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Formation of blood cells (Haemopoiesis)
Where blood is made
Haemopoietic cells (those which produce blood) first appear in the yolk sac of the 2-week embryo.
By 8 weeks, blood making has become established in the liver of the embryo, and by 12-16 weeks the liver has become the major site of blood cell formation. It remains an active haemopoietic site until a few weeks before birth. The spleen is also active during this period, particularly in the production of lymphoid cells, and the foetal thymus is a transient site for some lymphocytes.
The highly cellular bone marrow becomes an active blood making site from about 20 weeks gestation and gradually increases its activity until it becomes the major site of production about 10 weeks later.
At birth, active blood making red marrow occupies the entire capacity of the bones and continues to do so for the first 2-3 years after birth.
The red marrow is then very gradually replaced by inactive, fatty, yellow, lymphoid marrow. The latter begins to develop in the shafts of the long bones and continues until, by 20-22 years, red marrow is present only in the upper ends of the femur and humerus and in the flat bones of the sternum, ribs, cranium, pelvis and vertebrae. However, because of the growth in body and bone size that has occurred during this period, the total amount of active red marrow (approximately 1000-1500 g) is nearly identical in the child and the adult.
Adult red marrow has a large reserve capacity for cell production. In childhood and adulthood, it is possible for blood making sites outside marrow, such as the liver, to become active if there is excessive demand as, for example, in severe haemolytic anaemia or following haemorrhage.
In old age, red marrow sites are slowly replaced with yellow, inactive marrow.
Red marrow forms all types of blood cell and is also active in the destruction of red blood cells.
Red marrow is, therefore, one of the largest and most active organs of the human body, approaching the size of the liver in overall mass although as mentioned it is distributed in various parts of the body.
About two-thirds of its mass functions in white cell production (leucopoiesis), and one-third in red cell production (erythropoiesis). However as we have already seen there are approximately 700 times as many red cells as white cells in peripheral blood. This apparent anomaly reflects the shorter life span and hence greater turnover of the white blood cells in comparison with the red blood cells.
It is now generally accepted that all blood cells are made from a relatively few 'uncommitted' cells which are capable of mitosis and of differentiation into 'committed' precursors of each of the main types of blood cell.
The diagram on the left shows the formation of the different types of blood cells from a common source the stem cell
Row [a] represents the myelocytes showing neutrophilic, basophilic and eosinophilic from left to right
Row [b] represents the metamyelocyte cells again starting with neutrophilic on the left.
Red blood cells (erythrocytes)
The production of red blood cells is referred to as erythropoiesis.
Mature red blood cells develop from haemocytoblasts. This development takes about 7 days and involves three to four mitotic cell divisions, so that each stem cell gives rise to 8 or 16 cells.
The various cell types in erythrocyte development are characterised by
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the gradual appearance of haemoglobin and disappearance of ribonucleic acid (RNA) in the cell |
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the progressive degeneration of the cell's nucleus which is eventually extruded from the cell |
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the gradual loss of cytoplasmic organelles, for example mitochondria |
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a gradual reduction in cell size |
The young red cell is called a retlculocyte because of a network of ribonucleic acid (reticulum) present in its cytoplasm. As the red cell matures the reticulum disappears. Between 2 and 6% of a new-born baby's circulating red cells are reticulocytes, but this reduces to less than 2% in the healthy adult. However, the reticulocyte count increases considerably in conditions in which rapid erythropoiesis occurs, for example following haemorrhage or acute haemolysis of red cells. A reticulocyte normally takes about 4 days to mature into an erythrocyte.
In health, erythropoiesis is regulated so that the number of circulating erythrocytes is maintained within a narrow range. Normally, a little less than l% of the body's total red blood cells are produced per day and these replace an equivalent number that have reached the end of their life span. However that still represents a huge 200,000,000,000 cells
Erythropoiesis is stimulated by hypoxia (lack of oxygen). However, oxygen lack does not act directly on the haemopoietic tissues but instead stimulates the production of a hormone, erythropoietin. This hormone then stimulates haemopoietic tissues to produce red cells.
Erythropoietin is a glycoprotein. It is inactivated by the liver and excreted in the urine. It is now established that erythropoietin is formed within the kidney by the action of a renal erythropoietic factor erythrogenin on plasma protein, erythropoietinogen.
