BLOOD AND BLOOD DISORDERS

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Blood and blood disorders

Blood and blood disorders 1. Introduction

Liquid medium (plasma) containing several types of specialized cells in suspension. The circulatory system provides the mechanism by which the blood transports substances to and from the organs and tissues. The circulating blood continuously supplies oxygen, nutrient substances, and other materials necessary for the viability and activity of all the cells of the body and carries away cell products, including carbon dioxide and other waste materials. If blood flow ceases, death occurs within minutes because of the effects of an unfavorable environment on highly susceptible cells. The constancy of the composition of the blood is made possible by the circulation, which conveys blood through the organs that regulate the concentrations of its components. In the lungs blood acquires oxygen and releases carbon dioxide transported from the tissues. The kidneys remove excess water and dissolved waste products. Nutrient substances derived from food reach the bloodstream after absorption by the intestinal tract. Endocrine glands release their secretions into the blood, which transports these hormones to the tissues in which they exert their effects. Many substances are recycled through the blood; for example, iron released during the destruction of old red cells is conveyed by the plasma to sites of new red cell production where it is reused. Each of the numerous components of the blood is kept within appropriate concentration limits by an effective regulatory mechanism. In many instances feedback control systems are operative; thus a declining level of blood sugar leads to accelerated release of sugar into the blood so that a potentially hazardous depletion of blood sugar does not occur. Unicellular organisms, primitive multicellular animals, and the early embryos of higher forms of life lack a circulatory system, and exchange of substances between cell and environment is accomplished by simple diffusion. In larger and more complex animals transport of adequate amounts of oxygen and other substances requires some type of blood circulation. The diffusion process then occurs between the body cells and the fluid derived from the blood, which by its constant motion maintains the constancy of the internal environment. Some simple animals, including small worms and mollusks, have blood that lacks an oxygenbinding substance analogous to hemoglobin; others are provided with pigments capable of transporting relatively large amounts of oxygen. In many invertebrates the blood pigment is dissolved in the plasma. Hemocyanin, copper-containing protein chemically unlike hemoglobin, is found in certain crabs and other lower animals. Hemocyanin is blue in color when oxygenated and colorless when oxygen is removed. Some invertebrates have

Blood and blood disorders

hemoglobin in solution in the plasma. In almost all vertebrates, including humans, hemoglobin is contained exclusively within the red cells (erythrocytes) of the blood. The red cells of the lower vertebrates (e.g., birds) have a nucleus, whereas mammalian red cells lack a nucleus. Red cells vary markedly in size among mammals; those of the goat are much smaller than those of humans, but the goat compensates by having many more red cells per unit volume of blood. The concentration of hemoglobin inside the red cell varies little between species.

Blood and blood disorders 2. Blood

Blood is a specialized bodily fluid that delivers necessary substances to the body's cells (in animals) such as nutrients and oxygen and transports waste products away from those same cells. In vertebrates, it is composed of blood cells suspended in a liquid called blood plasma. Plasma, which constitutes 55% of blood fluid, is mostly water (92% by volume), and contains dissipated proteins, glucose, mineral ions, hormones, carbon dioxide (plasma being the main medium for excretory product transportation), platelets and blood cells themselves. The blood cells are mainly red blood cells (also called RBCs or erythrocytes) and white blood cells, including leukocytes and platelets. The most abundant cells in vertebrate blood are red blood cells. These contain hemoglobin, an iron containing protein, which facilitates transportation of oxygen by reversibly binding to this respiratory gas and greatly increasing its solubility in blood. In contrast, carbon dioxide is almost entirely transported extracellularly dissolved in plasma as bicarbonate ion. Vertebrate blood is bright red when its hemoglobin is oxygenated. Some animals, such as crustaceans and mollusks, use hemocyanin to carry oxygen, instead of hemoglobin. Insects and some molluscs use a fluid called hemolymph instead of blood, the difference being that hemolymph is not contained in a closed circulatory system. In most insects, this "blood" does not contain oxygen-carrying molecules such as hemoglobin because their bodies are small enough for their tracheal system to suffice for supplying oxygen. Blood is circulated around the body through blood vessels by the pumping action of the heart. In animals with lungs, arterial blood carries oxygen from inhaled air to the tissues of the body, and venous blood carries carbon dioxide, a waste product of metabolism produced by cells, from the tissues to the lungs to be exhaled.

2.1 Composition of Blood

A. Plasma - the bloods liquid portion y y y y wat 1+

sol t s - nut i nts, wast s, blood gases, elect ol tes, regulatory molecules proteins - albumin, fibrinogens, globulins

B. Plasma Proteins
albumins 65%, osmolarity and viscosity globulins transport and storage proteins Transferrin carries iron in blood globulins antibodies fibrinogens clotting proteins Ferritin stores in liver and marrow

Figure1. Blood

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Blood and blood disorders 2.2 F ci l

Blood performs many important functions within the body including:

Supply of oxygen to tissues (bound to hemoglobin, which is carried in red cells) Supply of nutrients such as glucose, amino acids, and fatty acids (dissolved in the blood or bound to plasma proteins (e.g., blood lipids)) Removal of waste such as carbon dioxide, urea, and lactic acid Immunological functions, including circulation of white blood cells, and detection of foreign material by antibodies Coagulation, which is one part of the body's self-repair mechanism (blood clotting after an open wound in order to stop bleeding) Messenger functions, including the transport of hormones and the signaling of tissue damage Regulation of body pH Regulation of core body temperature Hydraulic functions

Blood and blood disorders

2.3 Bl
2.3.1 O

c ll
ic li l c i :

4.7 to 6. million (male), 4.2 to 5.4 million (female) erythrocytes: In most mammals, mature red blood cells lack a nucleus and organelles. They contain the blood's hemoglobin and distribute oxygen. The red blood cells (together with endothelial vessel cells and other cells) are also marked by glycoproteins that define the different blood types. The proportion of blood occupied by red blood cells is referred to as the hematocrit, and is normally about 45%. The combined surface area of all red blood cells of the human body would be roughly 2,000 times as great as the body's exterior surface.

remove old or aberrant cells and cellular debris, as well as attack infectious agents (pathogens) and foreign substances. The cancer of leukocytes is called leukemia. 200,000500,000 thrombocytes: thrombocytes, also called platelets, are responsible for blood clotting (coagulation). They change fibrinogen into fibrin. This fibrin creates a mesh onto which red blood cells collect and clot, which then stops more blood from leaving the body and also helps to prevent bacteria from entering the body.

