L9: Haemoglobinopathies and Haemolytic Anaemias

Question 1

What are haemoglobinopathies?

Answer 1

Autosomal recessive inherited disorders

Defects in globin chain synthesis

Question 2

What are the two main categories for haemoglobinopathies?

Answer 2

Abnormal haemoglobin variants–> alter stability and/or function (sickle cell)

Absent or reduced expression of normal globin chains–> Thalassaemias

Question 3

What is the structure of normal haemoglobin?

Answer 3

Tetramer of 4 globin polypeptide chains–> 2α and 2 non α (β, delta, gamma)–> non covalent interaction
Chain associated with O2 binding haem group

Question 4

What are the different types of haemoglobin?

Answer 4

A–> 2α2β –> 95%
A2–> 2α2 delta–> 3%
F–> 2α2gamma–> <1% –> experessed in foetus and up to 6-9 months after birth–> >affinity for O2 than β

Question 5

Where are the globin genes located? How many of each gene do we have?

Answer 5

Both alpha encoded on chromosome 16
Beta encoded on chromosome 11 along with delta and gamma
4α globin genes= 2 paternal, 2 maternal
2β globin genes= 1 paternal and 1 maternal
Experession tightly regulated

Question 6

What are thalassaemias?

Answer 6

Normal globin expression tightly controlled
1:1 ratio alpha: non alpha
Thalassaemias–> defect in regulation–> abnormalities in relative and absolute amount of globin chains
α thalassaemias–> Alpha genes product expression defect
β thalassaemias–> Beta gene product expression defect

Question 7

Where are thalassaemias more prevalent?

Answer 7

Alpha thalassaemia–> Far east

Beta thalassaemia–> South Asian, Mediterranean, Middle East

Question 8

What are the different types of α thalassaemias? What are the features?

Answer 8

Different–> number of α chains affected
1α deficient–> Silent carrier –> assymptomatic
2α deficient–> α-Thalassemia trait–> minimal or no anaemia, microcytosis and hypochromia in RBCs, (both genes on one chromosome or one gene on each chromosome)
3α deficient–> Haemoglobin H (HbH) disease–> moderately severe–> tetrameres of β globin form–> microcytic, hypochromic, target cells and heinz bodies
4α deficient–> Hydrops fetalis–> Severe, intrauterine death–> gamma globin tetrameres–> O2 not released

Question 9

What are the different types of β thalassaemias? What are the features?

Answer 9

Only 2β genes one on each Chr11 (mutation rather than deletion)
β0–> total absence, β+–> reduction in globin production
β- thalassaemia minor or thalassemia trait–> assymptomatic–> heterozygous (β0/β or β+/β)
β-thalassaemia intermedia–> severe anaemia, no blood transfusion–> Homozygous mild or heterozygous severe or some double heterozygosity
β-thalassaemia major–> severe transfusion dependent–> 6-9 months old presents–> β0/β0 or β+/β+

Question 10

What does the blood profile of a person with thalassaemia look like?

Answer 10

Hypochromic and microcytis RBC–> low Hb

Anisopoikilocytosis–> variance in size/shape–> target cells, circulating nucleated red blood cells, Heinz bodies

Question 11

How does thalassaemias result in anaemias?

Answer 11

Relative excess of unaffected chain results in defective nature of RBCs–> insoluble aggregates–> α globin in β thalassaemias
Hb aggregates oxidised–> premature death of erythroid precusor cells in bine marrow–> ineffective erythropoiesis
Excessive destruction of mature RBC–> spleen–> shortened RBC survival (microlytic anaemia as RBC destroyed)

Question 12

What are the consequences of Thalassaemias?

Answer 12

Extramedullary haemopoisesis–> compensatory effort–> Splenomegaly, hepatomegaly, expansion of haemopoiesis into bone cortex (impaired growth and classical skeletal abnormalities)
Reduced O2 –> stimulation of EPO–> more defective RBCs
Iron overload–> premature death
–> excessive absorption of dietary iron–> ineffective erythropoiesis
–> Repeated blood transfusions–> treat anaemia but iron accumulates
Reduced Life expectancy

Question 13

What are the treatments for thalassaemias?

Answer 13

Transfusion
Iron Chelation–> bind iron reducing overload
Folic acids–> support erythropoesis
Immunisation–> reduced infection chance
Holisitic care–> Cardiology, endocrinology, psychological, opthamology–> manage complications
Stem cell transplant–> produce normal Hb and RBC
Pre-conception counselling for ‘at risk’ couples–> screening

Question 14

What is sickle cell disease?

Answer 14

Autosomal recessive--> point mutation in β globin gene
GAG--> GTG --> glutamic acid--> valine at position 6
Haemoglobin S (HbS)

Question 15

What are the different types of sickle cell disease?

Answer 15

Heterozygous–> HbS carrier–> Mild assymptomatic anaemia
Homozygous–> HbSS -> severe
Hbs can be co-inherited along with other abnormal Hb to cause sickling disorder

Question 16

Where is HbS most prevalent and why?

Answer 16

HbS–> 30% West Africa

Protection against Malaria

Question 17

When do the problems in HbS occur?

