BLOOD General Notes

BLOOD

The blood's importance to human life has been recognized since pre-history. Early man knew that if enough blood leaves the body then life ceases to function. As a result of this the blood has acquired mystic and religious significance throughout the ages. Blood was thought to carry rejuvenating properties or was used to represent desirable human characteristics such as purity or courage. Even today we talk of blood brothers or blood lines although we know that scientifically it is the genes which carry traits from generation to generation. The phrase "blood is thicker than water" is still commonly heard. We talk of our "blood boiling" when we get angry. Many people faint simply as a result of seeing blood.

Biologically the blood is of extreme importance in maintaining homeostasis by transporting needed materials to the appropriate part of the body and by protecting the body against disease.

Functions of the blood

Delivers nutrients from the digestive system to all parts of the body.

Transports oxygen from the lungs to all parts of the body.

Transports carbon dioxide from all parts of the body to the lungs.

Transports waste products from cells to the external environment mainly via the kidneys.

Transports hormones from the endocrine system to target cells or organs within the body.

Through continuous exchange of it's components with tissue fluids promotes fluid and electrolyte balance.

Defends the body against attack from foreign organisms via the white blood cells and antibodies.

Defends the body against injury or infection via the inflammatory response.

Prevents serious hemorrhage by the clotting process.

Maintains the body's temperature by circulating heat.

Blood is of huge importance clinically as a diagnostic aid because of it's many functions outlined above.

Samples of blood tissue are easily obtained and analysis of them will reveal much about the state of the body.

Composition of the Blood

The blood is a mixture of cells, fluid, proteins and metabolites.

Blood has four major elements

Red blood cells (RBC's or erythrocytes)

Transport oxygen from the lungs to organs and peripheral sites.

White blood cells (or leukocytes)

have a defensive role in destroying invading organisms e.g. bacteria and viruses

assist in the removal of dead or damaged tissue cells.

Platelets (or thrombocytes)

The first line of defense against damage to blood vessels.

They adhere to any defects and assist in the clotting process.

Plasma

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The proteinaceous substance in which the other three cellular elements circulate.

It carries nutrients, metabolites antibodies,

Proteins involved in blood clotting, as well as

Hormones and other molecules to all parts of the body.

In normal human blood the red blood cells account for about 45% of the total volume. Plasma accounts for just below 55% of the total volume with the other two cellular elements (platelets and white blood cells) making up less than 1% of total blood volume.

In the laboratory blood samples can be separated out in a centrifuge. This spins the blood sample at high speed in a specially calibrated tube. The plasma floats to the top and the red blood cells sink to the bottom leaving a very thin middle layer composing of the other components in the middle. This layer is known as the buffy coat. This is a good test for determining the percentage of red blood cells in the total blood count in order to determine if an individual is anaemic. The test is called a haematocrit.

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 fetal 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.

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.

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The various cell types in erythrocyte development are characterized by

the gradual appearance of haemoglobin and disappearance of ribonucleic acid (RNA) in the cellthe progressive degeneration of the cell's nucleus which is eventually extruded from the cellthe gradual loss of cytoplasmic organelles, for example mitochondriaa 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.

There 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

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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 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 B6Not clear what the role is but deficiency has occasionally 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 CRequired 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 heme 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

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.

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.

Granulocytes

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 characterized 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 may 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.

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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.

Lymphocytes

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 m; and large lymphocytes, which have a diameter of 10-14 m. 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

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.

At any one time, about two-thirds of the body's platelets are circulating in the blood and one-third is 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.

RED BLOOD CELLS

Erythrocytes in a peripheral blood smear derive their reddish colour from the protein haemoglobin, and usually appear round or oval with a pale-staining centre region.

They are biconcave in shape, as seen arrowed in this scanning electron microscopic image. This shape increases the cell's surface area and facilitates diffusion of O2 and CO2 into or out of the cell. Likewise, the lack of nuclei and organelles contribute to increased haemoglobin content and gas-carrying capacity. Cell shape is maintained by a cytoskeleton composed of several proteins (spectrin, actin, etc.), but normal erythrocytes must be very flexible. They become deformed when flowing through capillaries and narrow slits in the spleen (see section on the lymphatic system).

As mentioned above red blood cells (RBC's) or erythrocytes are highly specialized for the transport of oxygen. The nucleus is lost in the process of red blood cell formation in the bone marrow. This process is known as haemopoeisis. During this process all of the internal cell organelles are also degraded thus allowing the RBC to carry more haemoglobin.

All red blood cells have a limited life span of around 100 to 120 days and must therefore be continuously replaced. Mature red blood cells are unable to synthesize new enzymes to replace those lost during normal cell metabolic processes due to their lack of inner organelles.

It is probable that as the RBC's age they become less deformable due to diminishing efficiency of ion pumping mechanisms and as a result they are no longer able to pass through the filtering system of the spleen and are thus removed by being literally eaten up by white blood cells in a process known as phagocytosis.

Aged RBC's are removed by the spleen, liver and the bone marrow. Although it appears that the spleen is most active their relative importance to each other under normal circumstances is uncertain. Certainly we know that individuals who have lost their spleen are able to function normally with few limitations.

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RBC's have a specialized cytoskeleton in order to maintain their shape. This composes of an actin/spectrin network held together by another protein call ankyrin. A condition known as Hereditary Spherocytosis is caused by an abnormal arrangement of the internal cytoskeleton of RBC's. In this condition the ankyrin binding of spectrin is absent. As a result the cell membrane is not adequately braced and is too easily deformed. Individuals who suffer the condition have spherical RBC's which are abnormally fragile and do not resist osmotic pressure.

The most common cause is iron deficiency. Iron is essential for the formation of haemoglobin and a deficiency in the diet means that cells formed in the bone marrow are pale-staining (hypochromic) and smaller than normal (microcytic).

Excessive red cell destruction usually occurs if the red cells produced are structurally abnormal in some way and are therefore liable to damage in their passage around the body. Any such cells are removed prematurely and in excess by the spleen resulting in haemolytic anaemia this is often due to a genetic abnormality such as Hereditary Spherocytosis or Sickle Cell Anaemia.

