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Q1L2 Blood physiology Dr. Hassan Yashar Hassan Blood is a fluid connective tissue. It circulates constantly around the body, propelled by the pumping action of the heart. It transports: oxygen nutrients hormones heat antibodies and cells of the immune system • clotting factors wastes. Blood is...

Q1L2 Blood physiology Dr. Hassan Yashar Hassan Blood is a fluid connective tissue. It circulates constantly around the body, propelled by the pumping action of the heart. It transports: oxygen nutrients hormones heat antibodies and cells of the immune system • clotting factors wastes. Blood is composed of a clear, straw-coloured, watery fluid called plasma, in which several different types of blood cell are suspended. Plasma normally constitutes 55% of the volume of blood and the cell fraction 45%. Blood cells and plasma can be separated by centrifugation (spinning) or by simple gravity when blood is allowed to stand (Fig. 4.1A). The cells are heavier than plasma and sink to the bottom of the sample. Blood makes up about 7% of body weight (about 5.6 litres in a 70 kg man). This proportion is less in women and considerably greater in children, gradually decreasing until the adult level is reached. The total blood volume in adults is about 80 mL/kg body weight in males and 70 mL/kg in females. The continual blood flow maintains a fairly constant environment for body cells. Blood volume and the concentration of blood constituents are kept within narrow limits by homeostatic mechanisms. Heat produced from metabolically active organs, such as working skeletal muscles and the liver, is distributed around the body by the bloodstream, maintaining core body temperature. Figure 4.3 Haemopoiesis. Stages in the development of blood cells. (Photographic inserts from Telser AG, Young JK, Baldwin KM 2007 Elsevier's integrated histology. Mosby: Edinburgh; and Young B, Lowe JS, Stevens A et al. 2006 Wheater's functional histology: a text and colour atlas. Edinburgh: Churchill Livingstone. Reproduced with permission.) Q1L2 Blood physiology Dr. Hassan Yashar Hassan Plasma 55% Cells 45% Figure 4.1 Whole blood. (A) The proportions of blood cells and plasma in anticoagulated whole blood separated by gravity. (B) A blood clot in serum. Plasma The main constituent of plasma is water (90-92%), carrying a range of dissolved and suspended substances, including: plasma proteins inorganic salts (electrolytes) nutrients, principally from digested foods waste products • hormones • gases. Plasma proteins Plasma proteins, which make up about 7% of plasma, are normally retained within the blood because they are too big to escape through the capillary pores into the tissues. They are largely responsible for creating the osmotic pressure of blood, which keeps plasma fluid within the circulation. 2 Plasma viscosity (thickness) is due to the presence of plasma proteins, mainly albumin and fibrinogen. Plasma proteins, with the exception of immunoglobulins, are formed in the liver. Albumins These are the most abundant plasma proteins (about 60% of total) and their main function is to maintain normal plasma osmotic pressure. Albumins also act as carrier molecules for free fatty acids, some drugs and steroid hormones. Globulins The main functions of globulins are: As antibodies (immunoglobulins), complex proteins produced by lymphocytes play an important part in immunity. They bind to, and neutralise, foreign materials (antigens) such as microorganisms (see also p. 414). Transport of some hormones and mineral salts. For example, thyroglobulin carries the hormone thyroxine and transferrin carries the mineral iron. Inhibition of some proteolytic enzymes. For example, a2 macroglobulin inhibits trypsin activity. Clotting factors These are responsible for coagulation of blood. Serum is plasma from which clotting factors have been removed (Fig. 4.1B). The most abundant clotting factor is fibrinogen. Electrolytes These have a range of functions, including muscle contraction (e.g. Ca2+), transmission of nerve impulses (e.g. Ca2+, K+ and Na+), and maintenance of acid-base balance (e.g. phosphate). Blood pH is maintained between 7.35 and 7.45 (slightly alkaline) by an ongoing buffering system. Nutrients Nutrients, substances essential for cellular growth and metabolism, include glucose, amino acids and vitamins. They are transported in the bloodstream from sites of production or absorption to the tissues for immediate use or storage. Waste products Urea, creatinine and uric acid are the waste products of protein metabolism. They are formed in the liver and carried in blood to the kidneys for excretion. Carbon dioxide from tissue metabolism is transported to the lungs for excretion. Hormones Hormones are chemical messengers synthesised by endocrine glands; they are secreted into the blood and transported to their target tissues and organs around the body. Q1L2 Blood physiology Dr. Hassan Yashar Hassan Gases tissue. In the bone marrow, all blood cells originate from Oxygen is not very soluble in water, so only a small amount pluripotent (i.e. capable of developing into one of a number of (less than 2%) can be transported dissolved in plasma, an cell types) stem cells and go through several developmental additional oxygen transport mechanism is needed: oxygen is stages before entering the blood. Different types of blood cell bound to haemoglobin in red blood cells. Over 98% of oxygen follow separate lines of development. The process of blood in the blood is carried this way, as oxyhaemoglobin. cell formation is called haemopoiesis (Fig. 4.3). Haemoglobin also binds some carbon dioxide, although most For the first few years of life, red marrow completely fills carbon dioxide is converted to bicarbonate ions in red blood the space within bone. Over the next 20 years, it is largely cells, and then transported in the plasma. replaced by fatty yellow marrow that has no haemopoietic function. In adults, haemopoiesis in the skeleton is confined to flat bones, irregular bones and the ends of long bones, the main sites being the sternum, ribs, pelvis and skull. Cellular content of blood Red blood cells Red blood cells are by far the most abundant type of blood There are three types of blood cell (Fig. 4.2; see also Fig. 1.3). cell; 99% of all blood cells are erythrocytes (see Fig. 4.2). They • erythrocytes (red cells) are biconcave discs with no nucleus, and their diameter is • leukocytes (white cells) about 7 Jim (Fig. 4.4). Their main function is the transport of • platelets (thrombocytes). gas, mainly oxygen, but they also carry some carbon dioxide. Their characteristic shape is suited to their purpose; the Most blood cells are synthesised in red bone marrow. biconcavity increases their surface area for gas exchange, and Some lymphocytes, additionally, are produced in lymphoid the thin central portion allows fast entry and exit of gases. The cells are flexible, so they can squeeze through narrow capillaries, and contain no intracellular organelles, leaving Monocyte more room for haemoglobin, the large pigmented protein responsible for gas transport. Their flattened shape allows Neutrophi them to stack like dinner plates in the bloodstream, reducing Lymphocyte turbulence. Lifespan and function of erythrocytes Erythrocytes Their lifespan in the circulation is about 120 days. There are approximately 30 trillion (1014) red blood cells in the average Platelet human body, about 25% of the body's total cell count, and around 1%, mainly older cells, are cleared and destroyed daily. Figure 4.2 A blood smear, showing erythrocytes, a monocyte, a neutrophil, a lymphocyte and a platelet. (Biophoto Associates/ The process of erythrocyte development from stem cells Science Photo Library. Reproduced with permission.) takes about 7 days and is called erythropoiesis (see Fig. 4.3). The immature cells are released into the bloodstream as reticulocytes, and mature into erythrocytes over a few days within the circulation. During this time, they lose their nucleus and therefore become incapable of division. 3 Q1L2 Blood physiology Dr. Hassan Yashar Hassan Figure 4.4 The red blood cell. (A) Under the light microscope. (B) Drawn from the front. (C) Drawn in section. (D) Coloured scanning electron micrograph of a group of red blood cells travelling along an arteriole. (A, Telser AG, Young JK, Baldwin KM 2007 Elsevier's integrated histology, Edinburgh: Mosby. Reproduced with permission. D, Professors PM Motta and S Correr/Science Photo Library. Reproduced with permission.) 4 Oxygen Transport When all four oxygen-binding sites on a haemoglobin molecule are full, it is described as saturated. Haemoglobin binds reversibly to oxygen to form oxyhaemoglobin, according to the equation: As the oxygen content of blood increases, its colour changes too. Blood rich in oxygen (usually arterial blood) is bright red because of the high levels of oxyhaemoglobin it contains, compared with blood with lower oxygen levels (usually venous blood), which is dark bluish in colour because it is not saturated. The association of oxygen with haemoglobin is a loose one, so that oxyhaemoglobin releases its oxygen readily, especially under certain conditions. Low pH Metabolically active tissues, e.g. exercising muscle, release acid waste products, and so the local pH falls. Under these conditions, oxyhaemoglobin readily breaks down, giving up additional oxygen for tissue use. Low oxygen levels (hypoxia) Where oxygen levels are low, oxyhaemoglobin breaks down, releasing oxygen.. Temperature Actively metabolising tissues, which have higher than normal oxygen needs, are warmer than less active ones, driving the equation above to the left and increasing oxygen release. Control of erythropoiesis Red cell numbers remain fairly constant because the bone marrow produces erythrocytes at the rate at which they are destroyed. This is due to a homeostatic negative feedback mechanism. The hormone that regulates red blood cell production is erythropoietin, produced mainly by the kidney. The primary stimulus for increased erythropoiesis is hypoxia, i.e. deficient oxygen supply to body cells. Hypoxia can result from anaemia, low blood volume, poor blood flow, reduced oxygen content of inspired air (as at altitude) or lung disease. Each of these stimulates erythropoietin production in an attempt to restore oxygen supplies to the tissues. Figure 4.7 Control of erythropoiesis: the role of erythropoietin. . Destruction of erythrocytes The lifespan of erythrocytes (see Fig. 4.5) is about 120 days and their breakdown, or haemolysis, is carried out by macrophages in the