Pathophysiology

Ineffective erythropoiesis – bone marrow RBC
Excessive RBCs destruction
Intramedullary and extra medullary
Iron Overload
Extra-medullary haematopoiesis (EPO drive of anaemia)

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Beta Thalassaemia Major: Clinical features

1. Symptomatic anaemia in first few months of life
2. Jaundice
3. Growth retardation failure to thrive
4. Medullary hyperplasia – bony abnormalities especially of the facial bones (maxillary).
5. Extra medullary haematopoiesis – enlarged spleen and liver
6. Increased risk of thrombosis
7. Pulmonary hypertension and congestive heart failure

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Beta Thalassaemia Major: Prevention

Family screening, antenatal screening and prenatal diagnosis

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Beta Thalassaemia Major: X-Ray of skull

Ill-defined thin cortical layer – medullary hyperplasia

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Beta Thalassaemia Major: Blood film

Severe anaemia with marked hypochromic, target cells and nucleated red cells.

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Beta Thalassaemia Major: Treatment

1. Regular blood transfusions (life long) – trough Hb 90-100 g/l (aiming for v. high)
2. Iron chelation e.g. desferrioxamine, deferiprone, Deferaxirox (urine/faeces excretion)
3. Folic aid
4. Bone marrow transplantation in early life
5. (Splenectomy rarely indicated) – sign of poor management

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Beta Thalassaemia Major: Transfusion 2 aims

1. Prevent symptomatic anaemia allowing children to live grow and develop.
2. Suppress marrow hyperplasia with skeletal consequences

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Beta Thalassaemia Major: Problem with transfusions

With transfusions come the inevitable problem of iron overload (currently the life limiting factor) esp heart, liver endocrine. Compliance with transfusions and chelation is the biggest prognostic factor.
• Heart – arrhythmias
• Endocrine – diabetes, thyroid, ovaries – anaemia

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Beta Thalassaemia Major: Thalassemia specialist clinic review

1. Height, weight, pubertal development, menstrual pattern etc.
2. Medications and compliance with chelation
3. Pre and post transfusion Hb
4. RBC unit requirements
5. Assess for complications of Fe overload
6. Ferritin, MRI T2 (quantifies cardiac and liver iron – reduces need for liver transfusion), LFTs, bone deformity (osteoporosis risk), TSH, T4, HbA1c, FSH, testosterone
7. Assess for chelation side effects and toxicities (e.g. FBC, audiology, ophthalmology, urine dipstick and Cr, LFTs)

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Beta-Thalassaemia trait (Heterozygous): Features

Mild Microcytic hypochromic anaemia

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Beta-Thalassaemia trait (Heterozygous): Hb

10-11 g/dL (Low)

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Beta-Thalassaemia trait (Heterozygous): MCV

50-70 fl

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Beta-Thalassaemia trait (Heterozygous): MCH

20-22 pg (Flow)

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Beta-Thalassaemia trait (Heterozygous): Family screen

Asymptomatic; often identified on routine blood count

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Beta-Thalassaemia trait (Heterozygous): Haemoglobin type

Increased HbA2

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Beta-Thalassaemia trait (Heterozygous): Important to identify

Important to identify for family screening and avoidance of inappropriate iron therapy

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Alpha Thalassemia → Description

Deficient/absent alpha subunits resulting in
• Excess beta subunits
• Excess gamma subunits newborns

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Alpha Thalassemia → Three main types

Silent Carrier
Trait
Haemoglobin H disease
Major (Haemoglobins Bart’s)

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Alpha Thalassemia → Silent Carrier

1 gene not working

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Alpha Thalassemia → Trait

2 genes not working

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Alpha Thalassemia → Haemoglobin H disease

3 genes not working

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Alpha Thalassemia → Major (Haemoglobin Bart’s)

All 4 not working – fatal hydrops futalis occurs

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α – thal trait =

α – thal trait =

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Both Parents have α +/ α +

With an functional and non-functional gene on each chromosome, then all their children will be carriers, exactly as their parents → slightly abnormal blood parameters.

