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Haematopoiesis - Blood Cell Formation

Edit this Article | Original article by Tom Leach | Last updated on 19/5/2014 | View Revisions
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Introduction

All blood cells develop from haemocytoblasts
The process is called haematopoiesis (sometimes just haemopoiesis)
Haemocytoblasts are also known as pluripotential stem cells. These cells can replicate themselves as well as differentiate into other cells, thus providing the constant supply of blood cells.
The turnover of cells is very quick:
  • 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
As well as these three constituents, blood also contains plasma. Plasma is the liquid component of blood, including fibrinogen. Serum is plasma, without the fibrinogen (i.e plasma after clot formation has occurred)
 
Approximately 1013 new myeloid cells (all blood cells excluding lymphocytes) are produced each day.
 
Although the liver and spleen produce blood cells during gestation (from about 6 weeks to 7 months), the bone marrow is the only place production can occur in adults and children.
  • Pathological circumstances can cause blood cell production to switch back to the liver and spleen. Such an occurrence is known as extra-medually haemopoiesis
 
Throughout production of the cells, the cells need to receive various growth factors at the right stage in their development. Cells at different stages of development will express different surface receptors for the different growth factors. These factors include IL-3, IL-6, IL-7, IL-11, SCF (stem cell factor). There are also some factors that inhibit growth, to keep it under control, these include TNF, TGF-β.
  • 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)

This occurs entirely in the red bone marrow. Red marrow can be found in vertebrae, ribs, skull, sternum, scapula, and proximal ends of the limb bones (known as the trabecular area). Red marrow is also known as myeloid tissue. It is not generally found in other areas of the long limb bones; which are instead filled with fatty yellow marrow. However, during extreme times, the marrow in these areas can switch to become red marrow. During childhood, red marrow is far more extensive.
  • 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

This takes place in mainly in the spleen. Macrophages will recognise and destroy about 90% of old RBC’s before they rupture and release their products into the blood (haemolyse).
These cells will also recognise and phagocytose free haemoglobin. The Hb has to be phagocytosed for it to be recycled!
In the spleen, there is red pulp which contains blood vessels of a very small diameter (about 3μm). RBC’s have a diameter of about 8μm; thus the RBC’s have to bend to fir through these capillaries. Thus, the old ‘weak’ ones are likely to break, and thus be phagocytosed
  • 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?

  • Haemoglobin
  • Myoglobin
  • Cytochrome systems (all cells with mitochondria have these, thus al cells need some iron)
 

Haemoglobin

Haemoglobin synthesis takes place in the mitochondria of the developing RBC. The major rate limiting step is the conversion of glycine and succinic acid to ALA, by the molecules ALA synthase. Vitamin B6is a co-enzyme for this reaction.
Haemoglobin consists of 4 globin chains around 4 heme molecules. There are four types of globin chain:
  • α1
  • β
  • δ
  • γ
 
These go together in different combination, to make three types of haemoglobin:
Haemoglobin
Chains
% Hb in normal adult
Hb A
α2β2 (2xα and 2xβ)
97%
Hb A2
α2δ2
1.5 – 3.2%
Hb F
α2γ2
<1%
The affinity of Hb for oxygen changes with O2 concentration (amongst other things), and thus, Hb has a high affinity for oxygen when [O2] is high (in the lungs), and a low affinity for oxygen when [o2] is low (at the capillaries).
Note that low pH reduces the affinity of Hb for O2. Thus when pH is low, O2 is more likely to be released – imagine it like – when there is lots of CO2 (thus low pH), then the tissue is likely to have high metabolism, thus needs more oxygen, thus the Hb is more likely to release the oxygen.
 
Haemoglobin can exist in two formations; T & R. these letters stand for taut and relaxed. Deoxygenated Hb is T, and oxygenated Hb is R. this is significant because the Hb molecule alters its affinity for oxygen with the number of oxygen molecules already bound to it. This creates the shape of the oxygen dissociation curve.
  • 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.
 

Platelets

These also develop from myeloid stem cells, however, in this case these stem cells will grow to become massive, before finally breaking up to form platelets.
Platelet development is stimulated by TPO – thrombopoietin. Like EPO, TPO is produced by the liver and kidneys.
 