WHITE BLOOD CELLS

There are five main types of White Blood Cell

White blood cells use the blood as a means of transport from their origination in the bone marrow to their major sites of activity. The majority of the functions of the white blood cells occur when they leave the blood circulation to enter other body tissues.

There are five types of white blood cell

neutrophils 40 - 75 % eosinophils 5 %

basophils 0.5 % lymphocytes 20 - 50 %

monocytes 1 - 5 %

The figures show the relative proportions of the different types of white blood cell. The reason for the range of figures shown is that the requirement for different types of white blood cell will vary from time to time.

Neutrophils, eosinophils and basophils are collectively known as granulocytes due to prominent granules in their cytoplasm.

Lymphocytes and monocytes are classed as white blood cells because they are a constituent of blood and ultimately originate from the bone marrow. However they are mainly found in structures such as the lymph nodes and the spleen

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NEUTROPHILS

Neutrophils are the most common granulocyte. They have segmented nuclei, typically with 2 to 5 lobes connected together by thin strands of chromatin which can be difficult to see; the cell may thus appear to have multiple nuclei. The nuclear chromatin is condensed into coarse clumps. Small numbers of immature neutrophils or band form neutrophils may be seen in a blood smear. These are incompletely segmented and often have a 'C-shaped' nucleus.

The cytoplasm of neutrophils contains three types of granule.

Primary granules are non-specific and contain lysosomal enzymes, defensins, and some lysozyme. The granules are similar to lysosomes. They stain aviolet colour when prepared with Wright's stain which is commonly used in studying the blood. The enzymes produce hydrogen peroxide which is a powerful anti-bacterial agent.

Secondary granules are specific to neutrophils and stain light pink ('neutral stain'). They contain collagenase, to help the cell move through connective tissue, and lactoferrin, which is toxic to bacteria and fungi.

Tertiary granules have only recently been recognized. It is thought that they produce proteins which help the neutrophils to stick to other cells and hence aid the process of phagocytosis.

Once in the area of infection neutrophils respond to chemicals (called chemotaxins which are released by bacteria and dead tissue cells) and move towards the area of highest concentration. Here they begin the process of phagocytosis in which they engulf the offending cells and destroy them with their powerful enzymes. Because this process consumes so much energy the neutrophils glycogen reserves are soon depleted and they die soon after phagocytosis. When the cells die their contents are released and the remnants of their enzymes cause liquefaction of closely adjacent tissue. This results in an accumulation of dead neutrophils, tissue fluid and abnormal materials known as pus.

EOSINOPHILS

They increase greatly in many types of parasitic infection and defense against the larvae of parasitic worms and unicellular organisms seems to be one of their primary functions. The granules of eosinophils contain a substance called MBP (major basic protein) which is toxic to many parasitic larvae. Eosinophils also have surface receptors for the antibody immunoglobulin E (IgE). These receptors are not found in neutrophils and again this is thought to reflect their role in parasitic infection.

They also increase in number in some allergic states. For example their numbers increase in the nasal and bronchial mucosal linings in hay fever and asthma and in some adverse drug reactions. It is thought that they may neutralize the effect of histamine.

Eosinophils also have a marked diurnal variation with their numbers being highest in the morning and lowest in the afternoon although why this is the case is at present unclear.

BASOPHILS

Basophils are the least common of the white blood cells. They are characterized by their large cytoplasmic granules which obscure the nucleus in stained preparations. They have many similarities with mast cells and actually become mast cells on leaving the blood and entering surrounding tissues.

Mast cells are widely distributed throughout the body and are commonly found in close proximity to the walls of small blood vessels.

Both basophils and mast cells have highly specific receptors for IgE produced in response to various allergens.

Response to specific allergens is rapid and results in expulsion of the cells granular contents which contain histamines and other vasodilating agents. This results in the reaction known as immediate hypersensitivity. This can result in hay fever, some forms of asthma, urticaria (nettle rash) and most seriously anaphylactic shock.

MONOCYTES

Monocytes are the largest cell type seen in blood smears. Their nuclei are not multilobular like granulocytes, but may be deeply indented or U-shaped, with reticular-appearing chromatin. The cytoplasm of monocytes contains numerous lysosomal granules which give it a uniform grayish-blue "ground-glass" appearance. They form part of a cell network known as the monocyte-macrophage system. This comprises bone marrow precursor cells (monoblasts and promonocytes), circulating monocytes and both free and fixed tissue macrophages.

Monocytes eventually leave the bloodstream to become tissue macrophages which remove dead cell debris as well as attacking organisms such as Tubercule Bacilli (which causes TB) and some fungi. Neither of these can be dealt with

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effectively by the neutrophils. Unlike neutrophils monocytes are able to replace their lysosomal contents and are thought to have a much longer active life.

Cells which derive from monocytes include the

Kupffer cells of the liver sinus lining cells of the spleen and lymph nodes

pulmonary alveolar macrophages free macrophages in the synovial, pleural and peritoneal fluid

dendritic antigen presenting cells

LYMPHOCYTES

These are the most numerous white blood cell in young children and the second most numerous in older children and adults.

Their numbers increase in response to viral infections.

Lymphocytes are distinguished by having a deeply staining nucleus which may be eccentric in location, and a relatively small amount of cytoplasm. The small ring of cytoplasm contains numerous ribosomes and stains blue. Small numbers of lysosomal granules may also be seen in the cytoplasm of some lymphocytes.

In this image, a lymphocyte and a dumbbell-shaped Red Blood Cell (RBC) can be seen in the lumen of a small blood vessel. Note the pseudopodia and the small amount of cytoplasm of the lymphocyte.

The two major types of lymphocyte found in the blood are B-lymphocytes and T-lymphocytes. Both have different but linked roles in the generation of specific immune response. The small mature lymphocytes circulating in the blood are constantly sampling their environment for foreign materials. Their role is discussed more fully in the sessions on the immune system.

Increased numbers of white blood cells appear in the peripheral blood in a variety of disorders.

