Erythropoiesis and Anaemia Flashcards
How does iron get into the body
has to be taken in in the diet
what is the average intake of iron into the body per day
15mg
How much iron do we have in our body
3-5g
how much iron is found in haemoglobin
2g at least
what are haem proteins
these are proteins that contain iron
what is steric hinderance
this is the process by which oxygen is never fully attached to the haem group this is because the other 5 molecules that are bound to the haem group cause it to be slightly repelled therefore oxygen can easily leave and re attach to haemoglobin so can go into tissues
where does the main absorption of iron take place
in the duodenum by enterocytes in the duodenal lining
what is the specialisation of enterocytes that allow iron absorption
- have microvilli
- in the microvilli there are transporter proteins these pick up the ferrous iron atoms in the food
what is the main transporter protein that carries iron atoms
DMT-1 (divalent metal transporter 1)
what form must the iron be in in order to be picked up by iron transporter proteins such as DMT-1
ferrous form
what does ferric reductase enzyme do
- Ferric reductase enzyme in microvilli reduce FE3+ IN THE GUT TO FE2+ (ferrous form) to transport it into the cell through the transport proteins such as DMT-1
why are ferritin molecules in most cells
- Mitochondria need iron for haem therefore ferrtin moleucles are in most cells
what membrane is DMT-1 on
the apical membrane
Describe the structure of ferritin
- Ferritin is a large hollow ‘polyprotein’ made of 24 apoferritin subunits.
- It stores many iron atoms inside it in the inactive (Fe+++) form
what does ferritin act as
it acts as a buffer against iron deficiency and iron overload
how does iron get into the enterocyte
- Iron that has ben transported in by DMT-1 (apical membrane) is stored in the enterocyte in the ferritin molecule
where is ferritin found
- Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier.
what can be used as a diagnostic test for iron deficiency anaemia
- Plasma ferritin is an indirect marker of the total amount of iron stored in the body, hence serum ferritin can be used as a diagnostic test for iron deficiency anemia
how is iron removed from the enterocytes
- Iron can be removed from the ferritin and is transported out of the enterocyte by ferroprotein molecules which is in the basolateral membrane, this transports the iron into the blood where it is grabbed by transferrin
where are ferroprotein molecules
they are on the basolateral membrane
why does iron have to be bound to transferrin
- this is because it is reactive and can catalyse reactions
what are transferrin
- iron binding plasma glycoproteins that regulate the level of free iron in plasma and other extracellular fluids
how many iron atoms can transferrin carry
two iron atoms in the ferric form (Fe+++).
how is iron carried into cells from transferrin
- Transferrin receptors bind to the iron loaded transferrin and take it into the cell by endocytosis into an endosome (vesicle), the endosome is has a lower pH/ more acidic than the transferrin which makes it release the iron
- The empty receptor/transferrin complex is transported back to the cell surface and the transferrin released ready for another round of iron uptake.
- iron is then taken up by haemoglobin or ferritin molecules which store it for future use
what are serum transferrin levels measured for
- serum transferrin levels are measured in cases of suspected in iron deficiency and in iron overloaded disorders
what is ferric symbol
Fe+++
what is ferrous symbol
Fe++
what do myeloid stem cells become
erythrocytes
what do lymphoid stem cells become
lymphocytes
what are the different types of bone marrow
red marrow
yellow marrow
what’s another word for myeloid tissue
bone marrow
what bone marrow does erythropoiesis occur in the adult
- mostly occurs in red marrow
what does yellow marrow contain
fat droplets and cells
what takes up a large proportion of the circulating transferrin molecules
- Myeloid cells in the bone marrow take up a large proportion of the circulating transferrin molecules to incorporate the iron into hemoglobin in erythrocyte precursor cells.
what are the three stages of red blood cell formation in the foetus
mesoblastic stage
hepatic stage
myeloid stage
describe the three stages of red blood cell formation in the foetus
Mesoblastic stage
- At 3rd week: Nucleated red blood cells form in Yolk sac and mesothelial layers of the placenta
Hepatic stage
- At 6 weeks – Erythropoiesis mainly in Liver & Spleen, the liver has developed enough and there is no bone marrow at this stage
Myeloid stage
- 3rd month onwards - the bone marrow gradually becomes the principal source of the RBCs. Erythropoiesis occurs exclusively in Bone marrow in last month
as you grow older red blood cell formation is….