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Both parents have α o – thalassemia trait

If both parents have two non-functing genes on the same chromosome and normal genes on the other than there is a 1:4 chance of a child inheriting the normal genes, a 1:2 chance of being a carrier like the parents, but also a 1:4 chance of inheriting only the non functioning chromosomes which means that this child will have hydrops fetalis.

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Parents are different types of carriers

One parent (the father in this cause) has two non-functional gene on one chromosome while the other chromosome is “normal” (α o trait). The other parent (in this case the mother) has one non-functional gene (α + trait). Each child has a 1:4 chance of being either totally unaffected, or have the α o , or the α + trait or being affected by HbH disease.

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α -/ α α

• α + thalassaemia silent carrier
• Asymptomatic
• Minority show reduced MCV and MCH

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--/ α α

α o thalassaemia trait (indistinguishable from α +/ α + thalassaemia trait)

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α -/ α-

α +/ α + (indistinguishable from α o thalassaemia trait)
• Hb normal or slightly reduced
• MCV and MCH reduce
• No symptoms

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α -/--

HgH disease
• Reduced α chains; β4 tetramers (HbH) form
• Hb 7-11 g/dL; MCV and MCH reduced
• Jaundice, hepatosplenomegaly, leg ulcers, gallstones
• Folic acid, transfusions, splenectomy

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--/--

Hb Barts Hydrops
No α chains produced
Mainly γ chains: form tetramers γ4 = Hb Barts
Intrauterine death and stillborn

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How can we differentiate between Fe def & thal trait?

• Both cause microcytic anaemia
• Ethnicity
• Previous normal MCV (Fe more likely)
• Ferritin (low=Fe deficiency)

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• Almost all αo thal trait has MCH

<25 pg

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• α- thal trait in African and Indian populations is nearly always

α+ thal.

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α+ thal.

Inherited β globin mutations – changes Haemoglobin structure.

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S =

Sickle cell Hb gene

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If you have one healthy Beta and one HbS

you have Sickle cell trait (HbAS genotype) – asymptomatic

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If you have inherit 2 HbS genes )HbSS genotype)

You have sickle cell anaemia (no HbA only HbS)

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If you inherit one βo and one HbS (HbS βo) you have

Sickle cell anaemia (no HbA only HbS)

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Hbs can also combine with other βglobin chain mutations e.g

C (HbSc genotype)

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Sickle Cell disease phenotypes:

Sickle cell anaemia (SS)
Sickle Hb C disease (SC)
Sickle S beta plus (Sβ+ thalassemia)
Sickle Beta zero (Sβo thalassemia)

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Sickling disorders

A relatively common severe inherited cause of morbidity and mortality

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Sickle cell Incidence

1 in 10000 live births in UK

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Sickle cell African-American incidence

SCD is 1/375 for HbSS
1 in 835 for HbSC
1 in 1, 667 for Sickle Beta-thalassemia.

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Sickle cell Clinical phenotype

Variable

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Sickle cell HbS carriers

1 in 4 in West Africa
1 in 10 in Afro-caribeens

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Sickle cell Western country life expectancy

Approx. 40 yrs
In developing countries far less than this

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Sickle cell Underlying genetic changes

Glutamic acid is submitted for valine at the 6th amino acid.

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Sickle cell Pathophysiology

Polymerization of sickle haemoglobin when deoxygenated forming sickle cells.

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Normal cells

Disc-shaped
Deformable
Lifespan of 120 days

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Sickle cells

Sickle-shaped
Rigid
Lives for 20 days or less

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Haemolysis

• Reduced red cell survival due to increased destruction
• Partially compensated by increased production

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Vaso-occlusion

• Rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue.
• Produce tissue hypoxia
→ The result is pain and often damage to organs (acute and chronic).