The most important and most life threatening disorders are the leukaemias. Here there is a malignant proliferation of white cell precursors in the bone marrow. This produces vast numbers of white blood cells and their precursors which then spill over into the the blood stream. The various types of leukaemia are classified according to the cell line involved (granulocytic, monocytic, lymphocytic etc.) and also according to their degree of malignancy.

In chronic leukaemias the proliferating cells are more differentiated (i.e. they have more closely reached maturity) whereas in acute leukaemias the proliferating cells are the virtually undifferentiated precursor cells such as lymphoblasts in acute lymphoblastic leukaemia.

PLATELETS

Blood platelets, or thrombocytes, are not true cells, but rather cytoplasmic fragments of a large cell in the bone marrow, the megakaryocyte. The central portion of a platelet stains purple with Wright's stain and is referred to as the granulomere. The peripheral portion stains clear and is called the hyalomere.

Platelet contents include glycogen granules, the open canalicular system (OCS), which is composed of canaliculi formed from invaginations of the platelet plasma membrane, mitochondria, occasional Golgi elements and ribosomes. Platelets have several types of membrane-bound granules which contain a number of constituents including fibrinogen and several growth factors (e.g., PDGF).

Platelet activation occurs when injury to the vessel wall exposes sub-endothelial components, especially collagen. Platelets adhere to the damaged area and become cohesive to other platelets. This aggregation leads to the formation of a platelet plug, which prevents further blood loss and allows the repair process to begin.

Severe reduction in the number of circulating platelets results in a condition known as thrombocytopenia.

It is a condition which causes spontaneous bleeding as a reaction to minor trauma. This is due to failure of the platelets to seal over microscopic breaches in blood vessel walls.

In the skin this is manifest by a reddish-purple blotchy rash. This can be either small blotches called purpura or larger bruise like areas called ecchymoses.

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Cytotoxic drugs used in treatment of cancers may cause this condition. It is also seen associated with acute leukaemias.

BLOOD PLASMA

Blood plasma is a pale yellow fluid. It's total volume in a normal adult is around 2.5 to 3 liters.

Constituent (%)

Water90.0

Protein 8.0

Inorganic ions0.9

Organic substances 1.1

The table shows the constituents of plasma as percentages of the total volume

Plasma contains clotting agents and on exposure to air it will form a clot. The clear fluid exuded from clotted whole blood and clotted plasma is called serum. The quantities of the constituents of serum are the same as those for plasma minus the small amount of clotting agents, such as fibrinogen, destroyed during the clotting process.

Blood plasma comprises around 20 % of the boy's extracellular fluid and is very similar in composition to interstitial fluid. The main difference being the protein content. Interstial fluid contains much less protein at around 2% by volume.

This is because most of the plasma protein molecules are too large to pass through the capillary walls into the interstitial area. The small amount of protein which does leak through is eventually taken up by the lymph and then ultimately returned to the blood.

Plasma proteins form three major groups and these have various functions.

The three groups are :

albumin (60% of total plasma protein) fibrinogen (4% of total plasma protein)

globulins (36% of total plasma protein)

further fractions (alpha, beta and gamma) can be distinguished within the globulin group.

The relative proportions of plasma proteins can vary in certain diseases and electrophoretic tracings showing such changes can be a useful diagnostic aid.

Most of the plasma proteins are produced by the liver. The gamma globulins are produced by cells of the body's immune system.

Albumin is the smallest of the plasma proteins and is just small enough to pass through capillary walls. In normal circumstances this leads to the small amount of leakage into the interstitial fluid alredy mentioned. In svere kidney disease large amounts of albumin are able to leak out through the damaged kidney tubules and can be detected in the urine. Because the liver can quickly and easily replace lost albumin the body may lose large amounts of the protein without showing signs of disease.

Functions of the plasma proteins include :

Intravascular osmotic effect. This is important in maintaining fluid and electrolyte balance and is discussed more fully in those sessions.

Contributes to the viscosity of the plasma

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Transport of insoluble substances around the body by allowing them to bind to protein molecules. Protein reserve for the body

Clotting this is discussed further in sessions on wounds and wound healing Inflammatory response again discussed further in the sessions on the immune system.

Protection from infection the gamma globulins function as antibodies and their role is discussed more fully in the sessions on the immune system.

Maintenance of the acid-base balance. Again this is explored in more detail in the session on fluid and electrolyte balance.

The blood plasma contains inorganic ions which are important in regulating cell function and maintaining homeostasis. For example depletion of potassium may occur following severe diarrhoea and vomiting. Potassium affects cell excitability and severe loss will cause muscle weakness and abnormalities of the cardiac impulse. The same problems may result in severe sodium depletion. Lack odf sodium in the plasma will result in a reduction in the overall volume of extracellular fluid which in turn leads to a drop in blood pressure causing weakness, dizziness, mental confusion and fainting.

ION SYMBOLCONCENTRATION

(mmol/l)

Sodium Na+ 135-146

Potassium K+ 3.5-5.2

Calcium Ca++ 2.1-2.7

Chloride Cl- 98-108

Hydrogen Carbonate HCO3- 23-31

Phosphate PO4-- 0.7-1.4

The above table shows the normal range of concentration of inorganic ions in the blood plasma.

In addition to proteins and inorganic ions the blood plasma carries a wide range of substances in transit to various tissues throughout the body. These include dissolved gases (mainly carbon dioxide). Oxygen is not very soluble in water hence the need for the specialised oxygen transporing red blood cells.

Nutrients are carried in the blood plasma. The most abundant being glucose which is the primary source of energy for cell metabolism. Other nutrients in transit in the plasma include amino acids, fatty acids, triglycerides, cholesterol and vitamins.

Waste products of metabolism are also transported bty the plasma including urea, uric acid and cratinine from the kidneys and bilirubin from the gall bladder.

Hormones, such as cortisol and thyroxine are also transported around the body in plasma attached to plasma proteins.

Other substances can be transported in the plasma the most obvious examples being drugs and alcohol.

Anaemia

Introduction

The term anaemia is derived from Ancient Greek for "bloodlessness". It is a condition involving an abnormal reduction haemoglobin content.

