Haematopoiesis - Blood Cell Formation
- Red blood cell production (erythropoiesis)
- White blood cells
- Other general Properties of blood
- Tree Diagram of blood cell production
- Red blood cells have a lifecycle of about 120 days
- Platelets have a lifecycle of about 7 days
- Granulocytes have a lifecycle of only about 7 hours
- Pathological circumstances can cause blood cell production to switch back to the liver and spleen. Such an occurrence is known as extra-medually haemopoiesis
- Many of these growth factors are produced by activated T cells, monocytes, and bone marrow stromal cells (these are just found in the bone marrow matrix, surrounding the pluripotential stem cells, and are actually macrophages, fibroblasts and endothelial cells that exist in the bone marrow).
Red blood cell production (erythropoiesis)
- The haemocytoblast, in the presence of Multi-CSF, will develop into a Progenitor cell. These cells will go on to form all types of blood cell, except Lymphocytes. In the presence of EPO, the progenitor cell will become a proerythroblast.
- In the presence of EPO, this will develop into a basophilic erythroblast
- In the presence of more EPO, this will develop into a polychromatophilic erythroblast, then a normoblast, which will then eject its nucleus, and become a reticulocyte, before finally becoming a fully formed RBC.
The production of cells is as follows:
- Day 1 – proerythroblast
- Day 2 – basophilic erythroblast – nucleus condensing. Hb formation is taking place
- Day 3 – polychromatophilic erythroblast – cells getting smaller, losing organelles, nucleus shrinking, producing Hb
- Day 4 – normoblast – contains 35% of the Hb of a full RBC. Still contains a nucleus. Very rarely in some pathologies these may be present in the blood stream.
- Day 5-7 – reticulocyte – these take 2 days to mature. They will have no nucleus, and will synthesise loads of Hb. They gradually reduce in size and become the proper RBC cell shape (biconcave disc). In a healthy adult, about 0.8% of circulating RBC’s are reticulocytes. Note that reticulocytes are larger than normal RBC’s. they still contain some RNA (despite not having a nucleus), and this is used to synthesise the Hb.
- Day 8 – RBC – these do not contain any RNA, and cannot synthesise any more Hb.
- Erythroblasts frantically synthesis haemoglobin, whilst losing other organelles. They also become smaller as the process continues.
- Reticulocytes actually enter circulation just before their maturation occurs; they complete the final 24 hours of maturation in the blood stream
- Vitamin B12(as well as B6 and folic acid) are crucial for the development of RBC’s, as they are required for protein synthesis (and RBC’s are synthesising a lot of haem!). Without enough of this, the cells will be released at the same time as a normal RBC would, however, due to the lack of relevant nutrients present, they will be immature; thus a higher proportion of reticulocytes are released, and pernicious anaemia results.
- Normoblasts appear about 4 days into the process, and then take a further 2-3 days to become reticulocytes. Normoblasts still have a nucleus, and are not normally found in peripheral blood. They are the last cells in the RBC lineage to still have a nucleus.
- After a further 2 days in the bone marrow they are released into the blood. Thus the whole process takes about 8 days.
- EPO is produced by peripheral tissues (particularly this kidneys) when they are exposed to low levels of oxygen
- The life-cycle of an RBC is roughly 90-120 days.
- About 10% of erythroblasts die during normal erythropoiesis. This ineffectiveness is increased in megablastic anaemia and thalassaemia.
- EPO is produced in the kidneys (90%) and the liver (10%). Its production is regulated mainly by tissue oxygenation. Therefore, production is increased in hypoxia.
- You may get inappropriate excess production of EPO in people with renal disease, or cetain neoplasms at other sites. This can result in polycythaemia.
Breakdown of RBC’s
- After a splenectomy, the number of circulating RBC’s dramatically increases. Macrophages all over the body can recognise and phagocytose old RBC’s, but obviously the spleen has a large concentration of them, and thus provides a larger percentage of the removal capacity.
- Macrophages breakdown Hb to biliverdin and iron. Whilst sill in the macrophage, the biliverdin will be turned into bilirubin. This is then released into the blood by the macrophage, where it will travel to the liver, and be excreted in the bile. The iron is released and transported in the circulation by transferrin where it is taken to the bone marrow for use in a new RBC.