4,000

,000 leukocytes: White blood cells are part of the immune system; they destroy and

2.4 Erythro yte

Red blood cells (also referred to as eryt rocytes) are t e most common type of blood cell and t e vertebrate organism's principal means of delivering oxygen (O2) to t e body tissues via t e blood flow t rough the circulatory system. They take up oxygen in the lungs or gills and release it wh ile squeezing through the body's capillaries. These cells' cytoplasm is rich in hemoglobin, an iron-containing biomolecule that can bind oxygen and is responsible for the blood's red color. In humans, mature red blood cells are flexible biconcave disks tha lack a cell nucleus and most t organelles. 2.4 million new erythrocytes are produced per second. The cells develop in the bone marrow and circulate for about 1 120 days in the body before their components are recycled by macrophages. Each circulation takes about 20 seconds. Approximately a quarter of the cells in the human body are red blood cells. Red blood cells are also known as RBCs, red blood corpuscles (an archaic term), haematids, erythroid cells or erythrocytes (from Greek erythros for "red" and kytos for "hollow", with cyte translated as "cell" in modern usage). Packed red blood cells, which are made from whole blood with the plasma removed, are used in transfusion medicine.

Figure 2.Human red blood cells (6-8 m)

 

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2.5 White blood cell

Figure3. White blood cell

White blood cells, or leukocytes (also spelled "leucocytes," "leuco being Greek for white), -" are cells of the immune system involved in defending the body against both infectious diseas e and foreign materials. Five different and diverse types of leukocyte exist, but they are all s produced and derived from a multipotent cell in the bone marrow known as a hematopoietic stem cell. Leukocytes are found throughout the body, including th blood and lymphatic e system. The number of WBCs in the blood is often an in dicator of disease. There are normally between 4109 and 1.11010 white blood cells in a litre of blood, making up approximately 1% of blood in a healthy adult. An increase in the number of leukocytes over the upper limits is called leukocytosis, and a decrease below the lower limit is called leukopenia. The physical properties of leukocytes, such as volume, conductivity, and granularity, may change due to activation, the presence of immature cells, or the presence of malignant leukocytes in leukemia

    

 

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2.5.1 Neutrophil
Neutrophils defend against bacterial or fungal infection and other very small inflammatory processes that are usually first responders to microbial infection; their activity and death in large numbers forms pus. They are commonly referred to as polymorphonuclear (PMN) leukocytes, although technically PMN refers to all granulocytes. They have a multilobed nucleus which may appear like multiple nuclei, hence the name polymorphonuclear leukocyte. The cytoplasm may look transparent because of fine granules that are pale lilac. Neutrophils are very active in phagocytosing bacteria and are present in large amount in the pus of wounds. These cells are not able to renew their lysosomes used in digesting microbes and die after having phagocytosed a few pathogens.[citation needed] Most common cell seen in acute inflammation, comes in and kill foreign substance.They make up 60-70% of total leukocyte count.The life span of neutrophil is about 8 days.

Figure . Neutrophil

2.5.2 Eosinophil
Eosinophils primarily deal with parasitic infections and an increase in them may indicate such. Eosinophils are also the predominant inflammatory cells in allergic reactions. The most important causes of eosinophilia include allergies such as asthma, hay fever, and hi es; and also parasitic v infections. Generally their nucleus is bi-lobed. The cytoplasm is full of granules which assume a characteristic pink-orange color with eosin stain.

Figure . Eosinophil

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2.5.3 Basophil
Basophils are chiefly responsible for allergic and antigen response by releasing the chemical histamine causing vasodilation. The nucleus is bi- or tri-lobed, but it is hard to see because of the number of coarse granules which hide it. They are characterized by their large blue granules.

Figuere . Basophil

2.5.4 Lymphocyte
Lymphocytes are much more common in the lymphatic system. Lymphocytes are distinguished by having a deeply staining nucleus which may be eccentric in location, and a relatively small amount of

cytoplasm. The blood has three types of lymphocytes: B cells: B cells make antibodies that bind to pathogens to enable their destruction. (B cells not
only make antibodies that bind to pathogens, but after an attack, some B cells will retain the ability to produce an antibody to serve as a 'memory' system.)

T cells: CD4+ (helper) T cells co-ordinate the immune response and are important in the defense
against intracellular bacteria. In acute HIV infection, these T cells are the main index to identify the individual's immune system activity. Research has shown that CD8+ cells are also another index to identify human's immune activity.

Figure . Lymphocyte

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CD8+ cytotoxic T cells are able to kill virus-infected and tumor cells. T cells possess an alternative T cell receptor as opposed to CD4+ and CD8+ share characteristics of helper T cells, cytotoxic T cells and natural killer cells. Natural killer cells: Natural killer cells are able to kill cells of the body which are displaying a signal to kill them, as they have been infected by a virus or have become cancerous. T cells and

2.5.5 Monocyte
Monocytes share the "vacuum cleaner" (phagocytosis) function of neutrophils, but are much longer lived as they have an additional role: they present pieces of pathogens to T cells so that the pathogens may be recognized again and killed, or so that an antibody response may be mounted. Monocytes eventually leave the bloodstream to become tissue macrophages which remove dead cell debris as well as attacking microorganisms. Neither of these can be dealt with effectively by the neutrophils. Unlike neutrophils, monocytes are able to replace their lysosomal contents and are thought to have a much longer active life. They have the kidney shaped nucleus and are typically agranulated. They also possess abundant cytoplasm.

Figure . Monocyte Once monocytes move from the bloodstream out into the body tissues, they undergo changes (differentiate) allowing phagocytosis and are then known as macrophages.

1 2( 1 ( (

0( )(

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2.6 Platelet
Image from a light microscope (40x) from a peripheral blood smear surrounded by red blood cells. One platelet can be seen in the upper left side of the image (purple) and is significantly smaller in size than the red blood cells (stained pink) and the two large neutrophils (stained purple). Platelets, or thrombocytes are small, regularly shaped clear cell fragments (i.e. cells that do not have a nucleus containing DNA), 23 m in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days. Platelets are a natural source of growth factors. They circulate in the blood of mammals and are involved in hemostasis, leading to the formation of blood clots. If the number of platelets is too low, excessive bleeding can occur. However, if the number of platelets is too high, blood clots can form (thrombosis), which may obstruct blood vessels and result in such events as a stroke, myocardial infarction, pulmonary embolism or the blockage of blood vessels to other parts of the body, such as the extremities of the arms or legs. An abnormality or disease of the platelets is called a thrombocytopathy, which could be either a low number of platelets (thrombocytopenia), a decrease in function of platelets (thrombasthenia), or an increase in the number of platelets (thrombocytosis). There are disorders that reduce the number of platelets, such as heparininduced thrombocytopenia (HIT) or thrombotic thrombocytopenic purpura (TTP) that typically causes thromboses, or clots, instead of bleeding. Platelets release a multitude of growth factors including Platelet-derived growth factor (PDGF), a potent chemotactic agent, and TGF beta, which stimulates the deposition of extracellular matrix. Both of these growth factors have been shown to play a significant role in the repair and regeneration of connective tissues. Other healing-associated growth factors produced by platelets include basic

fibroblast growth factor, insulin-like growth factor 1, platelet-derived epidermal growth factor, and vascular endothelial growth factor. Local application of these factors in increased concentrations through Platelet-rich plasma (PRP) has been used as an adjunct to wound healing for several decades Platelet

Figure . Platelet

6 73 6 3 3

53 43

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Blood and blood disorders 2.7 P ci g i l c ll

In vertebrates, the various cells of blood are made in the bone marrow in a process called hematopoiesis, which includes erythropoiesis, the production of red blood cells; and myelopoiesis, the production of white blood cells and platelets. During childhood, almost every human bone produces red blood cells; as adults, red blood cell production is limited to the larger bones: the bodies of the vertebrae, the breastbone (sternum), the ribcage, the pelvic bones, and the bones of the upper arms and legs. In addition, during childhood, the thymus gland, found in the mediastinum, is an important source of lymphocytes. The proteinaceous component of blood (including clotting proteins) is produced predominantly by the liver, while hormones are produced by the endocrine glands and the watery fraction is regulated by the hypothalamus and maintained by the kidney.

