Flashcards in Haematology Haemoglobinopthies Deck (103):
Main Haemoglobin in adults
The main Hb in adults is HbA
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.
Crucial function in O2 and Co2 transport
2α and 2γ
2α and 2δ (small amounts in the body)
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)
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)
Fetal haemoglobin and globin structure
haemoglobin and structure
• 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
Reduced or absent synthesis of one or more of the globin chains of adult haemoglobin.
Imbalance in gobin chain synthesis
Thalassemia: Alpha thalassaemia usually caused by
Thalassemia: Beta thalassaemia usually caused by
Thalassemia: Results in
Hypochromic anaemia’s of varying severity (Pale)
Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma.
Beta Types of Genetic Defects
βo – nothing works
β+ - reduced synthesis
S – sickle cell
C (D, E, O) – a haemoglobin variant
Autosomal recessive – carriers are asymptomatic, but may mild abnormalities in blood tests.
A null absent gene
Reduced protein synthesis (to a variable degree)
Beta thal trait
One healthy β and one βo – can still make HbA
Beta thalassemia major
2 βo you cant make HbA (Both mum and dad are at least carriers)
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
β – thal trait
Homozygous β – thal (thal major)
No HbA. Transfusion dependence from 3-4/12
Variable. Maybe thal intermedia
Β-thal trait =
= Thalassemia indices + Increased HbA2 (increased HbF =in 50%)
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.
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)
Inheritance If both parents have βo trait children
• 25% children will have β thal major
• 50% will be carriers
• 25% will be unaffected
Beta Thalassaemia Major: Description
Complete absence of HbA
Excess alpha chains accumulate and damage red cells
Beta Thalassaemia Major: Pathophysiology
Ineffective erythropoiesis – bone marrow RBC
Excessive RBCs destruction
Intramedullary and extra medullary
Extra-medullary haematopoiesis (EPO drive of anaemia)
Beta Thalassaemia Major: Clinical features
1. Symptomatic anaemia in first few months of life
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
Beta Thalassaemia Major: Prevention
Family screening, antenatal screening and prenatal diagnosis
Beta Thalassaemia Major: X-Ray of skull
Ill-defined thin cortical layer – medullary hyperplasia
Beta Thalassaemia Major: Blood film
Severe anaemia with marked hypochromic, target cells and nucleated red cells.
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
Beta Thalassaemia Major: Transfusion 2 aims
1. Prevent symptomatic anaemia allowing children to live grow and develop.
2. Suppress marrow hyperplasia with skeletal consequences
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
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)
Beta-Thalassaemia trait (Heterozygous): Features
Mild Microcytic hypochromic anaemia
Beta-Thalassaemia trait (Heterozygous): Hb
10-11 g/dL (Low)
Beta-Thalassaemia trait (Heterozygous): MCV
Beta-Thalassaemia trait (Heterozygous): MCH
20-22 pg (Flow)
Beta-Thalassaemia trait (Heterozygous): Family screen
Asymptomatic; often identified on routine blood count
Beta-Thalassaemia trait (Heterozygous): Haemoglobin type
Beta-Thalassaemia trait (Heterozygous): Important to identify
Important to identify for family screening and avoidance of inappropriate iron therapy
Alpha Thalassemia → Description
Deficient/absent alpha subunits resulting in
• Excess beta subunits
• Excess gamma subunits newborns
Alpha Thalassemia → Three main types
Haemoglobin H disease
Major (Haemoglobins Bart’s)
Alpha Thalassemia → Silent Carrier
1 gene not working
Alpha Thalassemia → Trait
2 genes not working
Alpha Thalassemia → Haemoglobin H disease
3 genes not working
Alpha Thalassemia → Major (Haemoglobin Bart’s)
All 4 not working – fatal hydrops futalis occurs
α – thal trait =
α – thal trait =
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.
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.
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.