Answer 17

HbS usually well tolerated as HbS readily gives up O2 compared to HbA
Problem–> low O2–> HbS forms polymers (Hb normally form tetramers) –> sickle shaped cell
Irreversible ones (repeated sickling RC membrane looses elasticity)–> Less deformable–> occlusions in small BV- ‘Sticky’

Question 18

What are the types of crisis caused in sickle cell?

Answer 18

Vaso-occlusive episodes: occlusion of small capillaries, recurrent acute pain –> end organ damage
Aplastic anaemia: fail to produce enough RBC
Haemolytic anaemia: cells are removed
End organ damage occurs as a result of acute thromboses or O2 deprivation

Question 19

What are the signs and symptoms of sickle cell?

Answer 19

Retinopathy
Splenic atrophy
Avascular necrosis (femoral head etc...)
Acute chest syndrome
Stroke
Osteomyelitis
Skin Ulcers
Kidney Infarcts
Priaprism--> painful erection in men

Question 20

How is sickle cell anaemia treated?

Answer 20

Gold standard–> haematopoietic stem cell transplant (rare due to difficulty finding a donor)
Red cell exchange
Treat the symptoms

Question 21

What are haemolytic anaemias?

Answer 21

Abnormal breakdown of RBCs in BV (intravascular haemolysis) or in spleen or other reticuloendothelial system (extravascular haemolysis)
Bone can compensate but only up to a point (6 fold increase) –> rate of destruction&raquo_space; production= anaemia

Question 22

What are the two types of haemolytic anaemias?

Answer 22

Inherited (defective gene) and acquired (damage to cells)

Question 23

What are the different causes for inherited haemolytic anaemias?

Answer 23

Glycolysis defect–> pyruvate kinase deficiency
Pentose P pathway: G6PDH deficiency leads to oxidative damage
Membrane protein: Hereditary spherocytosis
Haemoglobin defect: Sickle cell

Question 24

How does glycolysis defect result in anaemias?

Answer 24

Glycolysis defect–> pyruvate kinase deficiency: autosomal recessive: PKLR gene: required for ATP synthesis (as no mitochondria so no OP): Na+/K+ ATPase stops working: K+ out of cell: H2O out cell shrivels and dies

Question 25

How does G6PDH deficiency result in anaemia?

Answer 25

X linked recessive
Rate limiting step of pentose phosphate pathway
Maintain NADPH levels–> protect OS–> maintain glutothione levels
↓ G6PDH= OS= Damaged RBC–> removed by spleen phagocytosis

Question 26

How do inherited defects in membrane proteins lead to haemolytic anaemias?

Answer 26

3 different types: Hereditary Spherocytosis, Hereditary Eliptocytosis and Hereditary Pyropoikilocytosis

Question 27

What happens in hereditary spherocytosis?

Answer 27

Autosomal dominant
Defects in Band 3 (transmembrane protein, binds ankryin and protein 4.2), Protein 4.2 (ATP binding protein, regulates association of Band 3 and ankyrin), Ankyrin (links spectrin to band 3), Spectrin (links PM to cytoskeleton)
Local dissociation of cytoskeleton and PM–> spherocyte shape
SA: volume ration reduced–> less deformable–> trapped and damaged as they pass through spleen

Question 28

What happens in hereditary eliptocytosis?

Answer 28

Defect in spectrin
Ellipitcal shape
Also defect in band 3, band 4.2 and glycophorin C

Question 29

What happens in hereditary pyropoikilocytosis?

Answer 29

Spectrin defect
Severe hereditary eliptocytosis
Abnormal senstivity of RBC to heat

Question 30

What are the different types of acquired anaemias?

Answer 30

Mechanical damage–> microangiopathic anaemia
Antibody damage–> Autoimmune
Oxidant damage–> exposure to chemical or oxidants
Heat damage–> severe burns
Enzymatic damage–> snake venom

Question 31

What are microangiopathic anaemias? What is the name of the fragments of cells produced?

Answer 31

RBC damaged by physical trauma
- Shear stress–> defective heart valve- aortic stenosis
- Cell snagging–> pass through small vessels laden with fibrin strands–> increased activation of coagulation cascade (Disseminated intravascular coagulation-DIC)–> bleeding and clotting at the same time
- Heat damage from severe burns
- Osmotic damage
Schistocytes–> good indicator in blood film of damaged cells

Question 32

What are autoimmune haemolytic anaemias?

Answer 32

Autoantibodies bind to the surface of RBC
Can result from infections (chest infection), lymphoproliferative disorders and reaction to drugs
Classified as warm or cold
–> Based on conditions in laboratory they react best in
—> Warm –> IgG antibodies recognise epitopes–> phagocytosis or nibbling by macrophages in spleen–> membrane lost cells round up –> spherocytes
–> Cold–> IgM antibodies recognise–> distal parts of body–> created agglutinates which block capillaries–> ischemia in periphery
Often splenomegaly

Question 33

How are autoimmune haemolytic anaemias diagnoses in lab?

Answer 33

Direct Coombs test
RBC mixed with anti-human globulin antibody
If RBC coated with antibody–> clump together–> suggest immune related