Healthy erythrocytes have a plasma life of about 20 days before they are degraded by the spleen, and the Kupffer cells in the liver. The liver also clears some proteins, lipids, and amino acids. The kidney actively secretes waste products into the urine.

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Blood and blood disorders

2.8 Pl
About 55% of whole blood is blood plasma, a fluid that is the blood's liquid medium, which by itself is straw-yellow in color. The blood plasma volume totals of 2.73.0 liters (2.83.2 quarts) in an average human. It is essentially an aqueous solution containing 92% water, 8% blood plasma proteins, and trace amounts of other materials. Plasma circulates dissolved nutrients, such as glucose, amino acids, and fatty acids (dissolved in the blood or bound to plasma proteins), and removes waste products, such as carbon dioxide, urea, and lactic acid. Other important components include:
y y y y y y

Serum albumin Blood-clotting factors (to facilitate coagulation) Immunoglobulins (antibodies) lipoprotein particles Various other proteins Various electrolytes (mainly sodium and chloride)

The term serum refers to plasma from which the clotting proteins have been removed. Most of the proteins remaining are albumin and immunoglobulins.

Blood and blood disorders 2.9 N w g Hv l

Blood pH is regulated to stay within the narrow range of 7.35 to 7.45, making it slightly alkaline. Blood that has a pH below 7.35 is too acidic, whereas blood pH above 7.45 is too alkaline. Blood pH, partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), and HCO3are carefully regulated by a number of homeostatic mechanisms, which exert their influence principally through the respiratory system and the urinary system in order to control the acid-base balance and respiration. An arterial blood gas will measure these. Plasma also circulates hormones transmitting their messages to various tissues. The list of normal reference ranges for various blood electrolytes is extensive.

Bones are especially affected by blood pH as they tend to be used as a mineral source for pH buffering. Consuming a high ratio of animal protein to vegetable protein is implicated in bone loss in women.

Tabl 1.
Parameter Hematocrit

al bl
Val

45 42

7 (38 52%) for males

5 (37 47%) for females 7.35 7.45 3 to 3

pH base excess PO2 PCO2 HCO3 Oxygen saturation

4.85.8 kPa (3545 mm Hg) 2 27 mM Oxygenated: 9899% Deoxygenated: 75%

3 kPa (80

A A 9

00 mm Hg)

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3. Cardi vascular sys em

Components of the Cardiovascular System Heart pumps blood Blood vessels: arteries carry blood to organs and tissues veins return blood to the heart capillaries allow for transport to and from tissues

Blood - The fluid medium for transport.

Figure . The circulation of blood through the human heart. Blood is circulated around the body through blood vessels by the pumping action of the heart. In humans, blood is pumped from the strong left ventricle of the heart through arteries to peripheral tissues and returns to the right atrium of the heart through veins. It then enters the right ventricle and is pumped through the pulmonary artery to the lungs and returns to the left atrium through the pulmonary veins. Blood then enters the left ventricle to be circulated again. Arterial blood carr es i oxygen from inhaled air to all of the cells of the body, and venous blood carries carbon dioxide, a waste product of metabolism by cells, to the lungs to be exhaled. However, one exception includes pulmonary arteries, which contain the most deoxygenated blood in the body, while the pulmonary veins contain oxygenated blood. Additional return flow may be generated by the movement of skeletal muscles, which can compress veins and push blood through the valves in veins toward the right atrium. The blood circulation was famously described by William Harvey in 1628.

E FB E B B

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Blood and blood disorders

I P

4. Blood di ord r
I

Abnormal condition that involves the corpuscular elements of the bloodred cells, white cells, and plateletsand the tissues in which they are formedthe bone marrow, the lymph nodes, the spleen (i.e., the hematopoietic system). This definition, however, needs expansion and modification. In certain types of illness (e.g., pneumonia, appendicitis) the number of leukocytes is increased. This is called leukocytosis and is a physiological response rather than a disease of the blood. In other diseases, as will be mentioned below, a reduction in the number of red cells in the blood (anemia) occurs; such anemia is not usually thought of as representing a blood disease, but it does represent the response of the hematopoietic system to the underlying disease. Strictly speaking, the term blood disease refers only to those types of anemia and those disorders of leukocytes, of platelets, of coagulation, and of the bone marrow, lymph nodes, and spleen in which the blood-forming organs or coagulation systems are the primary sites involved.

In the following, all varieties of alteration in the three corpuscular elements of the blood will be discussed. For convenience, disorders chiefly affecting the red cells, the leukocytes, the platelets, and the process of blood coagulation will be considered in turn, but, as will become apparent, alterations in disease do not necessarily occur in only one of these groups of blood cells; in its reactions in disease the hematopoietic system may demonstrate multiple changes.

Since the blood circulates throughout the body and carries nutritive substances as well as waste products, examination of it can be important in detecting the presence of disease. Examination of the blood may be considered in two categories; namely, the analysis of the plasma and the study of the corpuscles. Examination of the plasma includes measurement of plasma proteins, blood sugar, salts (which, being in solution and in the ionic state, are referred to as electrolytes), lipids, enzymes, urea, and various hormones. Such measurements are useful in the identification of diseases that are not classified as blood diseasese.g., diabetes, kidney disease, and thyroid disease. Special studies of plasma or its components can be carried out to determine the status of blood clotting.

Long before the nature and composition of blood were known, a variety of complaints were attributed to disordered blood. The red cells were not recognized until the 7th century, and it

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Blood and blood disorders

was another 00 years before one of the forms of the white cells, the lymphocyte, and the clotting of blood were described. In the 9th century other forms of leukocytes were

discovered, and a number of diseases of the blood and blood-forming organs were distinguished. In the 9th century and also in the first quarter of the 20th century much attention was given to descriptions of the morphological changesthe changes in form and structurethat take place in the blood during disease and to the signs and symptoms of the various blood diseases. In the years that followed, a more physiological approach began to develop, concerned with the mechanisms underlying the development of disease and with the ways in which abnormalities might be corrected. Following World War II, progress was greatly accelerated by the strong financial support that medical science received during a particularly productive age of medical research. The study of a particular instance of disease involves inquiry into the circumstances of its development, the symptoms, and the course of the illness (the history). A thorough physical examination of the affected person and specific laboratory tests are essential. In the case of the blood, certain features of the physical examination are especially important in diagnosis. These include noting the presence or absence of pallor or, the opposite, an excess of colour; jaundice, red tongue, enlargement of the heart or liver; the presence or absence of small purple spots or larger bruises in the skin; enlargement of lymph glands (nodes); enlargement of the spleen; and tenderness of the bones. Laboratory studies particularly valuable in diagnosis include ( ) determination of the numberand characteristics of red cells in the blood; i.e., the existence of anemia or polycythemia, (2)study of the white cells, their number and their proportions as to type, (3) enumeration of the blood platelets and a study of the blood-clotting process, and (4) in many instances a study of the bone marrow. It is sometimes necessary to remove a lymph node for microscopic examination, and X-ray examinations may be necessary for the detection of organ or lymph node enlargement or bone abnormalities. The more unusual cases may require further examinationse.g., special serological (serum-related) or biochemical procedures or various measurements using radioactive isotopes to outline an organ or quantitate blood volume.

