5. Heamopoiesis & Iron Flashcards
What are the main sites of haemopoiesis in adult marrow?
Pelvis, sternum, ribs, vertebrae, skull
What is the precursor for all of the blood cells?
Haematopoietic stem cell
Which cytokines trigger development of lymphocytes?
Interleukins
TNF
Which protein triggers myeloid cell development?
GM-CSF
Which hormones trigger erythrocyte and platelet development?
EPO - erythrocyte
Thrombopoietin (TPO) - platelet
In addition to GM-CSF, what other protein drives differentiation of myeloblasts?
G-CSF
What cells make up the RES?
Phagocytic cells - types of macrophages and neutrophils
What are the main organs of the RES?
Liver and spleen
What are the functions of the RES?
- remove senescent or damaged blood cells from circulation
- inflammatory and immune responses
What is the structure of an erythrocyte?
Biconcave, flexible disk with important membrane proteins in its bilayer. No nucleus.
What is the significant of the structure of RBC’s, what happens if this is altered?
Allows squezing through tiny microvasculature.
If membrane is damaged, the cells become weak and vulnerable to breaking down.
Why are the protein components of the erythrocyte membrane so important?
If they are altered, it will change the shape of the RBC and alter function.
What is the structure of haemoglobin?
Tetramer - 2 alpha chains and 2 beta chains
4 haem molecules
When does the switch from foetal to human haemoglobin occur, how does this alter the structure?
3-6 months
Fetal Hb has 2 gamma chains which are swapped for beta chains in adult Hb.
What is the average lifespan of a RBC?
120 days
What type of stem cell are haemoatopoietic stem cells?
Multipotent
Which cells are granulocytes?
Basophils, neutrophils and eosinophils
Where is EPO produced? What is it stimulated by?
Interstitial peritubular cells in the kidney in response to hypoxia.
What is the name of immature red blood cells which are released into the circulation?
Reticulocytes - 1/2 days to become mature
What does a reticulocyte count provide useful information about?
Estimate of the amount of erythropoiesis occurring in a patents bone marrow.
Which 2 enzyme deficiencies are particularly important in eryrthrocytes, why?
- Pyruvate kinase - no mitochondria so rely on glycolysis
- G6PDH - pentose phosphate pathway to generate NADPH
Genetic abnormality affecting these pathways means the membrane cannot be maintained and the cells are broken down, ANAEMIA.
How is haemoglobin metabolised?
Globin - degraded into amino acids
Haem - metabolised to bilirubin, which is removed in the liver, conjugated and secreted in bile.
How do bacteria in the colon affect bilirubin excretion?
Metablism bilirubin into urobilinogen which is oxidised into urobilin and stercobilin.
Which bilirubin metabolite can be reabsorbed, what is its fate?
Urobilinogen is reabsorbed and processed by the kidneys, giving urine its yellow colour.
What clinical sign results from excess erythrocyte breakdown, what metabolite is responsible?
Jaundice - excess bilirubin
How can kidney failure lead to anaemia?
Decreased EPO production
Which 4 proteins in the erythrocyte bilayer are important in maintaining struture? What is their function?
Spectrin Ankyrin Band 3 Protein 4.2 “vertical interactions” between the cytoskeleton and the lipid bilayer of the plasma membrane
What condition results from mutation in these membrane proteins, what structural change takes place?
Hereditary spherocytosis - lose biconcave shape and flexibility.
What form is iron present in within haem?
Ferrous state (Fe2+)
Why must iron uptake and absorption be carefully regulated?
There is no mechanism for excretion iron
Free iron exceeds transferrin capacity and reduced free Fe2+ catalyses the production of free radicals (fenton reaction).
What is iron essential for within the body?
- Haemoglobin and Oxygen transport
- Enzymes - energy metabolism, collagen formation, NT production, immune system
Which 2 forms is iron stored as?
Ferritin (soluble)
Haemosiderin (insoluble)
Where are the highest concentrations of stored iron found?
