What are haemoglobinopathies? (Inherited disorders?
Defect in the Hb chain synthesis
-sickle cell (abnormalities of chains- variance, so difference in stability/function)
-thalassaemia (reduced/absent expression of NORMAL globin chains)
(Inherited disorders)
What are the types of Hb as you age?
- embryonic Hb’s
- Hb F (2 alpha + 2 gamma) (Foetal)
- Hb A (2 alpha + 2 beta) (adult)
How many alpha globin genes does a person have?
4
2 on each chromosome
What is thalassaemia?
Defect in regulation of expression of globin genes
Beta/alpha gene expression affected (often in excess)
-genetic
What are the 4 types of alpha thalassaemia?
- HYDROPS FETALIS: No alpha genes remaining-results in early uterine death
- SILENT CARRIER STATE: 3 functional alpha globin genes (asymptomatic)
- ALPHA THALASSAEMIA TRAIT: 2 globin genes (both on 1 chromosome, or 1 on each chromosome 16 deleted)- microcytic and hypochromic RBC’s.
- HAEMOGLOBIN H DISEASE: 3 alpha globin genes deleted- moderately severe
Different types of B thalassaemia?
B0= total absence of production from the gene B+= reduction of globin chain production
- B thalassaemia minor/trait: asymptomatic, mild anaemia with microcytic/hypochromic RBC’s (carrier of abnormal gene)
- B thalassaemia intermedia: severe anaemia, not enough to require blood transfusion
- B thalassamia major:transfusion dependent anaemia (homozygous)
What does relative excess of unaffected globin chain cause?
In B thalassaemia you get insoluble aggregates of the alpha chains, which can be oxidised, causing premature death of erythropoietin precursors- ineffective erythropoiesis
- more RBC’s are being destroyed than being released into blood = reduced oxygen capacity
- spleen destroys RBC’s leading to shortened survival (haemolytic anaemia)
What does a blood smear for someone with thalassaemia look like?
-hypochromic
-microcytic
(Due to low Hb)
-target cells, Heinz bodies, uncleared red blood cells due to bone marrow working really hard
What are the consequences of thalassaemia?
- extramedullary haemopoiesis (results in splenomegaly, hepatomegaly,expansion of haemopoises to cortex of bone= as occurring in other sites than the marrow)
- reduced oxygen delivery= stimulation of erythropoietin making more defective RBC’s
- causes iron overload
What are some treatments for thalassaemia?
- red cell transfusion
- iron chelation (binding of iron to reduce iron loading into tissues)
- folic acid (to support ertyhropoiesis)
- holistic care (cardio, endocrine, psychological, ophthalmology-these are affected by iron overload)
- immunisation
- stem cell transplantation (to replace defective RBC production)
- pre-conception counselling for at risk couples + antenatal screening
- pre-conception counselling
What is sickle cell disease?
-autosomal recessive (HbSS: homozygous causes severe sickling)
-mutation in B globin gene
-have valine where glutamic acid should’ve been
Mutant Hb molecule containing the mutated B globin gene protein is HbS
-irreversible sickle cells cause occlusion in small blood vessels
Why is anaemia usually mild in sickle cell?
-HbS more readily gives up oxygen compared to HbA
-problems occur in low oxygen state: deoxygenated HbS forms polymers causing a sickle shape
(These sickle cells can bounce back to normal)
-eventually the sickle cells wil become irreversibly sickled which are less deformable so cause vasocclusion
When is the sickle shape permanent?
Repeated sickling of cells
How does sickle cell clinically present?
-end organ damage due to acute thromboses of oxygen depriveation
-retinopathy
-splenic atrophy
-avascular necrosis
-stroke (blood circulation affected in brain)
-acute chest syndrome
-osteomyelitis
-skin ulcers (as skin becomes oxygen deprived)
-kidney infarcts
-priapism (unwanted erection for long time)
All reduced life expectancy
Where can haemolysis occur?
- blood vessels (intravascular haemolysis)
- spleen/wider RES (extravascular haemolysis)
Can bone marrow compensate for haemolysis?
- it can compensate by increasing production of EPO: but only up to a point
- if haemolysis exceeds capacity of marrow to compensate (6 fold increase), rate of destruction exceeds rate of production leading to anaemia
What are some symptoms of haemolytic anaemia?
- overworking of red pulp leading to splenomegaly
- accumulation of bilirubin > jaundice
- pigment gallstones made of bilirubin and calcium salts
- massive sudden haemolysis can cause cardiac arrest due to lack of oxygen delivery
- cause hyperkalaemia due to release of intracellular contents
Lab findings in haemolytic anaemia?
- raised reticulocytes (as marrow tries to compensate)
- raised bilirubin (breakdown of haem)
- raised LDG (red cells rich in this enzyme)
What are some causes of haemolytic anaemia?
Inherited (defective gene making cells more fragile)
- glycolysis defect
- membrane protein (hereditary spherocytosis)
- defect in Hb (sickle cell)
- pentose P pathway (G6PDH deficiency leads to oxidative damage)
Acquired (damage to cells)
- mechanical damage
- antibody damage (autoimmune)
- oxidant damage
- heat damage
- enzymatic damage (snake venom)
How do symptoms present on sudden haemolytic anaemia ?
Badly
-if chronic body manages to adapt slightly so oxygen dissociation curve shifts
What is jaundice and how does it present?
Build up of bilirubin
- yellow discolouration of skin and sclera of eye
- urine dark due to conjugated bilirubin
What are some causes of acquired damage of haemolytic anaemia?
- microangiopathic haemolytic anaemia (from mechanical stress: defective heart valve-stenosis, snagging on fibrin strands where there is activation of clotting cascade)
- heat damage from burns
- osmotic damage (drowning)
What is autoimmune haemolytic anaemia?
- self antibodies binding to red cell membrane proteins
- differentially bind at different temperatures depending on the antibody
- spleen recognises antibody bound cells as abnormal and removes them
How are haemoglobinopathies usually inherited?
Autosomal recessive
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