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Blood and blood disorders 4.1 Di affec i g ed cell

The quantity of red blood cells in normal human beings varies with age and sex as well as with external conditions, primarily atmospheric pressure. At sea level an average normal manhas 5,400,000 red blood cells per cubic millimeter of blood. These carry an average of 6 grams of hemoglobin per 00 milliliters of blood. If such blood is centrifuged so that the red cells are packed in a special tube known as the hematocrit, they are found, on the average, to occupy 47 percent of the volume of the blood. In the average woman the normal figures are lower than this (red cell count 4,800,000; hemoglobin 4 grams; volume of packed red cells 42 percent). In the newborn infant these values are higher but decrease in the course of the first several weeks of postnatal life to levels below those of the normal woman; thereafter, they rise gradually. The differences in male and female blood begin to appear at about the time of puberty. It should be emphasized that these figures represent average values; those found in normal persons range approximately 5 percent on either side of this mean. From the physiological standpoint it is the quantity of hemoglobin in the blood that is important because this iron-containing protein is required for the transport of oxygen from the lungs to the tissues. In disease, as well as in certain situations in which physiological adjustments take place, the quantity of hemoglobin may be reduced below normal levels, a condition known as anemia, or may be increased above normal, leading to erythrocytosis (also called polycythemia).

4.2The anemias
Anemia varies in severity, and the tolerance of different persons for anemia varies greatly, depending in part upon the rate at which it has developed. When anemia has developed gradually, affected persons may endure severe grades of anemia with few or no complaints, whereas rapidly developing anemia causes severe symptoms; if sufficiently severe and rapidin development, anemia can be fatal. In anemia the blood is capable of carrying only a reduced amount of oxygen to tissues, a condition that stimulates the lungs to increase the respiratory rate in order to pick up more oxygen and the heart to increase its rate (pulse) in order to increase the volume of blood delivered to the tissues. Associated complaints include a pounding headache due to the increased blood flow. Anemia is always a sign, either predominant or incidental, of some underlying congenital condition or acquired disease. There are many varieties of anemia. Their clinical manifestations are generally similar, and yet they must be differentiated because their causes

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Blood and blood disorders

differ, and consequently their treatment is not the same. Differentiation is based on the history and physical examination, which may reveal an underlying cause, and on examination of the blood. The latter includes measurement of the degree of anemia and microscopic study of the blood cells. If the number of red cells, the hemoglobin concentration of the blood, and the volume of packed red cells are known, the mean volume and hemoglobin content can be calculated. The mean corpuscular volume (MCV) normally is 82 to 92 cubic micrometres, and about a third of this is hemoglobin (mean corpuscular hemoglobin concentration, MCHC, normally is 32 to 36 percent). If determined accurately, the MCV and the MCHC are useful indexes of the nature of an anemia. Under the microscope the red cells of humans appear as round biconcave disks of uniform size with an average diameter of approximately 7.8 micrometres, or 0.0078 millimetre (a common pin is about one millimetre thick). Microscopic inspection of films of blood dried on glass slides and stained with aniline dyes allows observation of variations in the size and colour and other abnormalities of individual red cells and also permits examination of the white cells and platelets.

4.3 The anemias. Derangement f functi n in anemia

Red cells are formed within the marrow cavities of the central bones of the adult human skeleton (skull, spine, ribs, breastbone, pelvic bones). The marrow contains nucleated red cells (normoblasts), as well as white cells of all stages of development and megakaryocytes, the source of blood platelets. The normoblasts are present in various stages of development toward the mature, adult, nonnucleated, hemoglobin-containing red cells that will be releasedinto the circulating blood. The newly arrived red cells in the circulation remain as reticulocytes, young red cells with a characteristic threadlike network, for two or three days. Each day's output of new red cells survives an average of 20 days before succumbing to old age. The red cells are able to withstand the vicissitudes of the circulation because glucose absorbed from the plasma is metabolized within the cell to supply energy in the form of adenosine triphosphate (ATP) as well as to provide reducing systems that protect against the products of oxidation (oxidationreduction systems).

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Blood and blood disorders

Ultimately the aged red cells are broken down by specialized reticuloendothelial cells that are found throughout the body and especially in the spleen and liver. The hemoglobin is digested into its components: iron, a red pigment with a ring-shaped structural formula (porphyrin), and a protein (globin). The iron remains within the body to be used over and over again in the formation of new hemoglobin. The porphyrin ring opens and is changed chemically to become the yellow pigment of the blood plasma, bilirubin. This is then excreted by the liver and gives the bile its characteristic colour. The globin is metabolized. In a healthy person, red cell production (erythropoiesis) is so well adjusted to red cell destruction that the levels of red cells and hemoglobin remain constant. The circulation is a closed system from which there normally is no loss of blood except that which occurs physiologically in menstruation. Anemia results when ( ) the production of red cells and hemoglobin lags behind the normal rate of their destruction, (2) excessive destruction exceeds production, or (3) blood loss occurs. The bone marrow normally is capable of increasing production as much as sixfold to eightfold through an increased rate of development from the primitive precursors. Anemia ensues when the normal fine balance between production, destruction, and physiological loss is upset and erythropoiesis has not been accelerated to a degree sufficient to reestablish normal blood values. The rate of production of red cells by the bone marrow normally is controlled by a physiological feedback mechanism analogous to the thermostatic control of temperature in aroom. The mechanism is triggered by a reduction of oxygen in the tissues (hypoxia) and operates through the action of a hormone, erythropoietin, in the formation of which the kidney plays an important role. Erythropoietin is released and stimulates further erythropoiesis. When oxygen needs are satisfied, erythropoietin production is reduced and red cell production diminishes. Failure of production of red cells may be caused by deficiency of certain essential materials, such as iron, folic acid, or vitamin B12. It may be due to other causes, such as the presence of certain types of diseasee.g., infection; damage of the bone marrow by ionizing radiation or by drugs or other chemical agents; or anatomical alterations in the bone marrow, as by leukemia or tumour metastases (migration of tumour cells to the marrow from distant sites oforigin). Accelerated destruction of red cells may occur for any one of a large variety of causes(see below Hemolytic anemias). Finally, blood loss may result from trauma or may be associated with a variety of diseases. Persons whose anemia is due to increased destruction of red cells have excessive amounts of bilirubin in the plasma. They appear to be slightly jaundiced, and the excess pigments darken

