haemoglobin structure and function Flashcards
what are the three main haemoglobin types and what are their subunits
-HBA is made of two alpha and 2 beta global subunits
-HBF is made of two alpha and two gamma
- HBA2 is made of two alpha and 2 delta (<3.5% in adult blood)
what is the globin structure
- primary structure (9 conserved amino acids for oxygen binding)
- secondary (75% alpha helix)
- tertiary (non polar resides face inwards)
- quaternary ( 1 dimer (alpha 1 and beta 1) on top of second dimer)
how man amino acids is in the alpha globin subunit
- 141 amino acids
how many amino acids is in the beta, delta and gamma globin structure
- 146 aa
what is the Haem structure
- protoporphyrin ring with iron atom at centre
- iron binds to 6 coordinating valencies with 4 linked to nitrogen which is found in the ring and 2 linked to histidine residues in globin
- bond between distal histidine and oxygen is unstable (hydrogen bonding) and easily replaced by oxygen
haemolytic synthesis overview and steps
- 1 rate controlling step- involves ALA synthase
- 3 enzyme controlled steps
- first step condensation of glycine and succinate which forms d-ALA
- intermediate step forms three intermediates
- final step- insertion of iron into proton-porphyrin
what is the genetic control of globin snythesis
- two chromosomes which have genes coding for specific haemoglobin subunits
- chromsome 16 and 11
- chromsome 16 has alpha 1, alpha 2 and zeta
- chromsome 11 has beta, gamma, delta, epsilson, pseudogenes (non functional)
how many exons and introns does the globin genes have, and what do the introns begin and end with
- 3 exons and 2 introns
- introns begin with G-T and end with A-G
what is the binding of oxygen to haemoglobin like
- positive co-orperativity
- binding of first oxygen makes it easier for subsequent oxygen to bind
what reduces affinity for oxygen
- low ph
- high temperatures
- carbon dioxide (Bohr effect)
- 2,3-DPG
what happens to hb structure when oxygen is bound
- when deoxygenated it is open and taut (T)
- bound it is compact and relaxed (R)
- rotation of dimer Paris over each other 15 degrees
- movement of histidine residue
how does DPG reduce oxygen affinity
- hb exist in two forms T and R
- during the T phase hb is open and taut and has a lower affinity for oxygen, when oxygen bind to hb it moves from the t state to the r state however the binding of dog during the t state stabilises the t state and prevents the transition to the r state and therefore oxygen affinity is reduced and makes hb more prone to release oxygen
what is the effect of DPQ on oxygen dissociation curve
causes it to shift to the right
more DPG formed with anaemia and hypoxia
what is the p50
the partial pressure of oxygen when haemoglobin is 50% saturated
increases in dpg causes increase in p50
what are the two main categories of haemoglobin disorders
- structural globin defects e.g sickle cell
- decreased globin synthesis e.g. thalassaemias
what is the distribution of thalassemia
- mediteranian e.g. greeks, Cypriots etc
- middle east
- south asia
- south east asia
- common in places were malaria was historically present
distribution of sickle cells
- African and Caribbean
- specifically west Africa
what is the pathophysiology of thalassemia
- unpaired globin
- haemolsis or ineffective erythropoiesis
- haemolytic goes to splenomegaly than to anaemia
- ineffective erythropoiesis goes to anaemia
- anaemia goes to either transfusionn which leads to iron overload or erythropoietin
- erythropoietin goes to erythroid marrow expansion
- bone marrow expansion goes to skeletal deformities or iron overload
what is the classification of alpha thalassemia
- alpha thalassemia is based on deleted genes not really mutations
- so if you are alpha thalassemia zero you have deletion of both alpha genes on same chromosome
- alpha thalassemia plus you have deletion of one of the alpha globin genes in one chromosome
- not there’s two alpha globin genes on one chromosome (16)
what is the 4 main types of alpha thalassemia
- alpha thalassemia minor or ‘trait’= deletion of one alpha globin gene (positive) in either one homologous chromosome or both homologous chromosome
- alpha thalassemia minor zero- both alpha globin genes deleted in one homologous chromosome
- HbH disease- 3 alpha globin genes deleted
- hydrops foetalis or alpha Thal major - 4 genes deleted no alpha globin chains produced at all
what are the clinical features of alpha thalassemia trait positive or zero
- microcytic red blood cells
what are the clinical features of Hbh
- splenomegaly
- anaemia
what are the clinical signs of alpha Thal major or also known as hydros foetalis
- death in utero (30-34 weeks)
- formation of hb bart (4 gamma chain)
- hb bart cause oedema and hepatospelnomegaly
what are the 3 types of beta thalassemia
- minor beta thalassemia or trait (heterozygous)
- beta thalassemia intermedia (homozygous)
- beta thalassemia major (homozygote)
what are the classification of beta thalassemia based off
- based on mutations not gene deletions
- more severely mutated genes means no beta globin is synthesised
- more minor mutated genes results in less beta globin chains being produced
- so if you are beta thalassemia positive the mutations are less severe and have reduced beta globin synthesis
- if zero means severe mutations and no globin chain synthesis
what are the clinical sign of beta thalassemia minor or trait
- microcytic not anaemia
- raised hba2
- genetic counselling
what is beta thalassemia minor or trait
- one defected/mutated gene can be positive or zero
what is beta thalassemia intermedia
- 2 defected genes but genes are positive so not severe mutation and therefore reduced beta goblin chain synthesis
- mutation can be also one severe and one mild so one positive and one negative
what is beta thalassemia major
- 2 mutated genes
- severely mutated
- both zero
clinical signs of beta Thal major
- severe anaemia dependant on transfusion
- present 1-2 months after birth
- bone marrow expansion
- cardiac death room iron overload
what organ system are affected by iron overload and how
- heart, pituitary gland, liver, pancreas, gonadal
- iron over load means non transferring bound iron and therefore increased iron uptake from selective organs and thus generation of free hydroxyl radicals which cause tissue damage
Thal major standard therapy
- transfusion
- chelation
-monitoring
examples of chelate
- desferrioxamine
- deferasirox
- deferiprone
other therapies for Thal major
- bone marrow transplantation
- gene therapy
- screening
what type of hb disorder is ss
- structural hb disorder
what causes ss/ pathophysiology
- point mutation from glutamic acid to valine
- when deoxygenated the hb molecules undergo polymerisation to form crystals
- this causes the red blood cell to be sickle cell shaped
what is the inheritance of ss
- co dominance
- if heterozygous would have 50% hbs and 50% hba
- if homozygous with mutation you would have no hba
what can sickle cell red blood cells cause
- haemolysis they are more prone to breaking leading to haemolytic anaemia
- vaso-occclusion ( vaso-occlusive episodes)= acute crisis and chronic vasodilation-occlusion can cause organ damage
- vaso occlusion can lead to sequestration e.g. of spleen or chest
what would you find on peripheral blood film of sickle cell
- sickle cells
- hypo chromatic cells
- neutrophils
- howell jolly body cells
clinical features of sickle cell
- haemolytic anaemia
- sequestration crises
- infracrtion of organs such as spleen- risk of infection
- acute crises
- stroke in 10% o children
- acute chest syndrome
what is sickle chest syndrome or acute chest syndrome and causes
- complication of sickle cell
causes: - ischaemia to lung/ reduced blood flow
- infection e.g. streptococcus pneumonia
- fat embolism- necrosis of spleen leads to fat deposited in blood which travel to lung
treatment of scd
- preventative measures and treat acute complications
-prevent organ damage - anti sickling options e.g. transfusion or increase hbf
- curative such as stem cell transplantation or gene therapy
