S5) Haemopoiesis, Erythropoeisis & Iron Flashcards
What is haemopoiesis?
- Haemopoiesis is the process by which blood cells are formed
- It involves the specification of blood cell lineages and proliferation to maintain an adequate number of cells in the circulation
Where does haemopoiesis occur before and after birth?
- Early embryo – process begins in the vasculature of the yolk sac before shifting to the embryonic liver by ~week 5-8 gestation
- After birth – sole site of haemopoiesis is in bone marrow
Describe bone marrow production in infants and adults respectively
- Infant – extensive throughout the skeleton
- Adult – limited distribution (pelvis, sternum, skull, ribs, vertebrae)
Which cells drive haemopoiesis?
Haemopoietic stem cells
Five major lineage pathways arise from the haemopoietic stem cells in bone marrow.
Identify them
- Thrombopoeisis
- Erythropoiesis
- Granulopoiesis
- Monocytopoiesis
- Lymphopoiesis
Describe the process of thrombopoiesis
- Thrombopoiesis results in the ultimate formation of platelets involved in clot formation
- Platelets have no nuclei and are membrane bound fragments of cytoplasm that bud off from megakaryocytes
What is another name for platelets?
Thrombocytes
Which substance drives thrombopoiesis?
Thrombopoietin (TPO) drives megakaryocyte formation, and hence thrombopoiesis
Describe the process of granulopoiesis
Granulopoiesis is the process by which granulocytes arise from myeloblast cells which in turn arise from common myeloid progenitor cells
Identify the three granulocytes
Describe the process of monocytopoiesis
Monocytopoiesis is the process which leads to the production of monocytes (and subsequently, macrophages)
What do monocytes do?
Monocytes circulate in the blood for ~1-3 days before moving into tissues where they differentiate into macrophages or dendritic cells
Describe the process of lymphopoiesis
Lymphopoiesis is the process in which lymphocytes develop from a common lymphoid progenitor cell
Identify some lymphocytes
- B cells
- T cells
- Natural killer cells
Compare and contrast B cell and T cell lymphopoiesis
- B cell lymphopoiesis commences in the foetal liver and is completed in the bone marrow
- T cell lymphopoiesis begins in the foetal liver but mainly occurs in the thymus
T cell maturation occurs in the thymus gland.
Describe this process
T cell receptor genes rearrange in immature T cells to be able to produce a vast array of different T cell receptors which recognise a wide range of antigens presented to them by APCs
B cell maturation occurs in the bone marrow.
Describe this process
- Immunoglobulin genes rearrange in immature B cells to allow production of antibodies with a wide array of specificities
- Final maturation requires exposure to antigen in the lymph nodes in to to gain the capacity to recognise non-self antigens and produce large quantities of specific antibodies
Describe the process of erythropoiesis
Erythropoiesis is the process by which red blood cells are produced from a common myeloid progenitor cell in the bone marrow
What is another name for red blood cells?
Erythrocytes
Why is erythropoiesis a continual process?
Red blood cells have a finite lifespan of approx. 120 days in the bloodstream and lack the ability to divide
Which substances drives erythropoiesis?
Erythropoietin (EPO), secreted from the kidneys
How does EPO increase erythropoiesis?
EPO promotes the expansion of the erythroid precursors in the bone marrow by inhibiting apoptosis in CFU-E progenitor cells
When is erythropoietin production by the kidneys increased?
EPO production increases in response to a decrease in the oxygen level in the bloodstream (hypoxia) thereby stimulating more red blood cell production
The main function of EPO is to inhibit apoptosis of CFU-E progenitor cells.
In four steps, describe how this process occurs
⇒ Activation of the erythropoietin receptor on CFU-E progenitor cells allows them to develop, proliferate and differentiate
⇒ Nucleated erythroblasts extrude their nucleus and most of their organelles
⇒ Reticulocytes (immature red blood cells) are formed
⇒ Reticulocytes are released into the circulation
Describe the maturation of reticulocytes into erythrocytes
Once in the bloodstream reticulocytes extrude their remnants of organelles, e.g. mitochondria and ribosomes, and take ~1 to 2 days to mature into red blood cells
Explain the clinical relevance of reticulocyte count
The reticulocyte count from a blood sample therefore provides a good diagnostic estimate of the amount erythropoiesis occurring in a patient’s bone marrow
Erythrocytes, once matured in the bloodstream, lack both nuclei and mitochondria.
Respectively, explain the consequences of this
- Lack of nuclei – susceptible to oxidative damage e.g. G6PDH deficiency
- Lack of mitochondria – reliance on glycolysis for energy production e.g. pyruvate kinase deficiency
What is the reticuloendothelial system and what does it do?
- The RE system is a network of cells located throughout the body and is part of the larger immune system
- Its role is to remove dead/damaged cells and to identify and destroy foreign antigens in blood and tissues
The cells which compose the RE system are phagocytic and include monocytes in blood and different types of macrophages in various tissues.
