L9: Haemoglobinopathies and Haemolytic Anaemias Flashcards
What are haemoglobinopathies?
Autosomal recessive inherited disorders
Defects in globin chain synthesis
What are the two main categories for haemoglobinopathies?
Abnormal haemoglobin variants–> alter stability and/or function (sickle cell)
Absent or reduced expression of normal globin chains–> Thalassaemias
What is the structure of normal haemoglobin?
Tetramer of 4 globin polypeptide chains–> 2α and 2 non α (β, delta, gamma)–> non covalent interaction
Chain associated with O2 binding haem group
What are the different types of haemoglobin?
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
Where are the globin genes located? How many of each gene do we have?
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
What are thalassaemias?
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
Where are thalassaemias more prevalent?
Alpha thalassaemia–> Far east
Beta thalassaemia–> South Asian, Mediterranean, Middle East
What are the different types of α thalassaemias? What are the features?
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
What are the different types of β thalassaemias? What are the features?
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+
What does the blood profile of a person with thalassaemia look like?
Hypochromic and microcytis RBC–> low Hb
Anisopoikilocytosis–> variance in size/shape–> target cells, circulating nucleated red blood cells, Heinz bodies
How does thalassaemias result in anaemias?
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)
What are the consequences of Thalassaemias?
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
What are the treatments for thalassaemias?
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
What is sickle cell disease?
Autosomal recessive--> point mutation in β globin gene GAG--> GTG --> glutamic acid--> valine at position 6 Haemoglobin S (HbS)
What are the different types of sickle cell disease?
Heterozygous–> HbS carrier–> Mild assymptomatic anaemia
Homozygous–> HbSS -> severe
Hbs can be co-inherited along with other abnormal Hb to cause sickling disorder
Where is HbS most prevalent and why?
HbS–> 30% West Africa
Protection against Malaria
When do the problems in HbS occur?
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’
What are the types of crisis caused in sickle cell?
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
What are the signs and symptoms of sickle cell?
Retinopathy Splenic atrophy Avascular necrosis (femoral head etc...) Acute chest syndrome Stroke Osteomyelitis Skin Ulcers Kidney Infarcts Priaprism--> painful erection in men
How is sickle cell anaemia treated?
Gold standard–> haematopoietic stem cell transplant (rare due to difficulty finding a donor)
Red cell exchange
Treat the symptoms
What are haemolytic anaemias?
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»_space; production= anaemia
What are the two types of haemolytic anaemias?
Inherited (defective gene) and acquired (damage to cells)
What are the different causes for inherited haemolytic anaemias?
Glycolysis defect–> pyruvate kinase deficiency
Pentose P pathway: G6PDH deficiency leads to oxidative damage
Membrane protein: Hereditary spherocytosis
Haemoglobin defect: Sickle cell
How does glycolysis defect result in anaemias?
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
