Haemoglobin and thalassaemia Flashcards
How many RBC do we have and how much Hb do they carry?
Have about 3.5-5 x10^12/L
Each contain about 640 million Hb
Why is it important for HB to be in RBC
Found exclusively in RBC
Free in plasma, it can be a powerful oxidative agent (toxic)-in heamolysis disease, can lead to damage
When and WHERE and how is heamoglobin synthesised?
Before the nucleus is expelled -65% in erythroblast state and 35% in reticuolocyte part
Heam-made in the mitochondria (Mito-glycine+succynilCOA+VitB6 ->ALA ->cytosol _>coproporphynogen->mito->protoprohyrin + Fe -> Haemx4) -ALA is regulatory (negative feedback) for heam
Globin-synthesised by ribosomes-a2B2 globin
Eight functional globin chains in 2 clusters (B-cluster-B, Ggamma (foetus), Agamma, delta and epsi on chr 11) and (a-cluster, a1,a2,Zeta on chr 16 (embryo))
What are the chains usually found in healthy adults?
Heam A and B - 98% normal Hb A
HbA2-a2delta-2%
tiny part of HbF(foetal)A2gamma2-0.5%
What form is the iron in haem? does haem vary between proteins?
Protoporphyrin + Fe -> Haem -mostly in Fe2+ forms
Haem is always the same across all proteins - eg myoglobin, cytochromes, etc
What chains make up different Hb during development?
Alpha cluster in embryo -start with zeta globin, but decrease v fast (gone by 7 weeks)-alpha becomes predominant (and also into adulthood). B starts around 7 weeks too, bit doesnt rise before birth
Gamma is the second one that rises, around 2 week, and nearly as abundant as alpha-drops after birth (exchange role with B)-B globin disorders start after birth
damage to a chain u§susally means embryonic death
Describe the structure of globin?
Primary is (a) is smaller than non a (141AA to 146AA)
Mostly helices
Approximate sphere, hydrophilic surface-heam in pocket in center
How does the oxygen-heam binding curve look like?
Cooperative binding-as O2 binds, O2 binds easier -> SIgmoid shape
P0 is the partial pressure at which half of the heam has O2 -> good way to approximate affinity
(Remember arterial is high O2 pressure-nearly 99% saturated, and venous closer to 75 normally)
What are factors that can shift the oxygen-heam curve to right/left?
Left-usually means it binds O2 better but doesnt release it to tissue as well
Hb F- so can take from mother. 2,3 DPG down (slower metabolism), pH up
Right-release oxygen easier-exercise conditions
HbS (sickle cell)-lower O2 affinity, increase 2,3 DPG-metabolising tissue, pH down
How do you classify thalassaemia?
By the globin chain affected (alpha, Beta, etc)
OR by clinical severity - minor “trait” (carriers), intermedia (transfusion independent), major (transfusion dependent)
What are the main genetics of B thalassaemia? What does Bo and B+ mean?
Only 2 B genes - usually results of deletion or mutated leading to reduced or no B globin
(alpha has 4 genes so difficult genetics)
Prevalent in medditeranean
Autosomous recessive-chances being trait, intermedia or major
Bo usually means a complete loss
B+ usually means Reduced B
Combining usually gives intermedia
What are the ways to diagnose thalassaemia?
Initially-full blood count-increased RBC relative to Hb (hyperchormic microcytic)
Film-target cells, poikilocytosis but no anisocytosis
Hb EPS- (electrophoresis)-a-thal-normal HbA2, HbF , +/- HbH (in more severe cases-usually intermedia with 3/4 a lost)-rememeber no a means death in utero
B-thal-raised HbA2 and HbF-easier to find
Globin chain synthesis/DNA studies
What is thalassaemia major? WHat are some features on a film?
2 abnormal Beta globin genes -non production
Severe aneamia, inconpatible with lift without transfusions
Appear 4-6 months after birth
(hyperchormic microcytic-sometimes a chain precipitates
Pappenheimer bodies (iron deposits in cells)
What is the clinical presentation of thalamsseamia major? what are the main symptoms and causes of death?
Severe aneamia
Hepatosplenomegaly (they start producing RBC to try and catch up) caused by extra meddullary heamatopoesis
Gross hypochromia, poikilocytosis and nucleated RBC
Bone marrow-Erthrtoid hyper plasia (enlagred maxillary bones)
Chronic fatigue, failure to thrive, jaundice, delay in growth and puberty, skeletal abnorm, infections (especially from Yersinia/Gram-negative-thrive in high iron)
Cholelithiasis and biliary sepsis, cardiac failure, endocrinopathies, liver failure . -> all due to Fe over load (iron depositing in those different organs)-caused by the transfusion
Main causes of death-cardiac disease-71%
What are the main treatment for thalasseamia major?
Transfusions from an early age and iron-chelation therapy (start after 10/12 transf)
Transfusions cause the iron overload with thal major (in non-transfusion dependent-due to increased iron absorb)
Other: Splenectomy, medical care, hormone therapy, Hydroxyurea to boost HbF, bone marrow transplant
