Haemoglobinopathies Flashcards
Haemoglobin
Four globin subunit proteins or ‘chains’
Each with iron-containing haem prosthetic group attached
Haemoglobin subunits
Each have slightly differing aa sequences
–> precise folding of each subunit + way the 4 fit together is critical in determining ability of molecules to carry + release O2
Adult Haemoglobin
2 alpha
2 beta
Alpha subunit
2 genes for subunit on chromosome 16
Therefore overall 4 genes for alpha subunit, 2 maternal + 2 paternal
Beta subunit
Five genes for subunit on chromosome 11
- -> epsilon, gamma A, gamma G, delta and beta
- -> each produce slightly different forms of beta globin
Different haemoglobins
Can be produced from different gene combinations from chromosomes 11 + 16
First form Haemoglobin
In Embryonic Yolk Sac (up to about 6wks)
Zeta 2 Epsilon 2 a.k.a Hb Gower-1
V high O2 affinity
After 6 weeks Haemoglobin
Haemoglobin F
2 alpha 2 gamma
Higher affinity than maternal haemoglobin, so O2 passed from maternal to foetal Hb
3-6 months after birth
HbA replaces foetal haemoglobin Some HbA2 (alpha 2 gamma 2) also present in adult
Thalassaemia
Genetic defect resulting in inadequate quantities of one or other of subunits that make up haemoglobin
Can be alpha or beta
Alpha thalassaemia
One or more of alpha genes on chromosome 16 deleted or faulty
Beta thalassaemia
Point mutation on chromosome 11
Thalassaemia genetic defect
Mutation in non-coding introns of gene –> inefficient RNA splicing to produce mRNA –> decreased mRNA production
Partial or total deletion of globin gene
Mutation in promoter –> decreased expression
Mutation in termination site –> production of longer, unstable mRNA
Nonsense mutation
Alpha thalassaemia epidemiology
Manifests immediately at birth
Severity depends on number of gene alleles defective or missing
Alpha thalassaemia- 1 alpha gene defective
Alpha thalassaemia minima Minimal effect on haemoglobin synthesis Individuals called silent carriers May have slightly reduced MCV and MCH 3 alpha globin genes enough to permit normal Hb production No clinical symptoms
Alpha thalassaemia- 2 alpha genes defective
Alpha thalassaemia minor
2 alpha globin genes permit normal RBC production, but mild microcytic hypochromic anaemia
Can be mistaken for iron deficiency anaemia –> inappropriately treated with iron
Alpha thalassaemia- 3 alpha genes defective
Haemoglobin H disease
2 unstable haemoglobins in blood
–> Haemoglobin Barts (4 gamma) and Haemoglobin H (4 beta)
Both unstable
Both have higher O2 affinity than Hb –> poor release of O2 in tissues
Microcytic hypochromic anaemia
Alpha thalassaemia- 4 alpha genes defective
Foetus can’t survive outside uterus
May not survive gestation
Most infants stillborm with hydrops fetalis
Oedematous
Little circulating Hb
–> all tetrameric gamma chains (Haemoglobin Barts)
Beta thalassaemia
Mutations in Haemoglobin beta gene on Chromosome 11
Autosomal recessive
Heterozygous, homozygous or intermedia
Beta thalassaemia- heterozygous
Thalassaemia trait Beta thalassaemia minor Decreased MCV, MCH Normal HbA and HbF Increased HbA2
Beta thalassaemia- homozygous
Beta thalassaemia major
No beta chains
Body’s inability to construct beta-globin leads to underproduction of Haemoglobin A
–> microcytic anaemia
Beta thalassaemia- intermedia
Both beta globin genes mutated
But still able to make some beta chains
Beta thalassaemia manifestation
When switch from gamma to B chain synthesis occurs several months after birth
May be a compensatory increase in g and d chain synthesis –> increased levels of Hb F and A2
Pathological effects B thalassaemia
Excess alpha globins produced in developing erythroblasts in marrow
–> alpha tetramers unstable + precipitate on erythrocyte membrane
Causes intra-medullary destruction of developing erythroblasts, erythroid hyperplasia + ineffective erythropoiesis
–> SEVERE HYPOCHROMIC MICROCYTIC ANAEMIA
Untreated B Thalassaemia Minor
Hypochromic Microcytic Anaemia Bone marrow expansion, Splenomegaly Bone deformity, extramedullary erythropoietic masses Failure to thrive 6 months HF and death age 3-4
Beta thalassaemia facial bone abnormalities
Bossing of skull
Hypertrophy of maxilla- exposed upper teeth
Depression of nasal bridge
Periorbital puffiness
Thalassaemia Major treatment
Regular transfusions
Iron chelation therapy
Splenectomy
Allogeneic BM transplant
Thalassaemia vs Iron deficiency
In Thalassaemia, although red cells are microcytic, serum iron and ferritin are normal
Iron overload
Excess haemolysis –> free iron released –> free iron in blood
If hydrogen peroxide present, Fenton reaction can occur
–> hydroxyl radicals produces –> oxidise and damage all biological tissues
Fenton reaction
Hydroxyl radicals oxidise + damage all biological tissues
Cirrhosis, diabetes, glandular dysfunction (GH deficiency)
Iron Chelating compounds
Bind to free iron
Prevent Fenton reaction
Desferoxamine
‘Desferal’
Iron Chelation therapy 8-12 hour s.c. infusion 5-7 days/week Chelation enhanced with ascorbate Toxicity with higher doses - diarrhoea, vom, fever
Deferiprone
Exjade
Oral iron chelator
75-100mg/kg/day
Agranulocytosis/neutropenia may occur
Not suited for pregnancy
Deferasirox
Exjade
Once daily iron chelator
GI bleeding
Kidney or liver failure
Sickle cell
Mutant form of one of beta haemoglobin subunits
Red cells sickles
Obstruct capillaries + restrict blood flow to organ
–> ischemia, pain + organ damage
Sickle cell signs
Haemolytic anaemia- Hb 6-8g/dL
Microvascular occlusion- rigid sickle cells adhere to endothelium, interact with WBC + vessel wall, cause NO depletion
Large vessel wall damage
Sickle cell Hb
Glutamic acid –> Valine (GAG-GTG)
Codon 6 of beta globin chain
Beta S produced
Produced abnormal Hb S- (2 alpha 2 BetaS)
HbS
May precipitate or crystallise
Distorts RBCs–> fragile + easily destroyed
Sickled RBCs
Decreased survival time
Occlude capillaries
Lead to ischaemia + infarction of organs downstream of blockage
Clinical consequence Sickle Cell
Anaemia
Increased susceptibility to infection
Vaso-occlusive crises
Chronic tissue damage
SCD management
Infection prophylaxis Analgesics for crises Education Transfusions Hydroxyurea (increases HbF, reduced painful crises) Bone marrow transplant
Carrier detection screening
Simple blood analysis
Newborn screening
Cord blood
Heel-prick sample
HbC
Mutation where abnormal beta subunit
Reduced plasticity + flexibility of erythrocytes
Red cell destruction
HbC homozygous
Mild haemolytic anaemia
HbC heterozygous
No anaemia
HbE
Single point mutation in Beta chain
Get from both parents
Increases after 3-6 months –> mild beta thalassaemia
G6PD deficiency
X linked recessive
Causes haemolysis + jaundice
Mediterranean
Triggers e.g. Fava beans, oxidative drugs like aspirin or infection