Red blood cells (containing haemoglobin) are the means by which oxygen is carried to the various parts of the body.

People who are anaemic develop symptoms caused by the inadequate delivery of oxygen to their body tissues. This can vary from simple fatigue to death according to the nature and severity of the anaemia.

The condition is far more common in women than in men.

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There are three primary causes:

1. reduced production of red blood cells, which may result from deficiency in nutrients or hormones, or from disease or other conditions

2. excessive destruction of red blood cells, often a hereditary problem3. excessive blood loss, such as that caused by gastrointestinal ulcers, heavy menstrual periods, or overdose of

aspirin.

The most usual symptoms of anaemia are pallor, shortness of breath, low vitality, dizziness, and digestive disorders.

The most common type of anaemia is iron-deficiency anaemia, which occurs when the body’s need for iron increases, as during certain periods of childhood and in pregnancy, or when there is insufficient iron in the diet.

Pernicious anaemia, a chronic ailment that mostly affects people over 40, is a result of vitamin B12 deficiency. Rather than a diet deficient in the vitamin, this is usually caused by intestinal malabsorption, resulting in decreased B12 uptake.

Sickle-cell anaemia is the result of a hereditary defect in the synthesis of haemoglobin.

Aplastic anaemia occurs when there is severe reduction in red blood corpuscles, and when the bone marrow is unable to regenerate them. Ionising radiation is one possible cause.

Past treatment of the condition has included removal of the spleen, repeated transfusions of blood, and a diet featuring beef or calf’s liver.

Transfusions are still used in cases of acute blood loss; iron supplements for iron-deficiency anaemia and injections of vitamin B12 for pernicious anaemia are often effective. Synthetically manufactured erythropoietin (normally produced by the human kidney) is now used to stimulate the production and growth of red blood cells. Other therapy focuses on curing the underlying causes of the nutritional or hormonal deficiency. Blood transfusions and, increasingly, bone marrow transplants, are necessary forms of treatment for aplastic anaemia patients.

Types of Anaemia

anaemia of B12 deficiency anaemia of chronic disease anaemia of folate deficiency drug-induced immune haemolytic anaemia haemolytic anaemia haemolytic anaemia due to g6pd deficiency idiopathic aplastic anaemia idiopathic autoimmune haemolytic anaemia immune haemolytic anaemia iron deficiency anaemia megaloblastic anaemia pernicious anaemia secondary aplastic anaemia sickle cell anaemia

Iron deficiency anaemia is a decrease in the red cells of the blood caused by too little iron.

Iron deficiency anaemia is the most common form of anaemia. Approximately 20% of women, 50% of pregnant women, and 3% of men are iron deficient. Iron is an essential component of haemoglobin, the oxygen carrying pigment in the blood. Iron is normally obtained through the food in the diet and by the recycling of iron from old red blood cells.

The causes of iron deficiency are too little iron in the diet, poor absorption of iron by the body, and loss of blood (including from heavy menstrual bleeding). It is also caused by lead poisoning in children. Anaemia develops slowly after the normal stores of iron have been depleted in the body and in the bone marrow. Women, in general, have smaller stores of iron than men and have increased loss through menstruation, placing them at higher risk for anaemia than men. In men and postmenopausal women, anaemia is usually due to gastrointestinal blood loss associated with ulcers or the use of aspirin or nonsteroidal anti-inflammatory medications (NSAIDs).

High-risk groups include:

women of child-bearing age who have blood loss through menstruationpregnant or lactating women who have an increased requirement for ironinfants, children, and adolescents in rapid growth phases

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people with a poor dietary intake of iron through a diet of little or no meat or eggs for several years.

Risk factors related to blood loss are peptic ulcer disease, long term aspirin use, colon cancer, uterine cancer, and repeated blood donation. The incidence is 2 out of 1000 people.

Prevention:

Dietary sources of iron are red meat, liver, and egg yolks. Flour, bread, and some cereals are fortified with iron. If the diet is deficient in iron, iron should be taken orally. During periods of increased requirements such as pregnancy and lactation, increase dietary intake or take iron supplements.

Symptoms:

pale skin colour (pallor) fatigue irritability weakness shortness of breath low blood pressure with position change from lying or sitting to standing (orthostatic hypotension) sore tongue brittle nails unusual food cravings (called pica) decreased appetite (especially in children) headache - frontal

Note: There may be no symptoms if anaemia is mild.

Signs and tests:

low haematocrit and haemoglobin in a CBC low serum ferritin (serum iron) level transferrin saturation stool for occult blood (stool guaiac) that reveals blood loss higher than normal TIBC levels

Treatment:

Identification of the cause of the deficiency is essential. Iron deficiency cannot be overcome by increasing dietary intake alone. Iron supplements are always required.

Oral iron supplements are in the form of ferrous sulphate. The best absorption of iron is on an empty stomach, but many people are unable to tolerate this and may need to take it with food. Milk and antacids may interfere with absorption of iron and should not be taken at the same time as iron supplements. Vitamin C can increase absorption and is essential in the production of haemoglobin.

Supplemental iron is needed during pregnancy and lactation because normal dietary intake cannot supply the required amount.

The haematocrit should return to normal after 2 months of iron therapy, but the iron should be continued for another 6 to 12 months to replenish the body's iron stores, contained mostly in the bone marrow.

Intravenous or intramuscular iron is available for patients when iron taken orally is not tolerated.

Iron-rich foods include raisins, meats (liver is the highest source), fish, poultry, eggs (yolk), legumes (peas and beans), and whole grain bread.

With treatment, the outcome is likely to be good. In most cases the blood counts will return to normal in 2 months.

Complications:

There are usually no complications; however, iron deficiency anaemia may recur, so regular follow-up is encouraged. Children with this disorder may have an increased susceptibility to infection.

Megaloblastic anaemia is a blood disorder characterised by red blood cells that are larger than normal, low white blood count, and low platelet count resulting from a deficiency of folic acid or vitamin B-12.

