4. Red blood cell disorders

Question 1

Haemolytic anaemia

Answer 1

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

Question 2

membrane defects

Answer 2

microskeletal defects such as hereditary spherocytosis HS, hereditary elliptocytosis HE
membrane permeability defects such as hereditary stomatocytosis

Question 3

enzymopathies

Answer 3

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

Question 4

hereditary spherocytosis

Answer 4

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

Question 5

what happens to rbc cytoskeleton in HS

Answer 5

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

Question 6

molecular pathophysiology of HS

Answer 6

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

Question 7

why does HS cause anaemia

Answer 7

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

Question 8

describe process of hereditary spherocytosis

Answer 8

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

Question 9

clinical features of hereditary spherocytosis

Answer 9

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

Question 10

haematological findings

Answer 10

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

Question 11

investigation and treatment of hereditary spherocytosis

Answer 11

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

Question 12

stomatocytes

Answer 12

expansion of inner surface of bilayer relative to outer aspect

Question 13

target cells

Answer 13

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

Question 14

acanthocytes

Answer 14

accumulation of cholesterol inouter lipid bilayer
accumulation of sphingomyelin in outer lipid bilayer
roundish elongations

Question 15

echinocytes

Answer 15

expansion of outer lipid bilayer relative to inner surface

spikes

Question 16

poikilocytes/fragments

Answer 16

fragments of rbc, strange looking cells due to severely impaired horizontal protein interactions

Question 17

hereditary elliptocytosis

Answer 17

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

Question 18

red cell metabolism importance

Answer 18

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

Question 19

three functions of glycolytic pathway in the rdc

Answer 19

NADPH production - hexose monophosphate shunt (pentose phosphate)
ATP production - Embden Meyerhof Pathway
2,3 diphosphoglycerate (2,3 DPG production) - Rapaport Luebering Shunt

Question 20

why does blood transfused earlier have healthier rbc

Answer 20

DPG levels havent decreased a lot so still take up considerable amount of oxygen

Question 21

hexose monophosphate (pentose phosphate) pathway

Answer 21

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

Question 22

G6PD function

Answer 22

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

Question 23

features of glucose 6 phosphate dehydrogenase deficiency

Answer 23

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

Question 24

genetics of G6PD deficiency

Answer 24

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

Question 25

haematological finding and treatment of G6PD deficiency

Answer 25

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

Question 26

embden Meyerhof pathway

Answer 26

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

Question 27

pyruvate kinase deficiency

Answer 27

defect of embden myerhof pathway
autosomal recessive
over 100 different mutations 
anaemia - severity varies 
jaundice usual, gall stones frequent

Question 28

haematological findings and treatment of pyruvate kinase deficiency

Answer 28

cells rigid due to reduced ATP levels and so prone again to destruction
reduced haemoglobin levels
microcytosis
treatment is splenectomy and blood transfusions