87

Haemolytic anaemia description

• Hb 6-10 g/dl (baseline)
• Increased reticulocytes, sickle cells, target cells and hyposplenic changes.
• Usually well-adjusted to anaemia: HbS has decreased oxygen affinity (releases O2 to tissues)
• Red cells contain >80% HbS (remainder HbF)

88

Vaso-occlusive crises

• Acute episodes of bone pain, worsening anaemia, pulmonary and neurological complications.
• Precipitated by cold, dehydration, infection.

89

Acute complications of sickle cell anaemia

• Hand-Food Syndrome
• Splenic Crisis
• Infections
• Acute Chest Syndrome (hypoxia)
• Stroke, VTE
• Priapism
• Aplastic Crisis

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Chronic complications of sickle cell anaemia

• Delayed growth and puberty in children
• Gallstone
• Blindness, kidney failure
• Ulcers on the legs
• Pulmonary Arterial hypertension
• Hip problems - AVN

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X-ray changes in ickle cell anaemia

White out in chest due to hypoxia

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Hip x-ray changes

Avascular necrosis of the femoral head

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Sickle cell trait


• If one parent has sickle cell anaemia (HbSS) and the other is completely unaffected (HbAA) then all the children will have sickle cells trait.
• None will have sickle cell anaemia
• The parent who has sickle cell anaemia (HbSS) can only pass the sickle haemoglobin gene to each of their children.

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Sickle cell anaemia

• If both parents have sickle cell trait (HbAS) there is a one in four (25%) chance that any given child could be born with sickle cell anaemia.
• There is also a one in four chance that any given child could be completely unaffected.
• There is a one in two (50%) chance that any given child will get the sickle cell trait.

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Treatment of Sickle Cell Anaemia:

• Early diagnosis (antenatal and newborns)
• Penicillin and folic acid prophylaxis
• Vaccinations
• Acute episodes treate with varying combinations of iv fluids, oxygen, prompt analgesia, antibiotics.
• Hydroxyurea (can reduce frequency of painful crises and acute chest syndrome)
• Bone marrow transplantation (rarely done in childhood as phenotype unpredictable. Occasionally considered in specific situations).

96

Transfusion:

• Reserved for specific indications (aim to reduce HbS%)
• CVA, acute chest syndrome, splenic sequestration, aplastic crisis, pre-major surgery etc.
• Don’t just transfuse patients because they are anaemic
• “Top up” or “ exchange” transfusion.

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Sickle Cell trait (HbAS) Incidence

<50% HbS

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Sickle Cell trait (HbAS) Clinically

Asymptomatic
Occasionally renal papillary necrosis
Inability to concentrate urine

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Sickle Cell trait (HbAS) Presentation

Only sickle under severe hypoxic conditions e.g. unpressurised aircraft, anaesthesia.
→ Otherwise normal life-expectancy and no health problems.

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Why is it important to diagnose asymptomatic carriers?

• Prenatal and antenatal genetic counselling
• Explain abnormalities in FBC or blood film – may end up on iron therefore important to do.
• Rarely can become symptomatic in extreme circumstances.

101

Important Hb carrier disorders to be detected

• Sickle cell disorders = HbA with: HbS, HbC, β-thal (Rarer: HbD-punjab, HbO-Arab)
• αo-thalassaemia – rare: non-deletional alpha+ (e.g. alphacs/alpha)
• βo and β+ thalassaemia (and interaction with:HbE) (SEE rare in notes)

102

Haemoglobinopathy diagnosis

Clinical information – age, ethnicity, gender, pregnancy, statusHb variant present
Laboratory information – RBC parameters, Fe status (Ferritin), film
HPLC:
• Hb variant present
• HbA2 and HbF quantification
Hb variant confirmation (e.g. electroph)
DNA analysis, Mass spectrometry (in minority)

103

Sickle cell solubility test

Is a widely used screening method for sickle cell anaemia. The sickle cell solubility test relies on the relative insolubility of HbS in concentrated phosphate buffers compared to HbA and other Hb variants. HbS precipitates causing a cloudy solution.

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