Haemoglobinopathies Flashcards
What chains make up adult haemoglobin?
What is it also known as?
2 alpha and 2 beta
Haemoglobin A
Where are the gene(s) for alpha subunit found
Chromosome 16
2 genes on each chromosome so 4 altogether
Where are the gene(s) for beta subunit found?
5 genes for beta subunit on chromosome 11
Name the 5 genes that can produce beta chain (5’ to 3’ direction)
Epsilon gamma A gamma G delta beta
Is adult or foetal haemoglobin better at binding oxygen?
Foetal
What is the first form of haemoglobin formed in the embryonic yolk sac
Hb Gower-1, also called Zeta 2 Epsilon 2
What haemoglobin is made after week 6 of gestation
HbF (foetal haemoglobin)
Alpha 2 gamma 2
Where in the foetus is HbF made?
Liver and spleen
Does HbA, HbF or Hb Gower-1 have higher affinity?
H Gower-1
When does HbA start to replace HbF
3-6 months after birth
What is HbA2
alpha 2 delta 2
What % of each haemoglobin type are present in adult
96-97% HbA
2-3.5% HbA2
<1% HbF
What % of each haemoglobin types are found in neonate
10% HbA
<1% HbA2
90% Hbf
Define thalassaemia
Genetic defect resulting in inadequate quantities of one of the haemoglobin subunits
What is alpha thalassaemia
Results when one or more alpha genes of chromosome 16 is deleted or faulty
What is beta thalassaemia
Results when there is a point mutation of chromosome 11
When does alpha thalassaemia manifest
Immediately at birth
What happens if one alpha gene is defective
Alpha thalassaemia minima
Minimal effect on synthesis
Silent carriers
What happens if two alpha genes are defective?
Alpha thalassaemia minor
Mild microcytic anaemia
Can be mistaken for iron deficiency anaemia
What happens if three alpha genes are defective?
Haemoglobin H disease
2 unstable haemoglobins present in blood: Hb Barts (y4) and haemoglobin H (beta 4)
Microcytic hypochromic anaemia
What happens if four alpha genes are defective
Foetus can’t live outside uterus
Many stillborn, rest die after birth
Circulating haemoglobin is barts- tetrameric gamma chains
How is beta thalassaemia inhertited
Autosomal recessive
What are the 2 main genotypes of beta thalassaemia
Heterozygous (beta thalassaemia minor)
Homozygous (major/ Cooleys anaemia)
When does beta thalassaemia manifest
Several months after bith when switch from gamma to beta chains begins
Describe the pathological effects of beta thalassaemia
Excess alpha globins produced which are unstable and cause intra-medullary destruction of developing erythroblasts, erythroid hyperplasia and ineffective erythropoiesis
How does HbF levels present in beta thalassaemia major
High
Effects of untreated beta thalassemia major (5)
- Hypochromic, microcytic anaemia
- Bone marrow expansion
- Bone deformity
- Splenomegaly
- Failure to thrive by 6 months, death aged 3-4
Usual treatments for thalassamia major
Regular transfusions with iron chelating therapy to prevent overload
Bone marrow transplant
HbF modulating treatments
What do iron chelating compounds do
Bind free iron and prevent Fenton reaction
What is the fenton reaction and what does it cause?
Free iron reacts with hydrogen peroxide producing free radicals
Responsible for cirrhosis, diabetes, glandular synfunction
Name an oral iron chelation therapy
Deferiprone
Side effects of desferoxamine
Toxicity- diarrhoea, vomiting, fever, hearing and eye probs
Side effects of deferasirox
GI bleeding, kidney and liver failure
What is problem with having sickle shaped red cells?
Can block capillaries, restrict blood flow to organ and cause ischaemia, pain and organ damage
Signs of sickle cell disease
Haemolytic anaemia (Hb 6-8)
Microvascular occlusion
Large vessel damage
What mutation occurs in sickle cell anaemia
What does this produce?
GAG–> GTG
Glutamic acid–> valine
Abnormal beta chain
What is the haemoglobin in sickle cell called
Haemoglobin S
alpha 2 beta S 2
How does survival time differ in sickle cells
It is decreased
4 major clinical consequences of sickle cell disease
- Anaemia
- Increased infection risk
- Vaso-occlusive crises
- Chronic tissue damage
How can sickle cell be managed
Analgesics for painful crises Transfusion Hyroxyurea increases HbF Bone marrow transplant Infection prophylaxis
How can couples be screened for sickle cell
Simple blood analysis (full blood count and haemoglobinopathy screen)
When is the highest risk time for sickle cell complication
6 months- 2 years
How is neonatal screening carried out
Heel prick
Implemented in UK since 2006
What is haemoglobin C?
Mutation causing abnormal Beta subunit
Reduced plasticity and flexibility–> haemolysis
Homo- mild haemolytic anaemia
What is haemoglobin E?
Single point mutation in Beta
3-6 months fetal haemoglobin disappears, HbE increases mild beta thalassamia
Which gene is switched off after 6 weeks of gestation
Zeta gene
Where is the first form of haemoglobin produced
Embryonic solk sac
Where is HbF produced
Liver/ spleen
What variants of Gower haemoglobin can occur in the early weeks
- Gower 2 alpha episilon 2
Portland
How does beta thalassaemia major lead to microcytic anaemia
Bodys inability to construct beta-globins–> underproduction of haemoglobin A.
Reduction in HBA available to fill red blood cells leads to microcytic anaemia
Describe the blood results of a heterozygous character of beta thalassaemia
- Mildly low Hb
- Low MCV
- Normal HbA
- High HBA2
- Normal HbF
How may HbS behave in deoxygenated blood
Precipitate or cystallise, distorting the cells and making them fragile and easily destroyed