α -/ α α
• α + thalassaemia silent carrier
• Minority show reduced MCV and MCH
--/ α α
α o thalassaemia trait (indistinguishable from α +/ α + thalassaemia trait)
α -/ α-
α +/ α + (indistinguishable from α o thalassaemia trait)
• Hb normal or slightly reduced
• MCV and MCH reduce
• No symptoms
• 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
Hb Barts Hydrops
No α chains produced
Mainly γ chains: form tetramers γ4 = Hb Barts
Intrauterine death and stillborn
How can we differentiate between Fe def & thal trait?
• Both cause microcytic anaemia
• Previous normal MCV (Fe more likely)
• Ferritin (low=Fe deficiency)
• Almost all αo thal trait has MCH
• α- thal trait in African and Indian populations is nearly always
Inherited β globin mutations – changes Haemoglobin structure.
Sickle cell Hb gene
If you have one healthy Beta and one HbS
you have Sickle cell trait (HbAS genotype) – asymptomatic
If you have inherit 2 HbS genes )HbSS genotype)
You have sickle cell anaemia (no HbA only HbS)
If you inherit one βo and one HbS (HbS βo) you have
Sickle cell anaemia (no HbA only HbS)
Hbs can also combine with other βglobin chain mutations e.g
C (HbSc genotype)
Sickle Cell disease phenotypes:
Sickle cell anaemia (SS)
Sickle Hb C disease (SC)
Sickle S beta plus (Sβ+ thalassemia)
Sickle Beta zero (Sβo thalassemia)
A relatively common severe inherited cause of morbidity and mortality
Sickle cell Incidence
1 in 10000 live births in UK
Sickle cell African-American incidence
SCD is 1/375 for HbSS
1 in 835 for HbSC
1 in 1, 667 for Sickle Beta-thalassemia.
Sickle cell Clinical phenotype
Sickle cell HbS carriers
1 in 4 in West Africa
1 in 10 in Afro-caribeens
Sickle cell Western country life expectancy
Approx. 40 yrs
In developing countries far less than this
Sickle cell Underlying genetic changes
Glutamic acid is submitted for valine at the 6th amino acid.
Sickle cell Pathophysiology
Polymerization of sickle haemoglobin when deoxygenated forming sickle cells.
Lifespan of 120 days
Lives for 20 days or less
• Reduced red cell survival due to increased destruction
• Partially compensated by increased production
• 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).
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)
• Acute episodes of bone pain, worsening anaemia, pulmonary and neurological complications.
• Precipitated by cold, dehydration, infection.
Acute complications of sickle cell anaemia
• Hand-Food Syndrome
• Splenic Crisis
• Acute Chest Syndrome (hypoxia)
• Stroke, VTE
• Aplastic Crisis
Chronic complications of sickle cell anaemia
• Delayed growth and puberty in children
• Blindness, kidney failure
• Ulcers on the legs
• Pulmonary Arterial hypertension
• Hip problems - AVN
X-ray changes in ickle cell anaemia
White out in chest due to hypoxia
Hip x-ray changes
Avascular necrosis of the femoral head
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.
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.
Treatment of Sickle Cell Anaemia:
• Early diagnosis (antenatal and newborns)
• Penicillin and folic acid prophylaxis
• 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).
• 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.
Sickle Cell trait (HbAS) Incidence
Sickle Cell trait (HbAS) Clinically
Occasionally renal papillary necrosis
Inability to concentrate urine
Sickle Cell trait (HbAS) Presentation
Only sickle under severe hypoxic conditions e.g. unpressurised aircraft, anaesthesia.
→ Otherwise normal life-expectancy and no health problems.
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.
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)
Clinical information – age, ethnicity, gender, pregnancy, statusHb variant present
Laboratory information – RBC parameters, Fe status (Ferritin), film
• Hb variant present
• HbA2 and HbF quantification
Hb variant confirmation (e.g. electroph)
DNA analysis, Mass spectrometry (in minority)