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Deficiencies of vitamin B12 and folic acid are the most common causes of megaloblastic anaemia. Other causes are leukaemia, myelofibrosis, multiple myeloma, certain hereditary disorders, drugs that affect nucleic acid metabolism such as chemotherapy agents (methotrexate), and other causes. Risk factors relate to the causes. (See also pernicious anaemia).

Adequate intake of vitamin B12 and folic acid is helpful.

Symptoms:

loss of appetite diarrhoea tingling and numbness of hands and feet pale skin colour tiredness headaches sore mouth and tongue pale skin colour or jaundice

Examination of neurological signs shows abnormal reflexes, decreased position sense, and decreased vibration sense.

Tests include:

CBC results showing low haematocrit with elevated MCV bone marrow examination serum LDH below normal serum B12 level Schilling test serum folate level elevated ferritin

The objective of treatment is to determine the cause of the anaemia, and the treatment depends upon the cause. Anaemias related to vitamin deficiencies are discussed separately.

The outcome is expected to be good with treatment.

Complications vary with the underlying cause

Pernicious anaemia is a form of anaemia caused by a lack of intrinsic factor, a substance needed to absorb vitamin B12 from the gastrointestinal tract.

People with pernicious anaemia lose their ability to make intrinsic factor, a substance that enables vitamin B12 to be absorbed from the intestine. Vitamin B12 deficiency results.

This condition may result from hereditary factors. Congenital pernicious anaemia is inherited as an autosomal recessive disorder.

Pernicious anaemia is also seen in association with some autoimmune endocrine diseases such as type 1 diabetes, hypoparathyroidism, Addison's disease, hypopituitarism, testicular dysfunction, Graves disease, chronic thyroiditis, myasthenia gravis, secondary amenorrhea, vitiligo, and candidiasis. Gradually the deficiency of vitamin B12 affects sensory and motor nerves, causing neurological effects. The anaemia also affects the gastrointestinal system and the cardiovascular system.

The disease can affect all racial groups, but the incidence is higher among people of Scandinavian or Northern European descent. Pernicious anaemia usually does not appear before the age of 30, although a juvenile form of the disease can occur in children. Juvenile or congenital pernicious anaemia is evident before the child is 3 years old.

Risk factors are a history of autoimmune endocrine disorders, a family history of pernicious anaemia, and Scandinavian or Northern European descent. The incidence is 1 out of 1,000 people.

In the infant or young child, pernicious anaemia may be secondary to poor absorption of vitamin B12 caused by some of the following conditions:

defect in absorption celiac disease (sprue) methylmalonic aciduria homocystinuria tuberculosis treatment with para amino salicylic acid

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poor diet in the infant maternal dietary deficiency while pregnant can cause pernicious anaemia in an infant less than 4 months old

This condition is not preventable. Treatment will prevent continued symptoms.

Symptoms:

shortness of breath fatigue pallor rapid heart rate loss of appetite diarrhoea tingling and numbness of hands and feet (paresthesias) sore mouth unsteady gait, especially in the dark slowing of mental processes

Additional symptoms that may be associated with this disease:

tongue problems smell, impaired gums, bleeding positive Babinski's reflex loss of deep tendon reflexes

Signs and tests:

Neurological signs or symptoms will develop if the disease goes untreated.

Tests that may indicate pernicious anaemia include:

CBC results that show low haematocrit and haemoglobin with elevated MCV CBC showing low white blood count and low platelets low reticulocyte count bone marrow examination serum LDH below normal serum vitamin B-12 level Schilling test

This disease may also alter the results of the following tests:

TIBC peripheral smear leukocyte alkaline phosphatase gastrin cholesterol test bilirubin

Treatment:

Vitamin B12 injections are the definitive treatment for this disorder. When treatment is initiated, 5 to 7 injections may be given in a short span of time. Response to this therapy is usually seen within 48 to 72 hours, so there is usually no need for blood transfusions as a treatment for very low blood counts. Life-long therapy (with vitamin B12 injections every month or two) is needed for this disorder. Oral (by mouth) vitamin B12 is not recommended because it will not produce the desired response (the problem is an inability to ABSORB vitamin B12, not a lack of the vitamin in the diet). A well-balanced diet is essential to provide other components for healthy blood cell development such as folic acid, iron, and vitamin C.

The outcome is usually excellent with treatment.

Complications:

People with pernicious anaemia may have gastric polyps and have twice the incidence of gastric cancer than the normal population.

Persistent neurological defects may be present if treatment is delayed.

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Vitamin B12 deficiency affects the appearance of all epithelial cells, therefore an untreated woman may obtain a false positive pap smear.

Anaemia of B12 deficiency is a decrease in the red cells in the blood caused by a vitamin deficiency.

Vitamin B12 is essential for normal nervous system function and normal red cell, white cell and platelet production. All sources of vitamin B12 come from the diet in animal products, including dairy and eggs.

For vitamin B12 to be absorbed by the body, it must become bound to an intrinsic factor, a protein secreted by cells in the stomach.

Causes of vitamin B12 deficiency include:

dietary (a strict vegetarian diet excluding all meat, fish, dairy products, and eggs)chronic alcoholismabdominal or intestinal surgery that eliminates the site of intrinsic factor production or absorptionCrohn's disease intestinal malabsorption disordersfish tape wormpernicious anaemia, which is caused by an inherited intrinsic factor deficiency.

Anaemia of B12 deficiency that is caused by a poor diet can be prevented through a well-balanced diet. Prophylactic (preventative) use of vitamin B12 injections can prevent deficiency after surgeries known to result in vitamin B12

deficiency. Anaemia resulting from other causes cannot be prevented, but early diagnosis can limit the severity of the anaemia.

Symptoms include:

loss of appetite diarrhoea numbness and tingling of hands and feet paleness shortness of breath fatigue weakness sore mouth and tongue

Treatment depends on the cause of the anaemia.

Pernicious anaemia requires life long therapy with vitamin B12 injections.

Anaemia caused by dietary insufficiency of vitamin B12 can be corrected by oral (by mouth) vitamin replacement in combination with a more balanced diet. Initially it may be treated with vitamin B12 injections.