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Blood and blood disorders

the excreta. Certain laboratory tests measure the degree of excessive pigment production. The bone marrow responds to increased destruction of red cells by increasing the rate of their production, thereby increasing the number of reticulocytes in the blood. These cells, in addition to their unique staining characteristics, are larger than fully mature red cells.If their number is increased sufficiently, the mean corpuscular volume of the cells in the circulation is increased. The anemia is then characterized as macrocytic. Macrocytic anemia also is produced when the anemia results from impaired production of red cells, e.g., when vitamin B12 or folic acid is lacking. In other circumstances, as for example when there is a deficiency of iron, the circulating red cells are smaller than normal and poorly filled with hemoglobinthis is termed hypochromic microcytic anemia. In still other forms of anemia there is no significant alteration in the size, shape, or coloration of the red cells normocytic anemias. Anemias may be classified according to the underlying abnormality in the basic physiologicalmechanism (decreased production, increased destruction, blood loss) or on morphological grounds (macrocytic, normocytic, or microcytic hypochromic) or according to their cause (e.g.,vitamin B12 deficiency). In practice it is by a combination of clinical, morphological, and physiological studies that the cause is determined. Accurate diagnosis is essential before treatment is attempted because, just as the causes differ widely, so the treatment of anemia differs from one patient to another. Indiscriminate treatment by the use of hematinics (drugs that stimulate production of red cells or hemoglobin) is wasteful and can be dangerous.

4.4 Thalassemia and the hemoglobinopathies

Hemoglobin is composed of a porphyrin compound (heme) and globin. Normal adult hemoglobin (Hb A) consists of globin containing two pairs of chains of amino acids, of which the alpha chain consists of 141 amino acids, the beta chain 146. (A chain of amino acids is called a peptide or, alternatively, when many amino acids make up the chain, a polypeptide.) A minor fraction of normal adult hemoglobin consists of hemoglobin A2, which contains alpha and delta chains. A different hemoglobin (Hb F) is present in fetal life and possesses a pair of the same alpha chains as does Hb A, but the second set is different (gamma chains). In normal hemoglobin the order in which the amino acids follow one

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Blood and blood disorders

another in the chain is always exactly the same. Studies by a number of investigators have now shown that qualitative and quantitative abnormalities in the globin chains can lead to disease. In thalassemia it is thought that a primary genetic defect results in reduction in the rate at which alpha, beta, or delta chains are manufactured, the chains being otherwise normal. The relative deficiency of one pair of chains and the resultant imbalance of chain pairs results in ineffective production of red cells, deficient hemoglobin production, microcytosis (small cells), and hemolysis. In sickle-cell anemia and in other abnormalities affecting hemoglobin, the substitution of one amino acid for another at a particular site in the chain is the underlying fault. The substitution of valyl for glutamyl in the sixth position of the beta chain, for example, results in the formation of Hb S (the hemoglobin of sickle-cell disease) instead of Hb A. The defect is inherited as a Mendelian recessive. Thus, if only one parent transmits the abnormality, the offspring inherits the trait but is harmed relatively little; the red cells contain more Hb A than Hb S. If the trait is inherited from both parents, the predominant hemoglobin in the red cell is Hb S; the serious and sometimes fatal disease sickle-cell anemia is the consequence. Since the first characterization of the nature of the abnormality in Hb S by Linus Pauling and his associates (1949), more than 100 abnormal hemoglobins have been identified, and other forms of molecular disease have been recognized as well. Fortunately, most abnormal hemoglobins are not sufficiently affected to alter their function, and therefore no observable illness occurs.

Sickle-cell anemia occurs almost exclusively in blacks. In the United States at least 8 percent of blacks carry the sickle-cell trait. The actual disease, sickle-cell anemia, is less common (about 1 in 400 blacks). In this condition most of the red cells of a sample of fresh blood look normally shapeddiscoidaluntil deprived of oxygen, when the characteristic sickle- or crescent-shaped forms with threadlike extremities appear. Re-exposure to oxygen causes immediate reversion to the discoidal form. Sickle-cell anemia is characterized by severe chronic anemia, punctuated by painful crises, the latter being due to blockage of the capillary beds in various organs by masses of sickled red cells. This gives rise to fever and episodic pains in the chest, abdomen, or joints that are difficult to distinguish from the effects of other diseases. Death results from anemia, from infections, or, ultimately, from heart or kidney failure. While the many complications of the disease can be treated and pain relieved, there is no treatment to reverse or prevent the actual sickling process.

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Thalassemia (Greek: sea blood) is so called because it was first discovered among peoples around the Mediterranean Sea, among whom its incidence is high. The thalassemias are another group of inherited disorders in which one or more of the hemoglobin subunits are synthesized defectively. This condition, when inherited from one parent, is called thalassemia minor; it causes serious disease only when inherited from both parents (thalassemia major, Cooley's anemia). Thalassemia now is known also to be common in Thailand and elsewhere in the Far East. The red cells in this condition are unusually flat with central staining areas and for this reason have been called target cells. In the mild form of thedisease, thalassemia minor, there is usually only slight or no anemia, and life expectancy is normal. Thalassemia major is characterized by severe anemia, great enlargement of the spleen, and body deformities associated with expansion of the bone marrow. The latter presumably represents a response to the need for greatly accelerated red cell production by genetically defective red cell precursors, which are relatively ineffective in producing maturered cells. Anemia is so severe that transfusions are often necessary; however, they are of only temporary value and lead to excessive iron in the tissues once the transfused red cells break down. The enlarged spleen may further aggravate the anemia by pooling and trapping the circulating red cells. Splenectomy may partially relieve the anemia but does not cure the disease. The defect in thalassemia may involve the beta chains of globin (beta-thalassemia), the alpha chains (alpha-thalassemia), the delta chains (delta-thalassemia), or both delta- and beta-chain synthesis. In the last (deltabeta-thalassemia), Hb F concentrations usually are considerably elevated since the number of beta chains available to combine with alpha chains is limited and gamma chain synthesis is not impaired. Beta-thalassemia comprises the majority of all thalassemias. A number of genetic mechanisms account for impaired production of beta chains, all of which result in inadequate supplies of messenger RNA available for proper synthesis of the beta polypeptide at the ribosome. In some cases no messenger RNA is produced. Most defects have to do with production and processing of the RNA from the beta gene; in alpha thalassemia, by contrast, the gene itself is deleted. There are normally two pairs of alpha genes, and the severity of the anemia is determined by the number deleted. Since all normal hemoglobins contain alpha chains, there is no increase in F or A1. The extra non-alpha chains may combine into tetramers to form beta4 (hemoglobin H) or gamma4 (hemoglobin Barts). These tetramers are ineffective in delivering oxygen and are unstable. Inheritance of deficiency of a pair of genes from both parents results in intrauterine fetal death or severe disease of the newborn child (hydrops fetalis).

