blood

blood has always held a great fascination, being regarded as a living substance, the very essence of life. The doctrine of the humours, which dominated Western medical thinking until the Renaissance, held that disease is the consequence of imbalance of the four components of which the human body is composed: blood; phlegm; black bile; and yellow bile. The English physician William Harvey (1578–1637) wrote that ‘blood acts above all the powers of the elements and is endowed with notable values and is also the instrument of the omnipotent creator.’ It is, he believed, ‘the fountain of life and the seat of the soul’.

Blood is of immense cultural significance. We talk of blood ‘being thicker than water’ to signify the strength of family loyalty, as also reflected in ‘blood brothers’. A massacre is a ‘blood bath’, the reward for assassination ‘blood money’. Blood signifies power, for good or evil; the consumption of blood, metaphorically, lies at the heart of the Christian sacrament, yet many societies produce legends of vampires, whose evil is signified by their taste for human blood. Blood is often equated with strength: the monthly loss of blood through menstrual flow frequently led doctors (mostly male) to assume an inherent weakness in women. But too much blood could also be troublesome: ruddy-faced, plethoric men would make an annual visit to the barber-surgeon each spring (blood's season, according to the doctrine of the humours) to be bled. Barbers and surgeons went their separate ways in the seventeenth and eighteenth centuries, but the red stripe down the barber's pole still commemorates this annual blood-letting ritual.

Knowledge of the structure of blood (such as the notion that it consists of cells suspended in a protein-rich fluid called plasma) slowly accumulated from the seventeenth century onwards. The Dutch microscopist Anton van Leeuwenhoek (1632–1723), examining his own blood under a simple microscope, first described the red corpuscles (cells), and measured their diameter. White corpuscles were first observed by the British physician William Hewson (1739–74), who also discovered the essential features of how blood coagulates, showing that it is due to the clotting of plasma rather than changes in the cellular constituents. In the latter half of the nineteenth century it was found that blood cells are the progeny of more primitive cells in the bone marrow. The modern science of haematology stemmed from the work of the German pharmacologist Paul Ehrlich (1854–1915), who developed a stain that led to a clear distinction between the different types of cells in the blood.

An understanding of the function of blood also evolved over several centuries. William Harvey described its circulation in 1628, and a few years later the English physician Richard Lower (1631–91) observed the change from the dark blue colour of venous to the bright red of arterial blood after its passage through the lungs. In 1790 the French chemist Antoine Lavoisier (1743–94) discovered oxygen and found that it was the constituent of air that is responsible for the change of the colour of blood. In the mid nineteenth century it was found that oxygen combines with a substance in the red cells, which was identified as the protein haemoglobin by the German biochemist Felix Hoppe-Seyler (1825–95). By 1900 it was also appreciated that the white cells play a crucial role in defence against infection, an idea first proposed by the Russian zoologist Ilya Metchnikoff (1845–1916).

Blood is the body's major transport system, carrying vital substances to all the tissues and removing their waste products. It delivers oxygen from the lungs and collects carbon dioxide to be excreted there; it takes up nutrients from the gut, and distributes them for use or storage; and by virtue of its passage through the kidneys it provides an important mechanism for the excretion of toxic waste products of metabolism. The blood also distributes hormones from their sites of secretion to their sites of action, and likewise the cells, antibodies, and other substances which combat injury and infection. In performing these functions, the blood continually exchanges substances across the capillary walls with the fluids that bathe all body cells. The total volume of blood, which remains remarkably constant in adults, is approximately 70 ml/kg body weight, or about 5 litres. It consists of a fluid component, plasma, in which are suspended red cells, white cells, and platelets (see figure). In health, the cells comprise about 45% of the total volume of blood: this value is known as the haematocrit, and reflects mainly the bulk of the red blood cells.

Red blood cells

The number of circulating red cells in a unit volume of blood — the red cell count — varies at different stages of development. It is relatively high in fetal life and falls quickly after birth, before gradually rising to reach its adult level by the age of 20 (about 5 million/mm³ of blood). Although it is approximately the same in males and females during childhood, it is higher in males after adolescence. Red cells survive for only about three months in the circulating blood, so production continues throughout life.

The major role of red cells (erythrocytes) is to transfer oxygen from the lungs to the tissues. Their rate of production is beautifully adapted to this function. It is regulated by a hormone called erythropoietin, produced in the kidney in the adult and in the liver in the fetus. Close to the gene that regulates erythropoietin production are regions of DNA that sense oxygen tension; when this falls, erythropoietin synthesis is stimulated, and more red cells are produced in the bone marrow. When adequate oxygenation of the tissues is achieved, erythropoietin production is reduced. By this biological feedback loop the body is able to respond to varying oxygen demands by modifying the rate of red cell production. In addition to erythropoietin, there is probably some fine tuning of the rate of erythropoiesis by other hormones and protein growth factors.