Identify some of these macrophages and their associated tissues
The spleen has a prominent role in the RE system in filtering blood to remove deformed and old cells from the circulation.
In 4 steps, describe this process
⇒ Haemoglobin is removed from senescent erythrocytes
⇒ The globin portion is degraded to its constitutive amino acids
⇒ The haem portion is metabolised to bilirubin
⇒ Bilirubin is removed in the liver, conjugated and secreted in bile
The spleen also holds a small reserve of blood.
What is the purpose of this?
The small reserve of blood can be released in haemorrhagic shock and also acts as a reservoir of platelets
Identify two indications for a splenectomy
- Accidental rupture due to trauma
- Treat diseases such as hereditary spherocytosis
Describe the structure of red blood cells
- Anucleate biconcave discs
- ~ 8 μm in diameter
- Flattened depressed centre
What are the benefits of the characteristic shape of RBCs?
- Optimises the laminar flow properties of blood in large vessels
- Allows cells to deform to squeeze through the smallest capillaries
Explain how the structure of the RBC plasma membrane is adapted to its function
- Lipid bilayer contains proteins such as spectrin, Ankyrin, Band 3 and protein 4.2
- These proteins facilitate vertical interactions with the cytoskeleton of the cell to maintain its biconcave shape and deformability
What is hereditary spherocytosis?
- Hereditary spherocytosis is a familial hemolytic disorder associated with a variety of mutations that lead to defects in RBC membrane proteins
- The morphologic hallmark is the microspherocytes which are sphere-shaped erythrocytes rather than biconcave shaped
Identify 3 clinical signs of hereditary spherocytosis
- Anaemia
- Jaundice
- Splenomegaly
Describe the use of iron in the body
- Function of haemoglobin
- Function of cytochromes involved in the ETC
- Function of catalase involved in the protection against oxidative stress
Why is free iron toxic to the body?
Free iron acts as catalyst in the formation of free radicals from reactive oxygen species
Where does iron absorption occur?
- Duodenum
- Upper jejunum
What are the different forms of iron found in the body?
- Haem iron (more readily absorbed)
- Inorganic iron – ferric (Fe3+) and ferrous (Fe2+) iron
In three steps, describe the mechanisms and process involved in the absorption of iron in the gut
⇒ Fe3+ in the intestinal lumen is reduced to Fe2+ by DcytB before uptake by DMT1
⇒ Transporter protein, DMT1 in apical surface of enterocytes facilitates uptake of Fe2+
⇒ Iron is stored in enterocytes as ferritin / transferred into the bloodstream via ferroportin
In two steps, describe the transport of iron in the blood
⇒ Iron is bound by the transferrin in the blood
⇒ Iron is mostly transported to bone marrow for erythropoiesis / taken up by macrophages in the RE system as a storage pool
What regulates iron absorption?
The absorption of iron is primarily regulated by a small peptide called hepcidin which is expressed by the liver
Describe the mechanism by which hepcidin functions
- Hepcidin directly binds to ferroportin resulting in its degradation
- Thus iron cannot leave the cell and iron uptake is down regulated by inhibiting the transcription of the DMT1 gene
The composition of the diet can also influence iron absorption.
Describe this observation
- Citrate found in citrus fruits can form complexes with iron that increase absorption
- Tannins found in tea and coffee can decrease absorption
Outline the concept of iron recycling
- Only small fraction of the daily total iron requirement is gained from the diet
- Most of the iron requirement is met from the recycling of old RBCs taken up by macrophages in the RE system and returned to the storage pool
Iron is stored in two forms.
Identify them
- Ferritin
- Haemosiderin (insoluble derivatives)
All cells have the ability to sequester iron as either ferritin or haemosiderin.
Describe how this occurs in phagocytes
Ferritin is a protein-iron complex which can be incorporated by phagolysosomes to form hemosiderin granule
Where are the highest concentrations of stored iron?
The highest concentrations of stored iron are in the liver, spleen and bone marrow
What is hereditary hemochromatosis?
- Hereditary hemochromatosis is an autosomal recessive disease characterised by excessive absorption of dietary iron
- Iron accumulates in tissues and organs disrupting normal function e.g. liver, adrenal glands, heart, joints, and pancreas
Which co-morbidities are associated with hereditary hemochromatosis?
- Cirrhosis
- Adrenal insufficiency
- Heart failure
- Arthritis
- Diabetes
What is the treatment of HHC?
Therapeutic phlebotomy to remove excess iron
Explain how the excessive iron absorption seen in HHC is due to a defect in the gene coding for the HFE protein
- HFE protein binds to the transferrin receptor reducing affinity for iron-bound transferrin
- Defects in the HFE protein therefore result in a greater cellular uptake of iron