Erythrogenin is present in the juxtaglomerular cells of the kidneys and is released into the blood in response to hypoxia in the renal arterial blood supply.
Various other factors can affect the rate of erythropoiesis by influencing erythropoietin production.
Thyroid hormones, thyroid-stimulating hormone, adrenal cortical steroids, adrenocorticotrophic hormone, and human growth hormone (HGH) all promote erythropoietin formation and so enhance red blood cell formation (erythropoiesis). In thyroid deficiency and anterior pituitary deficiency, anaemia may occur due to reduced erythropoiesis.
Polycythaemia (excess red blood cell production) is often a feature of Cushing's syndrome. However, very high doses of steroid hormones seem to inhibit erythropoiesis.
Androgens (male hormones) stimulate and oestrogens (female hormones) depress the erythropoietic response. In addition to the effects of menstrual blood loss, this effect may explain why women tend to have a lower haemoglobin concentration and red cell count than men.
Plasma levels of erythropoietin are raised in hypoxic conditions (low oxygen levels). This produces erythrocytosis (increase in the number of circulating erythrocytes) and the condition is known as secondary polycythaemia.
A physiological secondary polycythaemia is present in the foetus (and residually in the new-born) and in people living at high altitude because of the relatively low partial pressure of oxygen in their environment.
Secondary polycythaemia occurs as a result of tissue hypoxia in diseases such as chronic bronchitis, emphysema and congestive cardiovascular abnormalities associated with right-to-left shunting of blood through the heart, for example Fallot's tetralogy.
Erythropoietin is also produced by a variety of tumours of both renal and other tissues.
The oxygen carrying capacity of the blood is increased in polycythaemia but so is the thickness (viscosity)of the blood. The increased viscosity produces circulatory problems such as raised blood pressure.
Ther is a condition known as primary polycythaemia (polycythaemia rubra vera), where there are increases in the numbers of all the blood cells, and plasma erythropoietin levels are normal. The cause of this condition is unknown.
The underlying cause of secondary polycythaemia is treated with the aim of eliminating hypoxia. Venesection (blood letting) is sometimes employed to reduce red cell volume to normal levels. Frequently blood is removed, centrifuged to remove cells and the plasma returned to the patient (plasmapheresis).
In anaemia there is a reduction in blood haemoglobin concentration due to a decrease in the number of circulating erythrocytes and/or in the amount of haemoglobin they contain. Anaemia occurs when the erythropoietic tissues cannot supply enough normal erythrocytes to the circulation. In anaemias due to abnormal red cell production, increased destruction and when demand exceeds capacity, plasma erythropoietin levels are increased. However, anaemia can also be caused by defective production of erythropoietin as, for example, in renal disease.
In order for efficient production of red blood cells to take place certain dietary requirements must be adhered to.
In the UK most people are able to maintain sufficient intake of proteins, vitamins and minerals required for adequate red cell production. However some people who eat 'quirky' diets can have blood problems as a result. For example some individuals who have eaten strict fruitarian or vegan diets have required treatment for anaemia. There is no reason why people cannot adhere to these dietary lifestyles so long as they are aware of balancing their food intake with vitamin and mineral supplements and ensuring adequate protein intake. Patients with eating disorders such as Anorexia nervosa can also cause themselves to become severely anaemic as a result of an insufficient diet.
The effects of diet on anaemia are discussed further on the anaemia page on this site.
The following table shows the dietary requirements for sufficient red blood cell production.
| Dietary element | Role in red blood cell production |
| Protein | Required to make red blood cell proteins and also for the globin part of haemoglobin |
| Vitamin B6 | Not clear what the role is but deficieny has occassionally been associated with anaemia |
| Vitamin B12 and folic acid | Needed for DNA synthesis and are essential in the process of red blood cell formation |
| Vitamin C | Required for folate metabolism and also facilitates the absorption of iron. Extremely low levels of Vitamin C are needed before any problems occur. Anaemia caused by lack of Vitamin C (scurvy) is now extremely rare |
| Iron | Required for the haem part of haemoglobin |
| Copper and Cobalt | There is some evidence that these two trace minerals are essential for the production of red blood cells in other animals but not in humans |
Monocytes are produced in the bone marrow, developing from nucleated precursors, the monoblast and promonocyte. Mature cells have a life in blood of approximately 3-8 hours and, like granulocytes, there is a circulating and marginating pool.