The site of red cell production changes during development. In the embryo, they are made in the yolk sac, in the fetus in the liver and spleen, and in adult life in the bone marrow. These sites all contain a primitive, self-renewing population of blood-cell precursors, the haemopoietic stem cells, which are capable of producing all the different cells of the blood. Red cell production (erythropoiesis) takes about 7 days. The progeny of stem cells destined to become red cells start out as large, nucleated cells; during their development haemoglobin synthesis begins and, after several divisions, their nucleus is condensed and eventually extruded from the cell. This red cell precursor is now called a reticulocyte. Reticulocytes are released from the marrow into the blood; they undergo fine quality control in the spleen, where unwanted nuclear remnants are removed. (This process is different in birds and amphibians; the nucleus is not removed and is retained throughout the life of the red cell in the peripheral blood.) An adequate dietary supply of iron and of specific vitamins is necessary for the synthesis of haemoglobin and the production of normal red cells.

After their release from the bone marrow, red cells spend approximately 120 days in the circulation. During this time they travel over 100 miles, are buffeted at high velocities during their passage through the heart, and have to negotiate tiny capillaries narrower than their own diameter. As they age, subtle structural changes occur which render them identifiable to scavenger cells in the spleen and elsewhere, and they end their days being devoured and digested by these predators.

The red cells of most species are biconcave discs, a shape that offers maximum surface area for exchange of oxygen and carbon dioxide. They consist of a protein and lipid membrane, which encases haemoglobin together with water and a variety of enzymes and salts. Their chemistry is beautifully adapted to their function as an oxygen transporter and to protect them and their haemoglobin from chemical damage.

The oxygen-carrying protein of red cells, haemoglobin, is also closely adapted to its function. In most mammals, adult haemoglobin (haemoglobin A) comprises two unlike pairs of chains of amino acids, or globin chains, called a and b, each of which is folded round one iron-containing haem molecule, to which oxygen can bind. The resulting molecule is designated a₂b₂. In humans, and some other species, there is a different fetal haemoglobin, haemoglobin F, which has a chains combined with g chains (a₂g₂). In most species adult and fetal haemoglobins are preceded by an embryonic haemoglobin. These different haemoglobins are adapted to particular oxygen requirements at different stages of development. While taking up and giving off oxygen, subtle spatial alterations occur between the globin chains which are responsible for the oxygen dissociation properties of haemoglobin, essential for normal oxygen transport. These functions can be modified by carbon dioxide, pH, and intracellular substances such as 2,3-diphosphoglycerate, the control of which is itself regulated by intracellular pH and oxygen levels. Hence there is an elegant intracellular control network relating oxygen delivery to red cell metabolism which, in turn, reflects the oxygen requirements of the tissues.

White blood cells

The white blood cells, much less abundant than red cells, play a key role in the body's defence against environmental pathogens. They are subdivided — on the basis of their microscopic structure, differences in taking up stains, and functions — into phagocytic (‘eater’) cells (which include neutrophils, monocytes, and eosinophils), and non-phagocytic cells (lymphocytes and basophils).

Phagocytic white cells derive from precursors in the bone marrow. Their production and maturation is controlled by a family of proteins called haemopoietic growth factors. Following their release into the blood, many of them remain in a so-called storage pool, stuck to the wall of blood vessels. The numbers circulating freely in the blood therefore represent just a fraction of the total body content.

The main function of the neutrophils is to kill microorganisms. They are attracted to areas of damaged tissue, where they internalize bacteria and other foreign particles, killing any invaders by a complex combination of oxidative and non-oxidative mechanisms. Monocytes have similar properties to neutrophils, and play an important role as part of the macrophage (‘big eater’) system by presenting foreign proteins (antigens) to T cells (see below). Eosinophils, which are particularly active against parasitic infections, exert their action by discharging highly active elements from preformed granules. Basophils, and tissue cells called mast cells, to which they are related, also play an important role in combating parasitic infection.

The other important class of white cells is the lymphocytes. These cells play a major role in the body's immune system. They are also derived from haemopoietic stem cells and disseminated in the bloodstream; some migrate to sites known as the ‘primary lympho-epithelial organs’, including the thymus gland, where they differentiate further and eventually populate the ‘secondary lymphoid tissues’, including the spleen, lymphoid tissue in the alimentary canal, and the lymph nodes. One set of lymphocytes, thymus-derived or T cells, migrate to specific areas within these tissues and pass through them into the lymphatic vessels; thus they recirculate from the blood to the lymph, and then back to the blood where the lymphatic system drains into it via the thoracic duct. The Tcells are responsible for cellular immune responses. The other class of lymphocytes, B cells, populate different regions of the lymphatic system. Some of them also recirculate. They are the precursors of antibody-forming cells.

