4. Red blood cell disorders Flashcards
Haemolytic anaemia
anaemia due to increased red blood cell destruction or increased erythropoiesis
ie rbc broken down at increased rate so we get increased rate of rbc production but rate of destruction outweighs rate of production
membrane defects
microskeletal defects such as hereditary spherocytosis HS, hereditary elliptocytosis HE
membrane permeability defects such as hereditary stomatocytosis
enzymopathies
2 main red cell metabolism disorders:
deficiencies in hexose monophosphate shunt such as G6PD deficiency
deficiencies in the embden myerhof pathway such as pyruvate kinase deficiency
hereditary spherocytosis
most common hereditary haemolytic anaemia in Northern Europeans
autosomal dominant, variable expression
defects in proteins involved in vertical interactions between the membrane cytoskeleton and lipid bilayer
normal biconcae disc shape when rbc produced but as it progresses through the circulation becomes more spherical as loses the interactions. progresses thorugh spleen, small blood vessels affect rbc through splenic conditioning so spherical
more susceptible to damage as flexibility lost and cant move through circulation easily
die prematurely
what happens to rbc cytoskeleton in HS
various proteins affected
doesn’t matter where mutation arises ie which protein as all will lead to the cell becoming spherical
proteins interact closely together so d effect in one will affect the other
can have a mutation in spectrin ankyrin oor in band 3 protein
molecular pathophysiology of HS
defect in one protein affects the others
incorporation of these proteins into the membrane and therefore membrane stability is affected
proteins separate from lipid bilayer leaving rbc unstable
why does HS cause anaemia
the more times the rbc moves through the spleen the more it loses membrane surface area and the ess able it is to carry oxygen around the body and the person becomes anaemic
ie the rbc is not moved immediately and goes through the circulation several times
describe process of hereditary spherocytosis
defect in spectrin or ankyrin due to descreased synthesis, unstable or dysfunctional protein leads to spectrin deficiency
Band 3 defect due to reduced band 3 incorporation into the membrane or loss of band 3 associated lipids from membrane leads to band 3 protein deficiency
deficiencies in proteins lead to destabilisation of lipid bilayer which leads to loss of membrane surface area which is microspherocytosis
microspherocytosis leads to decreased RBC deformatbility and the entrapment of RBC in splenic cords for either splenic conditioning (further loss of membrane SA as through circulation again) or macrophage removal of severely abnormal rbc
clinical features of hereditary spherocytosis
anaemia
jaundice typically fluctuating due to destruction of rbc iron is recycled but some is broken down into bilirubin and bile, if conc of bilirubin increases skin goes yellow and get gall stones as body cant deal with the increased destruction of the red blood cells
splenomegaly - spleen increases in size as red blood cells are damaged and get stuck in splenic cords which causes the spleen to become palpable
haematological findings
in the lab, blood count, on a blood film
visible reticulocytes (5-20%), these are the precursors to rbcs in the erythrocyte lineage after they’ve lost their nucleus they stain blue as have some ribosomal DNA so can finish of production of Hb if necessary and become a fully dunctional rbc. increased number of reticulocytes shows bone marrow is under stress rbc produced not helathy kust to compensate for increased rbc destruction. rbc are ebing produced prematurely but still carry oxygen better than microcytes
blood film microcytes
investigation and treatment of hereditary spherocytosis
osmotic fragility test: add increasingly hypotonic solutions of saline solutions to red cells. water moves into cell and fragile cell explodes at certain concs of saline. HS more susceptible to damage so expand and explode in saline more quickly
treatment: splenectomy ie removing the spleen to allow the rbc to remain in circulation even though theyre not fully functional, for longer so less destruction of rbc. maintains some level of oxygenation
stomatocytes
expansion of inner surface of bilayer relative to outer aspect
target cells
increase in SA:V ratio
increase in SA to increase in phospholipid and cholesterol
relative increase in surface area due to decreased volume eg thalamssaemia
increased hill in centre
acanthocytes
accumulation of cholesterol inouter lipid bilayer
accumulation of sphingomyelin in outer lipid bilayer
roundish elongations
echinocytes
expansion of outer lipid bilayer relative to inner surface
spikes
poikilocytes/fragments
fragments of rbc, strange looking cells due to severely impaired horizontal protein interactions
hereditary elliptocytosis
deformation due to defects in horizontnal membrane interactions
eg various membrane protein abnormalities including spectrin, protein 4.1 and glycophorin C, and EL2 & EL3: the most commin genetic defecrs are in genes for alpha spectrin or beta spectrin
leads to pencil shaped rbc elliptocytes
red cell metabolism importance
red cell maturation means the loss of organelles for protein synthesis
but rbc still needs energy to maintain a healthy cell:
initiation and maintenance of glycolysis
maintenance of cation concentrations
maintenance of red cell in biconcave form
three functions of glycolytic pathway in the rdc
NADPH production - hexose monophosphate shunt (pentose phosphate)
ATP production - Embden Meyerhof Pathway
2,3 diphosphoglycerate (2,3 DPG production) - Rapaport Luebering Shunt
why does blood transfused earlier have healthier rbc
DPG levels havent decreased a lot so still take up considerable amount of oxygen
hexose monophosphate (pentose phosphate) pathway
approx. 5-10% of glycolysis occurs by this pathway
NADPH generated prolongs the life of the red cell
Pool of reducing energy- so iron and hence haemoglobin in correct functional state for carrying oxygen if person is healthy with fully functioning G6PD, if the cell comes under oxidative stress the amount of glucose passing through the shunt can be increasedto generate more reducing power
G6PD function
regenerates NADPH, allowing regeneration of glutathione
protects against oxidative stress
a lack of G6PD leads to haemolysis during oxidative stress - precipitated by infection , medication, or fava beans
oxidative stress leads to Heinz body formation (Hb that has been affected) and intravascular hemolysis (rbc break down within the circulation)
haemoglobinuria - blood in urine
features of glucose 6 phosphate dehydrogenase deficiency
enzyme activity reduced /deficient
most common enzymopathy (nearly 1% of the world population)
at least 400 variants, point mutations n deletions
resistance to malaria,- affected areas have a large overlap with malaria areas
genetics of G6PD deficiency
X linked recessive
x linked inheritance
synthesis of g6pd is determined by X chromosome, usually it is only the males affected
heterozygous females (have intermediate enzyme activity) and are usually not symptomatic
haematological finding and treatment of G6PD deficiency
Heinz bodies (oxidised denatured haemoglobin)
bite cells and blister cells
Heinz bodies bind to the red cell membrane altering its rigidity resulting in premature destruction of rbc in the spleen
treatment is to stop drug or treat infection ie take source of oxidative stress away
embden Meyerhof pathway
uses 90-95% of glucose in rbc
glucose is metabolised to lactic acid
1 molecule of glucose generates 2 molecules of ATP
provides energy for maintenance of red cell volume, shape and flexibility
pyruvate kinase deficiency
defect of embden myerhof pathway autosomal recessive over 100 different mutations anaemia - severity varies jaundice usual, gall stones frequent
haematological findings and treatment of pyruvate kinase deficiency
cells rigid due to reduced ATP levels and so prone again to destruction
reduced haemoglobin levels
microcytosis
treatment is splenectomy and blood transfusions