Anaemia caused by malabsorption (inadequate absorption of nutrients from the intestinal tract) is treated with vitamin B12 injections until the condition improves.

Prognosis for this form of anaemia is generally that it is corrected by therapy.

ComplicationsCentral nervous system signs and symptoms may be irreversible if treatment is not initiated within 6 months of the onset of these symptoms. Vitamin B12 affects the maturation of all epithelial cells (cells that form the outer surface of the body and line inner passageways) and a deficiency may cause a false positive pap smear.

Anaemia of folate deficiency is a decrease in the red cells in the blood caused by folate (folic acid) deficiency.

Folate or folic acid is necessary for red blood cell formation and growth. Dietary sources of folate are found in green leafy vegetables and liver. Some medications such as Dilantin interfere with the absorption of this vitamin. Because folate is not stored in the body in large amounts, a continual dietary supply of this vitamin is needed.

In folate deficiency anaemia, the red cells are abnormally large and are referred to as megalocytes, and in the bone marrow as megaloblasts. Subsequently, this anaemia may be referred to as megaloblastic anaemia

Causes of the anaemia are poor dietary intake of folic acid as in chronic alcoholism, malabsorption diseases such as celiac disease and sprue, and certain medications. A relative deficiency due to increased need for folic acid may occur in the third trimester of pregnancy. Risk factors are a poor diet (seen frequently in the poor, the elderly and in people

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who do not buy fresh fruits or vegetables), overcooking food, alcoholism, having a history of malabsorption diseases, and pregnancy. The incidence is 4 out of 100,000 people.

Adequate dietary intake in high-risk individuals and folic acid supplementation during pregnancy may help prevent the onset of this anaemia.

Symptoms include:

tiredness headache sore mouth and tongue pallor or jaundice

Signs and tests:

a folate - test low red blood cell folate level a CBC a bone marrow examination

The objective of treatment is to treat the underlying cause of the anaemia, which may be dietary or a malabsorption disease.

Oral or parenteral folic acid supplements may be taken on a short-term basis until the anaemia has been corrected, or in the case of loss of absorption by the intestine, replacement therapy may be lifelong.

Dietary treatment consists of increasing the intake of green leafy vegetables and citrus.

This type of anaemia usually responds well to treatment with correction of the abnormalities within 2 months.

Complications of the condition

Symptoms of anaemia can cause discomfort. In a pregnant woman, folate deficiency has been associated with neural tube defects (such as spina bifida) in the infant.

Anaemia of chronic disease is an anaemia that develops as a result of long-term infection or disease.

Certain chronic infections and diseases cause several changes in the blood production (haematopoietic) system. These include a slightly shortened red blood cell life span, decreases in the amount of iron that is available in the fluid portions of blood, and decreases in the activity of the bone marrow. In the presence of these three effects a low to moderate grade anaemia develops. The symptoms of the anaemia often go unnoticed in the face of the primary disease.

Conditions associated with the anaemia of infection and chronic diseases include such diverse diseases as chronic bacterial endocarditis, osteomyelitis, juvenile rheumatoid arthritis, rheumatic fever, Crohn's disease, and ulcerative colitis. Chronic renal failure may produce a similar anaemia because it causes reduced levels of erythropoietin, the hormone that stimulates the production of red blood cells in the bone marrow.

Treatment of the underlying disease can prevent or reverse the anaemia. Chronic diseases such as Crohn's disease are difficult to treat and patients may exhibit intermittent anaemia that varies with their condition.

Symptoms include:

presence of a chronic disease or infection pallor fatigue tiredness headache lethargy shortness of breath on exertion dizziness

Signs and tests:

haematocrit (low normal to below normal)

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haemoglobin (low) reticulocyte count (low to normal) serum ferritin level (normal to elevated) serum iron (low) total iron binding capacity (TIBC) (normal)

This type of anaemia responds to treatment of the primary disease and with successful treatment of the primary disease the anaemia will resolve.

Idiopathic aplastic anaemia is a failure of the bone marrow to properly form all types of blood cells.

Idiopathic aplastic anaemia is a condition that results from injury to the stem cell, a cell that gives rise to other cell types when it divides. Consequently, there is a reduction in all cell types--red blood cells, white blood cells and platelets--with this type of anaemia, which is called pancytopaenia. The cause of idiopathic aplastic anaemia is unknown, but is thought to be an autoimmune process (when the body reacts against its own cells). Causes of other types of aplastic anaemia may be chemotherapy, radiation therapy, toxins, drugs, pregnancy, congenital disorder, or systemic lupus erythematosus.

Symptoms arise as the consequence of bone marrow failure. Anaemia (low red blood cell count) leads to fatigue and weakness. Low white blood cell counts, or neutropaenia, causes an increased risk of infection. Low platelet counts, or thrombocytopaenia, results in bleeding of mucus membranes and skin. The disease may be acute or chronic, and is always progressive. Risk factors are unknown. The incidence is 2 out of 1 million people.

There is no known prevention for idioplastic anaemia.

Symptoms include:

fatigue pallor shortness of breath on exertion rapid heart rate irregular heartbeat rash easy bruising nose bleeds bleeding gums prolonged bleeding lymph nodes may be enlarged although this is rare

Signs and tests:

A physical examination reveals an enlarged spleen, tenderness of the sternum, and irregular heart rate.

Tests:

CBC that shows low haematocrit and haemoglobin levels white blood cell count, low reticulocyte count, low platelet count, low bone marrow biopsy, abnormal bilirubin level, elevated an abdominal X-ray or CT scan that shows enlarged spleen a sugar-water (haemolysis) test that shows fragile red blood cells

Mild cases of aplastic anaemia are treated with supportive care. Blood transfusions and platelet transfusions help correct the abnormal blood counts and relieve some symptoms.

Severe aplastic anaemia, as evidenced by very low blood cell counts, is a life-threatening condition. Bone marrow transplant for people 30 and under is indicated for severe disease. For adults over 40, or for those who do not have a matched bone marrow donor, antithymocyte globulin (ATG) is the alternative treatment. ATG is a horse serum that contains antibodies against human T cells and is used in an attempt to suppress the body's immune system, allowing the bone marrow to resume its blood cell generating function. Other medications to suppress the immune system may be used, such as cyclosporine.