Liver, spleen and bone marrow
Which cells can store iron?
All cells have the ability to sequester iron either as ferritin or haemosiderin.
Why is most of the bodies iron requirement met by?
80% come from recycling from old RBC’s
Only small amount from the diet
Where does iron absorption occur in the GI tract?
Duodenum and upper jejunum
Why is meat a better source of dietary iron on that pulses and nuts?
Haem iron is already in the ferrous form (Fe2+), whereas non-haem iron is ferric (Fe3+) and must be reduced before absorption can happen.
What transport protein is iron bound to in the blood?
Transferrin
Once Fe2+ is taken up into enterocytes, what its fate?
Storage as ferritin or release into circulation via ferroportin protein.
Once in the blood, what happens to most of the Fe2+?
Transported to bone marrow for erythropoiesis
Taken up by macrophages as a storage pool.
Which receptor is needed for iron uptake into cells, which cells are the present on in large numbers?
Transferrin receptor
Erythroid cells
How does Vitamin C affect iron absorption in GI tract?
Ascorbic acid, low pH promotes iron absorption.
How do chapatis, tea and antacids affect iron absorption in GI tract?
Chelating agents, inhibit absorption.
Antacids increase pH.
Which peptide negatively regulates iron absorption, where is it produced?
Hepcidin, produced in the liver.
How does hepcidin affect iron levels?
Binds to ferroportin,causing degradation.
- Inhibits gut absorption
- Inhibits macrophages release of recycled iron.
Increased non-functional iron (cannot be used).
What conditions would hepcidin synthesis be increased?
Iron overload
What conditions would hepcidin synthesis be decreased?
High erythropoetic activity
What symptoms are associated with iron deficiency?
Tiredness, pallor, decreased exercise tolerance, palpitations
What signs are associated with iron deficiency?
Pallor, tachycardia, increased RR
What physiological and pathological reason might explain iron deficiency?
Physiological - pregnancy
Pathological - bleeding
What is the most commonly used measure of iron status?
Serum ferritin
Why might serum ferritin be inaccurate?
Acute phase protein, so increased with inflammation, malignancy, liver disease and alcoholism.
Increased levels do not rule out iron deficiency, but low levels suggest an iron deficit.
What other parameter is recommended by NICE to identify iron deficiency, how does it differ to ferritin?
CHR - remains low during inflammatory response.
Which patients would it be inappropriate to measure CHR?
Patients with thalassaemia - CHR is lowered in this setting.
What are 2 causes of haemochromatosis?
- Hereditary haemochromatosis
2. Transfusion associated heamochromocytosis
Why is haemochromatosis a cause for concern?
Iron accumulates in tissues and organs, disrupting function.
Which gene is mutated in hereditary haemochromatosis, what is it’s inheritance pattern?
HFE gene
Autosomal recessive
How does a mutation in HFE gene cause iron excess?
HFE protein usually competes with transferrin for binding to TFR. Mutated HFE can no longer bind, so transferrin has no competition and iron uptake increases.
How is hereditary haemochromatosis treated?
Venesection (phlebotomy)
Which patients are likely to be at risk of transfusion dependent haemochromatosis, why?
Patients with thalassaemia and myelodysplasia as they are transfusion-dependent anaemias.
What do patients with hereditary haemochromatosis present with and why?
Liver cirrhosis, adrenal insufficiency, heart failure, arthritis or diabetes.
The organs most susceptible to iron overload and damage are the liver, adrenal glands, heart, joints and pancreas.
Which transporter facilitates uptake of ferrous iron (Fe2+) from the intestinal lumen into enterocytes?
DMT1
Which abnormality in white blood cells would you expect to observe in a patient suffering from asthma attack?
Eosinophilia
Which drugs would be most likely to precipitate haemolysis in a patient with glucose-6-phosphate dehydrogenase deficiency?
Anti-malarials