White blood cells

These are traditionally divided into two types; granulocytes and agranulocytes. They are so called because when using a microscope, the granulocytes have visible ‘granules’ (actually secretory veiscles and lysosomes), and the agranulocytes have much smaller (and therefore harder to see) vesicles. 
  • Granulocytes are a group of cells comprising of basophils, eosinophils, and neutrophils.
  • Agranulocytes are the monocytes and lymphocytes (B and T cells)
Granulocytes and monocytes are non-specific defence cells, attacking pretty much all pathogens, whilst lymphocytes are specific to one particular pathogen.
Generally, WBC’s do not spend much of their lifetime in the bloodstream. They use it to get from one organ to another – to find the pathogen.
 

Neutrophils

Account for 70% of circulating WBC’s. they have a very dense, segmented nucleus, with 2-5 lobes. As a result, these cells are referred to as polymorphonuclear leukocytes, or polymorphs. Their cytoplasm is packed with lysosomal enzymes, and bactericidal substances.
They are often the first WBC’s to ‘arrive at the scene’ of an infection, and will attack substances that have been marked by complement.
They will engulf bacteria and ingest it, in the process releasing superoxide anions, and hydrogen peroxide. Whilst this process is going on, the neutrophils will release cytokines, prostaglandins and leukotrienes. The prostaglandins increase vascular permeability in the area, thus aiding inflammation, whilst the other chemicals attract other cells to the site.
Neutrophils only last about 10 hours in the bloodstream. They will only last about 30 minutes whilst actively engulfing bacteria. The neutrophils will die after engulfing about 25 bacteria.
 

Eosinophils

Account for 2-4% of circulating WBC’s. they are similar in size to neutrophils, but always have a bilobed nucleus and deep red, obvious granules. They attack pathogens that have been marked by antibodies. They are capable of engulfing bacteria, but their main attack is through the release of toxic compounds. Thus, they are particularly useful against multicellular parasites. These are the cells responsible for an allergic reactionbecause they are sensitive to allergens.
 

Basophils

Have loads of granules that stain very darkly with various dyes. They are slightly smaller than eosinophils and neutrophils. They account for less than 1% of circulating WBC’s. they migrate to inflamed areas, where they discharge their granules, releasing heparin and histamine into the interstitial space. They enhance the local inflammation that has already been started by mast cells. they also release chemotaxic agents to attract eosinophils and other basophils.
 

Monocytes

Are spherical, and larger than neutrophils and eosinophils, and approximately twice as big as basophils. The nucleus is large and tends to be oval or kidney bean shaped. They account for 2-8% of circulating WBC’s. they use the blood mainly for transportation, and remain in the blood only for a maximum of 24 hours, before migrating to tissues to become macrophages. Macrophages are aggressively phagocytotic. They also release chemotaxic agents for pretty much all other WBC’s. they also release agents that are chemotaxic for fibroblasts, thus attracting fibroblasts to the area to begin forming scar tissue.
 

Lymphocytes

Are slightly larger than RBC’s and do not generally contain visible granules. They generally have a large round nucleus, and a ‘halo’ of cytoplasm. They account for 20-30% of the circulating WBC’s. they migrate from the blood to peripheral tissues, and are then able to migrate back to the blood again. Circulating lymphocytes represent only a tiny fraction of the total amount of lymphocytes, as a very large proportion are in your peripheral tissues and lymphatic system.
There are 3 types of lymphocyte, but these cannot be distinguished by light microscope.
  • 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
 

WBC production

All WBC’s except lymphocytes will mature in the bone marrow. Lymphocytes are discussed separately below.
There are various factors produced that stimulate the differentiation of the progenitor cell.
  • 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
 

Lymphocytes

Haemocytoblasts will develop directly into lymphoid stem cells (lymphoid progenitor cells) which are distinctly different from the progenitor cells that go on to form all other types of blood cell (see diagram below).
The thymus produces various factors that affect the differentiation of lymphocytes. They also develop in response to the presence of various antigens.
 

Other general Properties of blood

Characteristic
Average Value
Fraction of body weight
7-8%
Amount of blood
4-6L (men generally have more)
pH
7.35-7.45
Viscosity (water = 1)
4.5-5.5 (plasma = 2.0)
 

Tree Diagram of blood cell production