The immune system of a human can differentiate more than one million different foreign proteins, or antigens. T and B cells identify antigen by exposing receptor molecules on their surface: immunoglobulin for B cells, and T cell receptors for T cells. Before their first encounter each lymphocyte can only produce receptors to one particular antigen. When a lymphocyte binds to an antigen, it starts to divide to produce a clone of daughter cells, all with the same specificity — a process known as clonal selection. B cells produce immunoglobulins, or antibodies, in response to particular antigens, while T cells, after being activated by antigen presented to them by macrophages, either kill invading organisms directly, or play more subtle roles in co-ordinating other immune defence mechanisms. The extraordinary specificity and diversity of action of B and T cells is a reflection of a complex series of developmental rearrangements of the genes for immunoglobulins and the T cell receptor.

Platelets and blood clotting

It is vital to have ways to prevent the loss of blood after damage to blood vessels. It is equally important, however, that these processes occur only when they are needed, and do not spread from the site of injury to block off normal healthy vessels. These aims are achieved by the complicated series of cellular and biochemical interactions that constitutes blood clotting. Platelets, the other cellular elements of the blood, play a central role. These small, enucleate cells are produced from large parent cells, the megakaryocytes, in the bone marrow.

When a blood vessel ruptures there is immediate reflex constriction, thus narrowing the opening through which blood can escape. Platelets then aggregate at the site of the disruption. The adhesion of platelets to the exposed tissues beneath the wall of the blood vessel requires the action of a plasma protein called von Willebrand factor, which binds to specific receptors on the outer membrane of the platelet. As platelets adhere they release a variety of chemicals that cause further aggregation, leading to the production of a temporary haemostatic plug.

At the same time as platelets are forming aggregates in the damaged vessel wall, a sequence of reactions — the coagulation ‘cascade’ — is activated. The objective of this complex process is to convert a soluble plasma protein, fibrinogen, to an insoluble fibrin mesh, or blood clot. This conversion requires the action of the enzyme thrombin, which is normally present in the blood in its inactive form, prothrombin. Thrombin also stimulates platelets to release several clotting factors and aggregating agents.

The activation of prothrombin results from the action of a remarkable biological amplification system in which circulating, inactive blood clotting factors are converted to catalytically active forms. The properties, and potential dangers, of this system are phenomenal: a sufficient amount of thrombin can be generated from the prothrombin in 2 ml of blood to clot the entire circulating volume. One of the inactive precursors in the clotting cascade is defective in the blood in haemophilia. Four of the factors require vitamin K for their production in the liver. Ionized calcium is one of the necessary factors.

This system is further complicated by the fact that activation of thrombin can occur through the intrinsic coagulation system, that is by the interaction of circulating factors, as well as by an extrinsic system which requires a factor from the tissues to interact with some of the circulating factors.

There is continual minor damage to the lining of blood vessels, so that blood clotting is continually being activated. Therefore mechanisms must exist for terminating the clotting cascade or dealing with the consequences of its activation. These involve either the inactivation of some of the protein co-factors by the enzymatic action of other plasma proteins (such as protein C or antithrombin III), or the digestion of unwanted fibrin (fibrinolysis) by the enzyme plasmin, activated from the plasminogen which is normally present in the blood.

Haemostasis — the prevention of blood loss — and blood coagulation are thus dynamic processes in which there is continual activation of the complex coagulation pathways, kept in check by inactivation mechanisms together with the removal of unwanted blood clot by the fibrinolytic system.

Plasma

The liquid plasma, in which all the cells of the blood are suspended, contains a variety of substances both in solution and as colloidal particles. There are salts, nutrients from the food (lipids, sugars, and amino acids) and hormones. A complex mixture of proteins includes albumin — the main bulk of the plasma proteins, and of considerable importance in maintaining osmotic homeostasis, as it prevents the accumulation of excess fluid in the body tissues; globulins — some acting as ‘carriers’ for substances such as hormones, and others (gamma-globulins) which are part of the immune system; and also fibrinogen and other substances necessary for clotting.

The main functions of plasma are to transport nutrients, waste materials, and hormones; to provide an appropriate environment for different blood cells; to ensure, by exchange of water and solutes across capillary walls, that the chemical composition of the body fluids, both outside and inside cells, remains within normal, physiological concentrations; and — by carrying the coagulation proteins and their antagonists — to ensure that blood loss is prevented promptly after injury.

Mark Weatherall, and D. J. Weatherall

See also anaemia; blood circulation; blood transfusion;body fluids; haemoglobin; homeostasis; immune system; lymphatic system; menstruation; thymus.