Blood and blood disorders

In most forms of hemoglobin abnormality only a single amino acid substitution occurs, but there may be combinations of hemoglobin abnormalities, or a hemoglobin abnormality may be inherited from one parent and thalassemia from the other. Thus, sickle-thalassemia and Hb E-thalassemia are relatively common. A malfunction of the abnormal hemoglobin may result in erythrocythemia, or overproduction of red cells. In these cases there is increased oxygen affinity, limiting proper delivery of oxygen to tissues and thereby stimulating the bone marrow to increase red cell production. Inother cases the iron in heme may exist in the oxidized, or ferric (Fe3 ), state and thus cannot combine with oxygen to carry it to tissues. This results in a bluish colour of the skin and mucous membranes (cyanosis). The abnormality in the globin molecule that accounts for this is usually in an area of the molecule called the heme pocket, which normally protects the iron against oxidation, despite the fact that oxygen is being carried at this site.

4.5Disorders affecting red cells. Erythrocytosis

Erythrocytosis is an increase above normal in the number of red cells in the circulating blood, usually accompanied by an increase in the quantity of hemoglobin and in the volume of packed red cells. The increase may be either an actual rise in the total quantity of red blood cells in the circulation (absolute erythrocytosis), or it may be the result of a loss of blood plasma and thus a relative increase in the concentration of red cells in the circulating blood (relative erythrocytosis). The latter may be the consequence of abnormally lowered fluid intake or of marked loss of body fluid, such as occurs in persistent vomiting, severe diarrhea, or copious sweating or when water is caused to shift from the circulation into the tissue. Absolute erythrocytosis occurs in response to some known stimulus for the production of red cells. This is in contrast to a disease called polycythemia vera, in which an increased amount of red cells are produced without a known cause. In polycythemia vera there is usually an increase in other blood elements as well. Erythrocytosis is a response by the body to an increased demand for oxygen. It occurs when hemoglobin is not able to pick up large amounts of oxygen from the lungs; i.e., when it is not saturated. This may result from decreased atmospheric pressure, as a high altitudes, or t from impaired pulmonary ventilation. The sustained increase in red cells in persons who reside permanently at high altitudes is a direct result of the diminished oxygen pressure in the environment. Chronic pulmonary disease (e.g., emphysemaabnormal distension of the

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lungs with air) may produce chronic hypoxemia (reduced oxygen tension in the blood) and lead to erythrocytosis. Extreme obesity also may severely impair pulmonary ventilation and thereby cause erythrocytosis (Pickwickian syndrome). Congenital heart disorders that permit shunting of blood from its normal path through the pulmonary circuit, thereby preventing adequate aeration of the blood, can also cause erythrocytosis, as can a defect in the circulating hemoglobin. The latter defect may be congenital because of an enzymatic or a hemoglobin abnormality, as mentioned above; or it may be acquired as the result of the excessive use of coal-tar derivatives, such as phenacetin, which convert hemoglobin to pigments incapable of carrying oxygen (methemoglobin, sulfhemoglobin). Lastly, erythrocytosis can develop in the presence of certain types of tumours and as the result of the action of adrenocortical secretions. Treatment of erythrocytosis due to any of these causes involves the correction or alleviation of the primary abnormality. In polycythemia vera, the numbers of red cells, and often also the numbers of white cells and platelets, are increased and the spleen usually is enlarged. In this disease the stem cell precursor of the bone marrow cells produces excessive progeny. Afflicted persons have an exceptionally ruddy complexion and may complain of headaches, dizziness, a feeling of fullness, and other symptoms. Because of the excessive quantities of red cells, the blood is usually thick, and its flow is retarded; it sometimes clots in the blood vessels (thrombosis) ofthe heart, the brain, or the extremities with serious consequences. One of the simplest methods of treatment is to remove the blood, one pint at a time, from a vein until the cellular level approaches normal and the symptoms disappear. Occasionally it may be necessary to use drugs or radiation, in the form of radioactive phosphorus, to restrain the overactivity of the marrow cells. These treatments, however, must be avoided when possible because of their potential complications.

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Blood and blood disorders 4.6 Diseases related to white cells

Variations in the number of white cells in humans occur normally from hour to hour, the highest counts being recorded in the afternoon and the lowest in the early morning. Temporary increases also normally occur during muscular exercise, menstruation, pregnancy, and childbirth, as well as in certain emotional states. Abnormal changes in the count, appearance, or proportion of the various white cells are indicative of pathological conditions in the body.

4.7 Diseases related to white cells. Leukocytosis

The condition in which white cells are present in greater numbers than normal is termed leukocytosis. It is usually caused by an increase in the number of granulocytes (especially neutrophils), some of which may be immature (myelocytes). Most often leukocytosis is the result of the presence of an infection, usually caused by pyogenic (pus-producing) organisms such as streptococcus, staphylococcus, gonococcus, pneumococcus, or meningococcus. Leukocyte counts of 12,000 to 20,000 per cubic millimetre during infections are not unusual. As the number of cells increases, the proportion of immature cells usually rises, perhaps because the demands on the leukocyte-producing tissues in the bone marrow have increased to the point at which there is an insufficient number of mature cells for delivery into the circulation. This picture of immaturity is referred to as a shift to the left. As the infection subsides, the number of younger forms and the total white cell count decrease and ultimatelyreturn to normal. During the period of repair following an inflammatory reaction, the monocytes may increase in number, and subsequently the lymphocytes will become more numerous. Certain types of infection are characterized from the beginning by an increase in the number of small lymphocytes unaccompanied by increases in monocytes or granulocytes. Such lymphocytosis is usually of viral origin. Moderate degrees of lymphocytosis are encountered in certain chronic infections such as tuberculosis and brucellosis. Infectious mononucleosis, caused by the EpsteinBarr virus, is associated with the appearance of unusually large lymphocytes (atypical lymphocytes). Those cells represent part of the complex defense mechanism against the virus, and they disappear from the blood when the attack of infectious mononucleosis subsides. Infectious mononucleosis occurs predominantly in persons from 10 to 30 years of age. It is thought to be transmitted by oral

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contact with exchange of saliva. Discomfort, fever, sore throat, and grippelike symptoms,together with enlargement of lymph nodes and spleen, characterize the condition. The blood serum contains an antibody (sheep cell or heterophil agglutinin) that is characteristic of the disease, but antibodies against the EpsteinBarr virus itself are more specific markers of the infection. The symptoms of this disease vary in severity in different persons, but often they are mild. Recovery takes place, as a rule, within several weeks. Despite the immune response against the EpsteinBarr virus, the virus is never completely eliminated from the body. A small number of virus particles remain in latent form within B lymphocytes. In a normal person the immune system (the T lymphocytes in particular) keeps the latent viruses in check. If the natural responses of the immune system are suppressed (immunosuppression), however, the EpsteinBarr virus can emerge from its latent form and initiate a new round of infection. The EpsteinBarr virus is a member of the herpesvirus family, which also includes viruses that cause cold sores (herpes simplex type 1), genital ulcers (herpes simplex type 2), and shingles (herpes zoster) and the cytomegalovirus. All of these viruses show the property of latency, and in each case immunosuppression can lead to their activation. The most dramatic example of this can be found in acquired immunodeficiency syndrome (AIDS), which causes a pronounced deficiency of T lymphocytes. Patients with AIDS can develop severe and even fatal herpesvirus infections. Monocytosis, an increase in the number of monocytes in the blood, occurs in association with certain infectious processes, especially subacute bacterial endocarditisinflammation of the lining of the heartand malaria. Monocytosis also occurs when the bone marrow is recovering from a toxic injury. Eosinophilia, an increase in the number of eosinophilic leukocytes, is encountered in many allergic reactions and parasitic infections. It is especially characteristic of infestation by trichina larvae, which are ingested when infected and poorly cooked pork or pork products areeaten.