restricted to fewer bones
describe the age range and the bones that red blood cell formation occurs in
- up to 5 years
- 5 to 20-25 years
- 25+
- Age up to 5 years : The bone marrow in all bones
- Age 5 to 20-25 years : Marrow of the long bones
- Age 25+ years: Red cells produced mainly in the marrow of the membranous bones, such as Vertebrae, Sternum, Ribs, cranial bones and Ilium.
what is erythropoiesis
- this is the formation of the red blood cell
describe the process fo erythropoiesis
- starts with a haemotopoietic stem cell/haemocytoblast
- this develops into a common myeloid progenitor/proerythroblast
- the proerythrocytoblast develops into an erythroblast as the nucleus shrinks and the cytoplasm fills with haemoglobin
- when the nucleus is expelled and all cytoplasm is replaced with haemoglobin then the erythroblast becomes a reticulocyte
- these stay in the bone marrow to become erythrocytes and some are released into circulation where they mature into erythrocytes as well
- final stage is where the eyrhtorcytes squeezes through pores in the marrow capillary membrane into the blood known as diapedesis
what is diapedesis
final stage is where the eyrhtorcytes squeezes through pores in the marrow capillary membrane into the blood known as diapedesis
what is the hormone that controls erythropoeisis
- Erythropoietin EPO
where is EPO found
- It is a protein produced in fibroblast interstitial cells in the kidney around the proximal tubule
How does the EPO work
- EPO secreting cells are sensitive to hypoxia therefore if hypoxia occurs the reason is due to reduced carriage of oxygen
- hypoxia causes EPO release which acts on erythropoietic stem cells to increase red celll production
- EPO main effect is to increase speed of maturation of committed bone marrow cells
why is EPO in the kidney
- the kidney is tightly regulated GFR (glomerular filtration rate) therefore a steady usage of oxygen
- oxygen levels in the proximal tubule are not altered by exercise or changes in blood pressure therefore the oxygen level is determined by the level of haemoglobin in the arterial blood
why do men have higher haemoglobin levels than women
- testosterone increases EPO production therefore men have slightly higher
EPO doesn’t increase the number of cells being produced…
but does speed up the whole process of maturation of red blood cells
why can red blood cells not use oxidative metabolism to make ATP
because they have no mitochondria
why to red blood cells need ATP
- they need ATP to power GLUT1 transporters which take up glucose
- to power sodium pumps in the membrane - they would burst without them
how do red blood cells make ATP
anaerobic glycolysis
- the pyruvate from glycolysis instead of going into the citric acid cycle reacts with NADH to form lactic acid and NAD+ to keep the glycolysis going.
describe what happens from the lactate from the erythrocyte
- The lactate is exported from the erythrocyte, taken up by liver or muscle cells (especially myocardium), converted back to glucose which is re-exported back into the blood. This is a similar mechanism to the CORI CYCLE
- protein pumps pump out the lactate
describe why the ESR (erythrocyte sedimentation rate) takes a long time
- Erythrocytes have a negative surface charge This is due to membrane glycoproteins containing sialic acid
- Therefore, they electrostatically repel each other thus preventing them from sticking together
what causes the ESR to decrease in the time it takes
- Inflammatory reactions or bacteria in the blood increase the amount of fibrinogen in the plasma.
- The fibrinogen binds to the red cell membrane and reduces the negative charge, causing the red cells to adhere together.
- The red cells clump to form stacks called rouleaux which settle faster due to their increased density which increases the ESR
what are red blood cell stacks called
rouleaux
a raised ESR is a non-specific,…
marker of infection in the blood
how do you work out the normal ESR
age +10(if female)/2
how long do red blood cells last
120 days
how are old red blood cells removed
the spleen detects old RBCs - - is by their lack of deformability. Old cells become more rigid and this enables them to become entrapped in the spleen capillaries.- monitored by the macrophages
- Trapped RBCs are engulfed by splenic macrophages and broken open by osmotic lysis.