spleen, bone marrow and liver. As erythrocytes age, their cell membranes become more fragile and so more susceptible to haemolysis. Iron released by haemolysis is returned to the bone marrow to form new haemoglobin molecules. Biliverdin is formed from the haem part of the haemoglobin. It is almost completely reduced to the yellow pigment bilirubin, before being bound to plasma globulin and transported to the liver (see Fig. 4.5). In the liver it is changed from a fat-soluble to a water-soluble form to be excreted in bile. Table 4.2 Normal leukocyte counts in adult blood Number x 107L Percentage of total Granulocytes Neutrophils Eosinophils 2.5-7.5 0.04-0.44 40-75 1-6 Basophils 0.015-0.1 <1 Agranulocytes Monocytes 0.2-0.8 2-10 Lymphocytes 1.5-3.5 20-50 Total 5-9 100 Leukocytes (white blood cells) These cells have an important function in defence and immunity. They detect foreign or abnormal (antigenic) material and destroy it, through a range of defence mechanisms Leukocytes are the largest blood cells but they account for only about 1% of the blood volume. They contain nuclei and some have granules in their cytoplasm. There are two main types: • granulocytes (polymorphonuclear leukocytes) -neutrophils, eosinophils and basophils • agranulocytes - monocytes and lymphocytes. Rising white cell numbers in the bloodstream (leukocytosis) usually indicate a physiological problem, e.g. infection, trauma or malignancy. Granulocytes (polymorphonuclear leukocytes) All granulocytes have multilobed nuclei in their cytoplasm. Their names represent the dyes they take up when stained in the laboratory. Eosinophils take up the red acid dye, eosin; basophils take up alkaline methylene blue; and neutrophils are purple because they take up both dyes. Neutrophils These small, fast and active scavengers protect the body against bacterial invasion, and remove dead cells and debris from damaged tissues. They are attracted in large numbers to any area of infection by chemicals called chemotaxins, released by damaged cells. Neutrophils are highly mobile, and squeeze through the capillary walls in the affected area by diapedesis. Their numbers rise very quickly in an area of damaged or infected tissue. Once there, they engulf and kill bacteria by phagocytosis Their nuclei are characteristically complex, with up to six lobes (see Fig. 4.2), and their granules are lysosomes containing enzymes to digest engulfed material. Neutrophils live on average for 6-9 hours in the bloodstream. Pus forming in an infected area consists of dead tissue cells, dead and live microbes, and phagocytes killed by microbes. Eosinophils Eosinophils, although capable of phagocytosis, are less active in this process than neutrophils; their specialised role appears to be in the elimination of parasites, such as worms, which are too big to be phagocytosed. They are equipped with certain toxic chemicals, stored in their granules, which they release (degranulation) when the eosinophil binds to an infecting organism.Local accumulation of eosinophils may occur in allergic inflammation, such as the asthmatic airway and skin allergies. There, they promote tissue inflammation by releasing their array of toxic chemicals. Basophils Basophils, which are closely associated with allergic reactions, contain cytoplasmic granules packed with heparin (an anticoagulant), histamine (an inflammatory agent) and other substances that promote inflammation. Usually, the stimulus that causes basophil degranulation is an allergen (an antigen that causes allergy) of some type. This binds to antibody-type receptors on the basophil membrane. Mast cells are very similar to basophils, except that they are fixed in the tissues. Mast cells degranulate within seconds of binding an allergen, which accounts for the rapid onset of allergic symptoms following exposure to, for example, pollen in hay fever Fig. 4.11 Phagocytic action of neutrophils Agranulocytes The monocytes and lymphocytes make up 25-50% of the total leukocyte count (Fig. 4.12; see also Fig. 4.3). They have a large nucleus and no cytoplasmic granules. Monocytes These are the largest of the white blood cells (see Fig. 4.2). Some circulate in the blood and are actively motile and phagocytic, while others migrate into the tissues and develop into macrophages. Both types of cell produce interleukin 1, acts on the hypothalamus, causing the rise in body temperature associated with microbial infections • stimulates the production of some globulins by the liver enhances the production of activated T-lymphocytes. The mononuclear phagocyte system This is sometimes called the reticuloendothelial system; it consists mainly of the body's complement of monocytes and macrophages. Some macrophages are mobile, whereas others are fixed, providing effective defence at key body locations. The main collections of fixed macrophages are shown in Fig. 4.13. Macrophages have a diverse range of protective functions. They are actively phagocytic (their name means 'big eaters') and are much more powerful and longer-lived than the smaller neutrophils. They synthesise and release an array of biologically active chemicals, called cytokines, including interlukin 1. Lymphocytes Lymphocytes are smaller than monocytes and have large nuclei. Some circulate in the blood but most are found in tissues, including