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Blood and blood disorders 4.8 Diseases related to white cells. Leukemia
The terms acute and chronic refer to the duration of the untreated disease. Before the advent of modern chemotherapy, patients with acute leukemia usually died within weeks or months of the first manifestations of the disease. The life span of patients with chronic leukemia is now measured in years. Leukemia primarily involves the bone marrow, but the lymph nodes and spleen may also be affected. For example, the spleen usually is enlarged in chronic myelogenous leukemia, and in chronic lymphocytic leukemia there often is enlargement of lymph nodes. Changes also take place in the leukocytes, red cells, and platelets, with consequent anemia and bleeding manifestations. The first symptoms may be weakness and an increased tendency to become fatigued because of anemia, or hemorrhages into the skin and nosebleeds, or gum bleeding due to a decrease in the number of platelets. In the acute leukemias these symptoms may be severe, the anemia may progress rapidly, and there may be fever. Chronic leukemia is more insidious in development, and the early manifestations may be overlooked until enlargementof the spleen or lymph nodes is discovered. Leukemia is recognized by examination of the blood, supplemented in most instances by examination of the bone marrow. Acute leukemia is marked by the presence in the blood of immature cells normally not found there. In acute lymphocytic anemia (also called acute lymphoblastic leukemia), most frequently seen in children, the cells are immature forms of the lymphatic series of cells. In myeloblastic leukemia the predominant cells are the youngest recognizable precursors (myeloblasts) of the neutrophils of the blood. In a third and the least common variety, acute monocytic leukemia, the immature cells appear to be precursors of the monocytes of the blood. Myeloblastic and monocytic leukemia occur more commonly in adults and adolescents than in young children. In general, acute leukemia occurs in young persons, but no age group is exempt. The total white cell count usually is increased but not uncommonly is normal or lower than normal (leukopenic). In such cases, abnormal immature cells may nevertheless be seen in the blood. In all forms of acute leukemia the typical cells are found in abundance in the bone marrow. Aleukemic leukemia refers to those instances of leukemia in which no abnormal cells are found in the blood; in these instances the leukemia is identified by examinations ofthe bone marrow.

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Chronic granulocytic (myelogenous) leukemia is characterized by the appearance in the blood of large numbers of immature white cells of the granulocytic series in the stage following the myeloblast, namely, myelocytes. The spleen becomes enlarged, anemia develops, and the affected person may lose weight. The platelets may be normal or increasedin number, abnormally low values being found only in the late stages of the disease or as an unintended result of therapy. The disease is most commonly encountered in persons between the ages of 30 and 60 years. With treatment the leukocyte count falls to normal, anemia is relieved, and the size of the spleen is greatly reduced. When the leukocyte count rises again, treatment is reinstituted. Such cycles of treatment, remission, and beginning relapse with rise of leukocyte count can be repeated many times, but a stage ultimately is reached when treatment no longer is effective. The disease then often terminates in a form resembling acute leukemia (blastic crisis). There is considerable variation in the duration of the disease. Although in various series mean life span has been about 3 1/4 years, many affected persons live in good general condition for five to 10 years and sometimes longer. Chronic lymphocytic leukemia differs in many ways from other forms of leukemia. It occurs most often in people over 50 years of age, and its course usually is rather benign. It is mainly characterized by an increase in the number of lymphocytes in the blood, often accompanied by more or less generalized enlargement of lymph nodes and the spleen. Affected persons may carry on for many years without treatment and without any other manifestations. There may be no anemia and no loss of weight. Life span in this disease is measured in terms of five, 10, and even 15 years, occasionally even longer. Two events mark a change in the state of relative good health. One is the development of anemia, sometimes hemolytic in type, often accompanied by some decrease in the number of platelets. The other is impairment of immune mechanisms, resulting in great susceptibility to bacterial infections. Treatment differs according to the type of leukemia. Consequently, proper classification of the leukemia is the first step, once the diagnosis of leukemia has been made. Treatment of alltypes of leukemia reduces illness and, in acute leukemia, prolongs life. A number of drugs are used for the treatment of leukemia and, now less frequently than before chemotherapy was available, various forms of irradiation. The therapeutic agents are all myelotoxic; i.e., they injure all the cells of the bone marrow, normal cells as well as leukemic cells. Their mode of action is through direct damage to the dividing stem cell (unspecialized cell from which specialized cells develop) or by slowing or cessation of cell division. These effects may be accomplished (1) by antimetabolites, substances that interfere with the synthesis of DNA, a constituent of the chromosomes in the cell nucleus; (2) by

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blocking DNA strand duplication through the binding of drugs such as the nitrogen mustards with the base groups of DNA; (3) by disruption of the mitotic spindle during cell division; or (4) by interfering with the formation or functioning of RNA, which is manufactured in the cell nucleus and plays an essential role in the production of protein and in other cell functions. Drugs with different modes of action are often combined, especially in the treatment of the acute leukemias. Much skill and experience are needed in steering the narrow path between maximum possibledestruction of the leukemic cells and tolerable injury to the normal cells of the host. In the process of treatment anemia may increase; the body defenses, through the decrease in the number of neutrophils, may be impaired, and the platelets may be greatly reduced in number. Anemia can be treated with blood transfusions, and serious reductions in platelets can be met for a time with platelet transfusions. Acute lymphoblastic leukemia is more successfully treated than are other forms of acute leukemia; prolonged remissions and even cures can be brought about in children with the disease. Certain drugs are used to bring about remission; if the remission is complete, the patient becomes well, and no signs of the disease are demonstrable in the blood or bone marrow; drugs other than those used to induce remission often are more useful in maintaining the remission than the remission-inducing drugs. Acute myeloblastic leukemia and acute monocytic leukemia are less effectively treated by available drugs than is acute lymphoblastic leukemia. Nevertheless, new and aggressive forms of chemotherapy can induce lengthy remissions of the disease. Transplantation of normal bone marrow, following total irradiation of the patient to destroy all his normal bone marrow cells as well as the leukemic cells, has shown promise. With the advent of refined techniques of tissue typing, it is no longer necessary that the donor of the bone marrow be an identical twin. Marrow from histocompatible siblings (brother, sister) are effective. Best results have been obtained in patients younger than 35 years of age. When this form of treatment is successful, the patient's marrow is replaced by the donor's marrow. Although the treatment is arduous and complex, cures of acute lymphocytic and acute myelogenous forms of leukemia are now possible with bone marrow transplantation. Chronic myelogenous leukemia is treated with a drug, busulfan, in daily doses until the leukocyte count has returned to normal. Treatment then is interrupted until the leukocyte count has risen to about 50,000 cells per cubic millimetre, when treatment is resumed. This can be repeated many times, and thus the affected person is maintained in good health for years. Not infrequently the intervals between treatments are six months in duration or