what products is haem broken down into
- prosthetic groups
- globin protiens - these are broken down into amino acids
what is oxidised haemoglobin called
methaemoglobin
describe how haem is covered to bilirubin
- haem to biliverdin by heme oxygenate
- biliverdin to bilirubin by biliverdin reductase this happens in the macrophage
describe what happens to the haem
- The haem is then broken open by the haemoxygenase enzyme. Iron atoms from haem are collected by transferrin. Transferrin carries the iron in the blood to the liver and thence the bone marrow where it can be re-used to make new haemoglobin
what is haem minus the iron atom called
- The haem is then broken open by the haemoxygenase enzyme. Iron atoms from haem are collected by transferrin. Transferrin carries the iron in the blood to the liver and thence the bone marrow where it can be re-used to make new haemoglobin
what is more stable bilirubin or biliverdin
bilirubin
what do both bilirubin and biliverdin have
Both biliverdin and and bilirubin are antioxidants and may have local antioxidant effects
what happens to bilirubin
- Stuck to albumin in the spleen and then the albumin bilibrubin is released into the blood
- Bilirubin is not very soluble. It binds to albumin in the splenic macrophages and the complex released into the blood. This is called unconjugated bilirubin
what happens when the unconjugated bilirubin reaches the liver
- When the unconjugated bilirubin reaches the liver it is attached to glucuronic acid by the hepatocytes to make it more soluble. When bound to glucuronic acid it is called conjugated bilirubin.
- Conjugated bilirubin passes in the bile to the small intestine where bacteria convert it into urobilinogen.
what happens to the urobilnogen
- Most urobilinogen passes out of the body in faeces but about 10% passes back in the portal vein to the liver.
- The recycled urobilinogen leaves the liver in venous blood. When it passes through the kidney it is excreted in urine (giving it its yellow colour)
what is anaemia
Anaemia is defined as a blood Hb level below the reference range for that age, and gender: it is the commonest blood disorder
what are the types of anaemia defined in terms of red blood cell volume
- microcytic <80fl * <76 fl as the threshold for microcytic anaemia in 2-12 year olds.
- normocytic 80-96fl
- macrocytic >96fl
what can microcytic anaemia occur to
microcytic as there is not enough iron and the iron regulates the size of the erythroblasts
1fl= 1 femolitre - 10-15 =
lt =1 cubic micrometer
what are the symptoms of anaemia
- Tiredness
- Fainting
- Shortness of breath – due to not enough oxygen
- Worsening angina/claudication
- Rapid heart beat (palpitations)
what are the signs of anaemia
- Pallor – with normal skin circulation because the red cells aren’t as red as they should be
- Rapid heart rate – usually due to chronic anaemia
- Bounding pulse
- Systolic flow murmur
- Cardiac failure – usually due to chronic anaemia
- Retinal haemorrhages
what are the common causes of anaemia
- decreased production of red blood cells
- destruction of red cells
- increased loss of red cells
what can cause decreased production of red blood cells
- Iron deficiency
- B12 or folate deficiency
- Marrow infiltration e.g. cancer
- Any chronic disease e.g. rheumatoid, cancer
- Infections e.g. HIV, parvovirus
what can cause destruction of red cells
- Haemolytic anaemia - Disorders of RBC membrane/enzyme/haemoglobin or Immune destruction
how much blood loss results in iron deficiency
- 1ml blood contains ~0.5 mg iron
- 10ml loss/day will result in iron deficiency
what is another word for reduced amounts of haemoglobin
- hypo chromic
what is absorption of iron in plants low
- Many plants contain iron but absorption is often very limited due to low solubility and the presence of powerful chelators (chemicals which hold iron and prevent absorption)
what has the highest bioavailability of iron
- Haem iron (in meat) has highest bioavailability (easily imported by enterocytes
what factors increase iron absorption
- Haem iron
- Ferrous salts
- Acid stomach pH
- Iron deficiency
- Pregnancy
- Hypoxia
what factors impair iron absorption
- Non haem iron
- Ferric salts
- High stomach pH
- Iron overload
- Inflammatory disorders – can effect the enterocytes thus imparing absoption
- Proton pump inhibitors used for acid reflux or indigestion may reduce stomach acid and decrease iron absorption
how do you confirm iron deficiency anaemia
- Full blood count (low RBC number)
- Blood film (microcytic, hypochromic RBCs)
- Serum ferritin (is it low?)
- Serum iron total iron binding capacity (TIBC) (is it low?)
how do you treat iron deficiency anaemia
- Replace the iron
o Improve Diet (include haem-containing proteins eg meat)
o Iron supplement as ferrous sulphate tablets
o Avoid blood transfusion
o Once Hb normal continue iron supplements for ~3 months