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Untreated aplastic anaemia is an illness that leads to rapid death. Bone marrow transplantation has been successful in young people, with long term survival of 80%. Older people have a survival rate of 40 to 70%.

Complications of treatment may lead to rejection of bone marrow graft, or severe reaction to ATG.

Haemolytic anaemia refers to any condition causing inadequate number of circulating red blood cells caused by premature destruction of red blood cells. There are a number of specific types of haemolytic anaemia which are described individually elsewhere in this text.

Haemolytic anaemia occurs when the bone marrow is unable to compensate for premature destruction of red blood cells by increasing their production. When the marrow is able to compensate, anaemia does not occur.

There are many types of haemolytic anaemia, which are classified by the location of the defect. The defect may be in the red blood cell itself (intrinsic factor) or outside the red blood cell (extrinsic factor).

Causes of haemolytic anaemia include infection, certain medications, autoimmune disorders, and inherited disorders. Types of haemolytic anaemia include:

aplastic anaemia secondary aplastic anaemia haemoglobin SC disease haemolytic anaemia due to G6PD deficiency hereditary elliptocytosis hereditary spherocytosis hereditary ovalocytosis idiopathic autoimmune haemolytic anaemia non-immune haemolytic anaemia caused by chemical or physical agents secondary immune haemolytic anaemia sickle cell anaemia

The over all incidence of "haemolytic anaemia" is 4 out of 100,000 people.

Drug induced immune haemolytic anaemia is an acquired form of haemolytic anaemia caused by interaction of certain drugs with the red blood cell membrane, resulting in antibody production against the red blood cells and premature red blood cell destruction

Drug-induced immune haemolytic anaemia occurs when certain drugs interact with the red blood cell membrane, causing the cell to become antigenic (the body identifies the cell as tissue not belonging to the body). Antibodies form against the red blood cells. The antibodies combine with the affected red blood cells and result in their premature destruction. The incidence is rare in children.

Drugs that can cause secondary immune haemolytic anaemia are penicillins, cephalosporins, levodopa, methyldopa, mefenamic acid, quinidine, salicylic acid, sulfonamides, Thiazide diuretics, antazoline, chlorpromazine, isoniazid, streptomycin, and Motrin. Drug-induced haemolytic anaemia is most often associated with G6PD deficiency.

If the disorder occurs, the individual should avoid the offending drug and its analogues (similar medications) in the future.

Symptoms: fatigue pale colour shortness of breath rapid heart rate yellow skin colour (jaundice) dark urine

Signs and tests:

A physical examination shows an enlarged spleen. A direct Coombs' test is positive. An indirect Coombs' test is positive if the offending drug is added to the test. Indirect bilirubin levels are elevated. Serum haptoglobin may be low. Haemoglobin may be present in the urine. Haemosiderin may be present in the urine. Urine and faecal urobilinogen are increased. An absolute reticulocyte count is elevated. A CBC shows red blood cell count and haemoglobin are low.

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A direct measurement of the red cell longevity by isotope tagging techniques shows a decreased life span. See RBC (nuclear) scan.

Discontinuation of the suspected causative drug may alleviate or control the symptoms. Treatment with prednisone is the first additional therapy that may be tried.

Blood transfusions with carefully typed packed red blood cells may be advised for severe symptoms.

The outcome is expected to be good. The process subsides when the offending agent is eliminated from the body.

Complications: Death caused by severe anaemia may result but it is very rare. Transfusion can cause a transfusion reaction.

Haemolytic anaemia due to G-6-PD deficiency is a hereditary, sex-linked, enzyme defect that results in the breakdown of red blood cells when the person is exposed to the stress of infection or certain drugs.

G-6-PD deficiency is an inheritable x-linked recessive disorder whose primary effect is the reduction of G-6-PD in the red blood cell, with resultant haemolysis of the cell. The ultimate effect of the disease is to produce anaemia, either acute haemolytic or a chronic spherocytic type.

The incidence of G-6-PD is much higher among Afro-Caribbean population affecting males.

The disorder may occasionally affect a few females to a mild degree (depending on their genetic inheritance).

Another type of this disorder can occur in whites who originated in the Mediterranean basin. It, too, is associated with acute episodes of homeless. Episodes are longer and more severe than the other type of disorders.

People with the disorder are not normally anaemic and display no evidence of the disease until the red cells are exposed to an oxidant or stress.

Drugs that can precipitate this reaction include:

antimalarial agents sulfonamides (antibiotic) aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) nitrofurantoin quinidine quinine others exposure to certain chemicals such as those in mothballs

The risk of acute haemolytic crisis can be decreased by reviewing the family history for any evidence of haemolytic anaemias or spherocytosis or testing before giving any medications belonging to the above class of chemicals.

The episodes are usually brief, because newly produced (young) red cells have normal G6PD activity.

People with G-6-PD must strictly avoid factors that can precipitate an episode, especially drugs known to cause oxidative reactions.

Genetic counselling or genetic information may be of interest to heterozygous women and affected men.

Symptoms:

fatigue pale colour shortness of breath rapid heart rate yellow skin colour (jaundice) dark urine enlarged spleen

Note: Severe homeless may cause haemoglobinuria.

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If the cause is an infection, it should be treated, or if the cause is a drug, the offending agent should be stopped. People with the Mediterranean form or those in haemolytic crisis may occasionally require transfusions.

Spontaneous recovery from haemolytic crises are the normal outcome.

Rarely, death may occur following a severe haemolytic event.

Idiopathic autoimmune haemolytic anaemia is a disorder resulting from an abnormality of the immune system that destroys red blood cells prematurely. The cause is unknown.

It is an acquired disease that occurs when antibodies form against the person's own red blood cells. In the idiopathic form of this disease, the cause is unknown. There are other types of immune haemolytic anaemias where the cause may result from an underlying disease or medication. Idiopathic autoimmune haemolytic anaemia accounts for one-half of all immune haemolytic anaemias. The onset of the disease may be quite rapid and very serious. Risk factors are not known.