The diagram on the right shows
the process of macrophage formation.
Monocytes are actively phagocytic (engulf other cells) and, on migration into the tissues, they mature into larger cells called macrophages (Derives from the Ancient Greek: macro = big, phage = eat), which can survive in the tissues for long periods. These cells form the mononuclear phagocytic cells of the mononuclear phagocytic system (reticuloendothelial system) in bone marrow, liver, spleen and lymph nodes. Tissue macrophages (sometimes called histiocytes) respond more slowly than neutrophils to chemotactic stimuli. They engulf and destroy bacteria, protozoa, dead cells and foreign matter. They also function as modulators of the immune response by processing antigen structure and facilitating the concentration of antigen at the lymphocyte's surface. This function is essential in order that full antigenic stimulation of both T and B lymphocytes can take place.
As already mentioned granulocytes is the collective name given to three types of white blood cell. Namely these are neutrophils, basophils and eosinophils.
In terms of their formation (granulopoiesis) they all derive from the same type of committed stem cells called myeloblasts. After birth and into adulthood granulopoiesis occurs in the red marrow.
The process of producing granulocytes is characterised by the progressive condensation and lobulation of the nucleus, loss of RNA and other cytoplasmic organelles, for example mitochondria, and the development of cytoplasmic granules in the cells involved.
The development of a polymorphonuclear leukocyte make take a fortnight, but this time can be considerably reduced when there is increased demand, as, for example, in bacterial infection. The red marrow also contains a large reserve pool of mature granulocytes so that for every circulating cell there may be 50-100 cells in the marrow.
Mature cells pass actively through the endothelial lining of the marrow sinusoid into the circulation. In the circulation, about half the granulocytes adhere closely to the internal surface of the blood vessels. These are called marginating cells and are not normally included in the white cell count. The other half circulate in the blood and exchange with the marginating population.
Within 7 hours, half the granulocytes will have left the circulation in response to specific requirements for these cells in the tissues. Once a granulocyte has left the blood it does not return. It may survive in the tissues for 4 or 5 days, or less, depending on the conditions it meets.
The turnover of granulocytes is, therefore, very high. Dead cells are eliminated from the body in faeces and respiratory secretions and are also destroyed by tissue macrophages (monocytes).
No precise mechanisms for the control of granulocyte production have, so far, been found. However, in health, the count remains relatively constant so it is likely that homeostatic control mechanisms operate.
Refer back to the diagram above for a visual representation of granulopoiesis
Lymphocytes are round cells containing large round nuclei. The cytoplasm stains pale blue and appears non-granular under light microscopy. However, some cytoplasmic granules and organelles are present.
Morphologically, lymphocytes can be divided into two groups: the more numerous small lymphocytes, with a diameter of 7-10 mm; and large lymphocytes, which have a diameter of 10-14 mm. Lymphocytes are produced in bone marrow from primitive precursors, the lymphoblasts and prolymphocytes. Immature cells migrate to the thymus and other lymphoid tissues, including that found in bone marrow, and undergo further division, processing and maturation.
Platelets are produced in bone marrow by a process known as thrombopoiesis. They are formed in the cytoplasm of a very large cell, the megakaryocyte. The cytoplasm of the megakaryocyte fragments at the edge of the cell. This is called platelet budding. Megakaryocytes mature in about 10 days, from a large stem cell, the megakaryoblast.
It is likely that there are thrombopoietic feedback mechanisms as the platelet count remains fairly constant in health, and platelet production is reduced following an infusion of platelets and increased following removal of platelets. However, these feedback mechanisms have not been discovered yet.
This looping diagrammatic animation shows
the process of platelet formation from a megakaryocyte
At any one time, about two-thirds of the body's platelets are circulating in the blood and one-third are pooled in the spleen. There is constant exchange between the two populations. The life span of platelets is between 8 and 12 days. They are destroyed by macrophages, mainly in the spleen and also in the liver.
This page last updated Wednesday, 28 April 1999 20:32 +0100
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