Iron uptake and transport
The body requires an average of 1mg iron per day from the diet. this can be slightly higher for women (1.3-1.7g) as on average, they lose more through menstruation. The body will naturally excrete about 0.6mg iron per day.
The body actually requires 20mg of iron per day, but recycles its own, and thus only need to take in about 1mg per day
Absorption from the small intestine is incredibly slow. No matter how much you eat, you can only absorb about 2-3mg per day
Pregnancy (particularly in the last trimester) is a very large drain on a woman’s iron reserves. It can lead to iron deficiency anaemia
Iron can exists in two forms – ferrous (Fe2+) and ferric (Fe3+) – only ferrous iron can be absorbed by the small intestine. Thus, stomach exists creates the conditions for iron to exist in its ferrous form.
- Gastroferritin – produced by the stomach, and binds ferrous acid
- Apotransferrin – produced by the liver, released in bile; binds to free ferrous iron in the duodenum. It can also bind to haemoglobin and myoglobin in meat
- Tranferrin – this is the complex of apotransferrin-iron. This binds to the small intestine and is pinocytosed. It is then released into the bloodstream as transferrin.
- Excess iron is deposited in the liver, and in the red marrow
- Transferrin cannot cross cell membranes. It releases iron to cells, and once in the cell, iron binds to apoferritin to become ferritin. Apoferritin is a very large molecule, and can hold loads of Fe2+. Thus, ‘ferritin’ can contain a lot or a little iron.
- Iron held as ferritin is known as storage iron.
- When levels of iron in blood get low, then iron is released from ferritin, crosses the cell membrane and goes back into the blood, where it will once again bind to transferrin and be transferred to the red bone marrow.
What do we need iron for?
- Cytochrome systems (all cells with mitochondria have these, thus al cells need some iron)
% Hb in normal adult
α2β2 (2xα and 2xβ)
1.5 – 3.2%
- Each Hb molecule can hole 4 O2’s – one for each of the four heme molecules.
- The binding of the first O2 shifts the Hb from T to R, thus making it more easy for the second O2 to bind. The same is true for the binding of the second (making it easier for the third). However, the binding of the fourth is made more difficult by the binding of the third, hence the levelling off of the graph
- The effect is known as ‘cooperativity’, and thus Hb is an example of an allosteric protein. This means that the binding of various factors to the protein influences its affinity for both the factor bound to it, and other factors.
- The Haldane effect – this is the effect that the binding of O2 to Hb reduces the Hb’s affinity for CO2.
- The P50is the concentration at which the Hb is 50% saturated. By looking at the curve, you should be able to say what alters the P50. For example, it is shifted downwards by an increase in temperature – thus making O2 more freely available during exercise.
White blood cells
- Granulocytes are a group of cells comprising of basophils, eosinophils, and neutrophils.
- Agranulocytes are the monocytes and lymphocytes (B and T cells)
- T cells – are responsible for cell-mediated immunity – they can directly attack pathogens, or can co-ordinate other cells to do so
- B cells – produce antibodies, but only after they have been activated, and turn into plasma cells, which produce antibodies against a specific pathogen.
- NK (natural killer cells) – these detect and destroy abnormal native cells. they are important in protecting against cancer, and are sometimes called large granular lymphocytes.
- Dendritic cells – are antigen presenting cells
- When exposed to multi-CSF, the progenitor will become a myeloblast. This cell is the precursor of neutrophils, basophils and eosinophils.
- In the context of cell production, CSF stands for colony-stimulating factor.
- M-CSF stimulates the production of monocytes
- G-CSF stimulates the production of granulocytes
- GM-CSF stimulates the production of granulocytes and monocytes
- Multi-CSF stimulates the production of granulocytes, monocytes, platelets and RBC’s
Other general Properties of blood
Fraction of body weight
Amount of blood
4-6L (men generally have more)
Viscosity (water = 1)
4.5-5.5 (plasma = 2.0)
Tree Diagram of blood cell production