There is no known prevention for idiopathic autoimmune haemolytic anaemia, because the cause is unknown.

Symptoms:

fatigue pale colour shortness of breath irregular heartbeat (rapid) yellow skin colour dark urine enlarged spleen

Signs and tests:

positive Coombs' test, direct Coombs' test, indirect elevated bilirubin levels low serum haptoglobin haemoglobin in the urine elevated reticulocyte count low red blood cell count and serum haemoglobin antithyroid microsomal antibody antithyroglobulin antibody

Treatment with prednisone is the first therapy that is tried. If prednisone does not improve the condition, a splenectomy (removal of the spleen) may be considered. Immunosuppressive therapy is given if the person does not respond to prednisone and splenectomy. Imuran and Cytoxan have both been used.

Blood transfusions are given with caution, if indicated for severe anaemia, because of the potential that blood may not be compatible and precipitate a reaction.

Adults commonly have long-term disease, but in children the anaemia is usually short-lived.

Complications:

bleeding infection

Sickle-Cell Anaemia, also sickle-cell disease is a hereditary condition in which haemoglobin, an oxygen-carrying protein in the blood is altered. This leads to periodic interruptions in blood circulation. The disease is found predominantly in Afro-Caribbean people; it also occurs in the Middle East and the Mediterranean area.

Symptoms of the condition appear at about six months of age and may include enlargement of the abdomen and heart and painful swelling of the hands and feet. In adolescence, sexual maturation may be delayed. The disturbances in blood flow associated with the disease also dispose affected people to infections and leg ulcers. These symptoms are due to the altered haemoglobin, which changes shape when the amount of oxygen in the blood is reduced for any reason. The red blood cell in which the haemoglobin is contained also changes its shape, from round to crescent (sickle shaped). The sickle-shaped red cells interfere with normal blood flow by plugging up small blood vessels.

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Sickle-cell anaemia occurs when an individual inherits a sickle-cell gene from each parent. Programmes have been initiated to detect carriers of the gene, who do not themselves show the trait. Such carriers are informed that a child resulting from the union of two carriers runs a one-in-four risk of having sickle-cell disease.

Therapy for sickle-cell anaemia is largely to allay symptoms. Preventive administration of penicillin to affected children by the age of four months greatly decreases mortality from infections. For this reason, routine screening of new-borns for sickle-cell anaemia is currently carried out in most developed countries.

Sickle-Cell Anaemia

Sickle-cell anaemia arises from a mutation in haemoglobin, the protein that carries oxygen in the bloodstream. A substitution in its amino-acid sequence (valine, where glutamic acid should be) causes the four-chained haemoglobin molecule to form incorrectly when oxygen is low. Defective haemoglobins bind together, forming long rods that stretch the red blood cell into a crescent. These "sickled" red blood cells cannot fit through small blood vessels.

Thalassaemia, inherited form of anaemia in which there is reduced synthesis of one or more of the four globin chains, usually 2 (alpha) and 2 (beta), which make up haemoglobin in red blood cells.

The function of haemoglobin is to carry oxygen between the lungs and the tissues of the body; in anaemia this is insufficient to meet the oxygen requirements of the tissues (for example, the muscles and the brain).

The word "thalassaemia" is derived from the Greek word for "sea"; the disease was called this because it is more common in people of Mediterranean origin. However, it has been recognised that the disorder is found worldwide. There are several types of this condition, the main forms in adults being broadly characterised as a- or b-thalassaemias according to whether the genes for the a or the b chain are abnormal. The severity of the disease varies according to the precise genetic conformation. They are probably the most commonly inherited disorders of the blood, and the most common disorders to be caused by an abnormality in a single gene.

In thalassaemia, the structure of both haemoglobin chains remains unchanged, but either the a or the b chain is absent—not produced at all—or is produced in reduced quantities because of abnormalities in the genes encoding these proteins. This sets up an imbalance in the amount of the globin in chains being produced with either the a or the b predominating. The chains precipitate in the absence of sufficient chains for them to bind to and this precipitation interferes with the formation of red blood cells. Fewer red blood cells are produced than normal and those that are able to develop include the precipitated haemoglobin chains, so that they do not pass through the capillaries correctly and are prematurely destroyed by the body. This leads to a severe anaemia, and in order to attempt to compensate for it, the bone marrow expands to try to make sufficient red blood cells; the spleen is also enlarged. This can lead to severe deformities of the skull and long bones.

Homozygous Thalassaemia (Cooley’s Anaemia)

Homozygous thalassaemia, where both copies of the gene for a haemoglobin chain are defective, occurs when no chains are synthesised. The symptoms develop after birth during the first few months of life. If affected patients are correctly diagnosed when babies and treated with regular blood transfusions, they will develop normally during childhood until puberty. However, at puberty a variety of liver, heart, and glandular problems can result from the iron overload caused by the transfusions. Death normally occurs before the age of 30 from cardiac damage. In the absence of transfusion, children die within the first year of life. If they receive insufficient blood transfusions, they tend to develop deformities of the skull and the bones, leading to a characteristic mongoloid appearance; they have enlarged spleens, severe anaemia, and are subject to repeated infections and a tendency to bleed. They also fail to thrive and if they survive to adolescence they run the risk of the same complications of iron overloading as those who are sufficiently transfused.

Heterozygous Thalassaemia

Heterozygous thalassaemia occurs when only one copy of the gene for the chain is affected. Sufferers are normally free from symptoms except during pregnancy, when they may become anaemic.

Alpha () Thalassaemia

Alpha thalassaemia can lead to two main disorders. The most severe is Bart’s hydrops syndrome; the other is haemoglobin H disease. Bart’s hydrops syndrome occurs when no chains are made, even in the foetus; these infants are usually stillborn at between 28 and 40 weeks, and if born alive, they die within the first hour. Haemoglobin H is produced by four normal chains. It is formed when some chains are being produced, but not enough. The symptoms are not as severe as for Bart’s hydrops syndrome, but anaemia is present and the spleen is enlarged. Patients usually survive to adult life.

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