lymphatic tissue such as lymph nodes and the spleen. Lymphocytes develop from pluripotent stem cells in red bone marrow and from precursors in lymphoid tissue. Although all lymphocytes originate from only one type of stem cell, the final steps in their development lead to the production of two distinct types of lymphocyte -T-lymphocytes and B-lymphocytes. Platelets These are very small, disc-shaped cell fragments, 2-4 |am in diameter, budded off from the cytoplasm of megakaryocytes in red bone marrow (see Figs 4.2 and 4.3). Although they have no nucleus, their cytoplasm is packed with granules containing a variety of substances that promote blood clotting, which causes haemostasis (cessation of bleeding). The normal blood platelet count is between 200 x 109/L and 350 X 109/L (200,000-350,000/mm3). The mechanisms that regulate platelet numbers are not fully understood, but the hormone thrombopoietin from the liver stimulates platelet production. The lifespan of platelets is between 8 and 11 days and those not used in haemostasis are destroyed by macrophages, Fig 4.13 The mononuclear phagocyte system mainly in the spleen. About a third of platelets are stored within the spleen rather than in the circulation; this is an emergency store, released as required to control excessive bleeding. Haemostasis When a blood vessel is damaged, loss of blood is stopped (haemostasis; Fig. 4.14) and healing occurs in a series of overlapping processes, in which platelets play a vital part. The more badly damaged the vessel wall is, the faster coagulation begins, sometimes as quickly as 15 seconds after injury. 1. Vasoconstriction When platelets come into contact with a damaged blood vessel, their surface becomes sticky and they adhere to the damaged wall. They then release serotonin (5-hydroxytryptamine, 5-HT) and thromboxanes, which constrict the vessel, reducing or stopping blood flow through it. Other vasoconstrictors, e.g. endothelins, are released by the damaged vessel itself. Platelet plug formation The sticky platelets clump together and release other substances, including adenosine diphosphate (ADP), which attract more platelets to the site. Passing platelets stick to those already at the damaged vessel and they too release their chemicals. This is a positive feedback system by which many platelets rapidly gather at the site of vascular damage and quickly form a temporary seal - the platelet plug. Coagulation (blood clotting) This is a complex process that also involves a positive feedback system and only a few stages are included here. The clotting factors involved are listed in Box 4.1. Their numbers represent the order in which they were discovered and not the order of participation in the clotting process. These clotting factors activate each other in a specific order, eventually resulting in the formation of prothrombin activator, which is the first step in the final common pathway. Prothrombin activates the enzyme thrombin, which converts inactive fibrinogen to insoluble threads of fibrin. The final common pathway can be initiated by two processes, which often occur together: the extrinsic and intrinsic pathways (Fig. 4.15). Box 4.1 Blood clotting factors Fibrinogen Prothrombin Tissue factor (thromboplastin) IV Calcium (Ca2+) V Labile factor, proaccelerin, Ac-globulin (There is no factor VI) Stable factor, proconvertin Antihaemophilic globulin (AHG), antihaemophilic factor A Christmas factor, plasma thromboplastin component (FTC), antihaemophilic factor B Stuart-Prower factor Plasma thromboplastin antecedent (PTA), antihaemophilic factor C Hageman factor XHI Fibrin stabilising factor Vitamin K is essential for synthesis of factors II, VII, IX and X. The extrinsic pathway is activated rapidly (within seconds) following tissue damage and is probably the more important of the two. Damaged tissue releases a complex of chemicals called thromboplastin or tissue factor, which initiates coagulation. The intrinsic pathway is slower (3-6 minutes) and is triggered when blood comes into contact with damaged blood vessel lining (endothelium). serum, a clear sticky fluid that consists of plasma from which clotting factors have been removed. 4. Thrombolysis After the clot has formed, the process of removing it and healing the damaged blood vessel begins. The breakdown of fibrin, or fibrinolysis, is the first stage. Plasminogen, trapped within the clot as it forms, is converted to the enzyme plasmin by activators released from the damaged endothelial cells. Plasmin breaks down fibrin, progressively removing the clot to allow tissue repair to proceed. Control of coagulation The process of blood clotting relies heavily on several self-perpetuating processes - that is, once they have started, a positive feedback mechanism promotes their continuation. For example, thrombin is a powerful stimulator of its own production. Control and braking mechanisms are therefore essential to limit clotting to the affected area and terminate the process at the appropriate time. These include: The perfect smoothness of normal blood vessel lining prevents platelet adhesion in healthy, undamaged blood vessels. Activated clotting factors are rapidly deactivated by anticoagulants, such as heparin and antithrombin III. Activated clotting factors are quickly cleared from the blood by the liver. 11