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longer.Busulfan, however, like other antileukemic agents, can injure the bone marrow, and other adverse effects may occur. Other drugs and X-ray therapy also have been used but are somewhat less valuable than busulfan. In suitable young patients, bone marrow transplantation has been used successfully in chronic myelogenous leukemia. In its early stages, chronic lymphocytic leukemia seems best untreated, as long as anemia is not present or glandular enlargement is not too troublesome. None of the current treatments are curative. The high leukocyte counts in themselves are not harmful. When there is severe anemia, however, or when the platelet count is very low and bleeding manifestations are severe, adrenocorticosteroid hormones are often given. The lymphomas are malignant tumours of lymphocytes that are usually not associated with aleukemic blood picture. Instead, enlargement of lymph nodes and/or spleen are characteristic. The lymphomas are classified into two main groups: Hodgkin's disease and non-Hodgkin's lymphoma (or lymphocytic lymphoma). Hodgkin's disease usually begins with a painless swelling of a lymph node, and it may involve lymph nodes anywhere in the body. The disease seems to begin in one lymph node and spread from there to others. Exact determination of the extent of the disease (staging) is important in planning its treatment. Hodgkin's disease is a potentially curable lymphoma, so details of its treatment are crucial. The early stages of the disease can be cured with radiotherapy. More-advanced stages are still curable with chemotherapy, and in some patients a combination of chemotherapy and radiotherapy is used. The staging of the disease entails a thorough medical examination, bone marrow biopsy, and X rays. The latter usually include computerized axial tomography (CAT) scanning to identify enlarged lymph nodes in the interior of the body. In many cases, surgery (laparotomy) is required to obtain for examination lymph nodes from deep within the abdomen. The goal of all these staging procedures is to enable the physician to select the therapy with the maximum curative potential. The non-Hodgkin's lymphomas constitute a heterogeneous group that arise from either B lymphocytes or T lymphocytes. They may have an indolent course, as in the nodular welldifferentiated B lymphocyte lymphomas, or the tumour may be aggressive, as in the diffuse T lymphocyte forms. Unlike Hodgkin's disease, the lymphocytic lymphomas spread through the bloodstream. Therefore, the staging procedure is not as extensive as in Hodgkin's disease. Combination chemotherapy, usually given in cycles over a period of months, is effective in certain types of diffuse lymphocytic lymphomas. Prolonged remissions with eradication of the disease are difficult to achieve in the indolent nodular lymphomas.

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Another malignant disease, probably related to the above conditions, is multiple myeloma, which is characterized by a malignant overgrowth of plasma cells within the bone marrow. This severely painful disorder causes defects in the bone of the skull, the ribs, the spine, and the pelvis that ultimately result in fractures. As the bone marrow becomes more involved, anemia develops and hemorrhages occur: the number of leukocytes may be low, and abnormal myeloma or plasma cells are found in the bone marrow. This disorder is associated with a marked overproduction of immunoglobulin by the malignant plasma cell (the normal plasma cell is the source of the antibodies). The plasma cells in multiple myeloma are the progeny of a single malignant clone, and they secrete into the blood a single type of immunoglobulin moleculea monoclonal immunoglobulin. In some cases, a component of immunoglobulin, the light chain, may be produced in excess. These light chains appear in the urine, and in multiple myeloma they are called Bence-Jones protein. A type of chronic kidney disease often develops, probably as a result of the high concentration of Bence-Jones protein in the kidney tubules; this frequently is the ultimate cause of death. In some cases the condition remains quiescent for a time, but death is inevitable. Adrenocorticosteroid hormones and chemotherapeutic agents have been used in the treatment of multiple myeloma.

4.9 Diseases related to platelets and coagulation proteins. Bleeding disorders

In humans hemostatic failure may result from inherited or acquired defects of clotting or platelet function. The usual consequence is persistent bleeding from injuries that would normally cause little trouble. Some persons may bleed more easily than normal, perhaps even spontaneously, as a result of an increased fragility of the blood vessels. This fragility isnot itself a hemostatic defect but may be associated with one.

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Blood and blood disorders 4.10 oagulation disorders

Deficiencies in any of the protein factors involved in coagulation can result in hemorrhages following minor injuries. In some of these disorders, a specific deficiency is due to an inherited defect (e.g., hemophilia). In others, an acquired pathological condition may be responsible for the deficiency (e.g., conditions interfering with absorption of vitamin K and severe infection).

4.11 Diseases related to platelets and coagulation proteins. disorders. Thrombosis

oagulation

Thrombosis, the formation of a blood clot (thrombus) that tends to plug functionally normal blood vessels, is one of the major causes of death in Western societies. In this condition, the normal tendency of platelets to form a clot at the site of a vascular injury is a contributing factor. While the process of thrombosis is not completely understood, the chief underlying cause is believed to be a lesion that destroys the normal endothelial surface of the blood vessel. Platelets tend to adhere to such lesions and eventually form masses that, when reinforced by fibrin, may completely obstruct the blood flow. This obstruction may have disastrous consequences in arteries such as the coronary or cerebral blood vessels or a major artery of a limb or organ. In veins, the local results are less apparent or perhaps not even detected; however, behind the original thrombus, the whole blood content of the vein may clot to form a large mass. This occurs most frequently in the leg veins and may be due to slowing of the blood flow during prolonged surgical operations or confinement to bed. The danger is that the thrombus may become detached (an embolus) and be swept into the pulmonary artery, causing circulatory obstruction in the lung. Disorders of the regulation of blood coagulation may be either inherited or acquired. The hereditary deficiency of antithrombin III, protein C, protein S, and plasminogen can be associated with a thrombotic tendency; i.e., the inappropriate formation of clots in vessels. The most common of the thrombotic disorders include pulmonary embolism (clots in the lung)and deep vein thrombosis (clots in the leg veins). Other predisposing causes of thrombosis are an increase in platelet numbers in the blood and the formation of functionally abnormal platelets in diseases of the bone marrow. Birth control pills, pregnancy, and many disorders may be associated with a thrombotic tendency, but the reasons for this association are not understood.

Blood and blood disorders

The prevention and treatment of thrombosis aims at balancing the overactive clotting tendency and a bleeding tendency. The formation of clots may be prevented by the administration of anticoagulant drugs. Sodium warfarin inhibits the action of vitamin K and renders the blood less able to clot. Heparin facilitates the inhibition of activated clotting enzymes with the inhibitor, antithrombin III. These commonly used medications prevent the formation of clots or the enlargement of already existing clots. Streptokinase, urokinase, and tissue plasminogen activator are enzymes that dissolve clots. As agents that cause the lysis of fibrin clots, they are known collectively as fibrinolytic agents. Their administration, although attended by the possibility of bleeding complications, can restore blood flow through a vessel blocked by a clot.

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