Unit 3: Blood
Unit outline
Part 2: Production of the Formed Elements
- Vascular Spasm
- Formation of the platelet plug
- Coagulation
- Clotting factors involved in coagulation
- Fibrinolysis
- Plasma anticoagulants
- Disorders of clotting
Practice Questions
Learning Objectives
At the end of this unit, you should be able to:
I. Describe the general nature and functions of blood, specify the main components of blood and describe the importance of each.
II. Describe the production of the formed elements of blood.
III. Describe the major factors that stimulate the body to produce more erythrocytes.
IV. Specify the two main components of blood that give blood its viscosity, and describe the importance of each to the blood.
V. Define hemostasis and describe the mechanisms involved in achieving hemostasis: vascular spasm, platelet plug formation, blood clotting.
VI. Describe how the process of blood clotting is regulated, particularly with respect to prevention of blood clotting when it is not required, rapid initiation and progression of blood clotting when damage occurs, localization of blood clotting to the damaged region, and the dissolution of blood clots (fibrinolysis).
Learning Objectives and Guiding Questions
At the end of this unit, you should be able to complete all the following tasks, including answering the guiding questions associated with each task.
I. Describe the general nature and functions of blood, specify the main components of blood and describe the importance of each.
- How do the functions of blood contribute to homeostasis?
- What are the formed elements of blood?
- Describe the composition of plasma, and list at least three plasma proteins.
II. Describe the production of the formed elements of blood.
- Describe the origin, site(s) of production, structure and function of erythrocytes.
- Describe the structure and function of hemoglobin.
- Briefly explain how to determine the hematocrit of a blood sample, then explain:
- What specific information does it give you about an individual’s blood?
- What can that information be used to determine?
- Describe the origin, site(s) of production, structure and function of each leukocytes.
- List the types of leukocytes (white blood cells), their origins and relative quantities in normal blood (I.e. most common to least common)
- Describe in detail the function(s) of the five types of leukocytes. Be sure to include the 2 main subtypes of lymphocyte in your answer.
- What is a differential count? What information can it provide?
- Why are neutrophils found in high numbers in people recovering from burn injuries? What could be consequences of an abnormally low neutrophil count?
- How does one of the functions of eosinophils explain their high counts in individuals fighting a parasitic worm infestation?
- How would allergies affect the basophil count? Explain why.
- Why is a low lymphocyte count observed in individuals with an active HIV infection? Why is this a dangerous situation?
- Bone marrow disorders cause a low monocyte count. Why?
- Describe the origin, site(s) of production, structure and function of platelets.
III. Describe the major factors that stimulate the body to produce more erythrocytes.
- For the hormone erythropoietin, state:
- Its site of production and release.
- The stimuli for its release.
- Its physiological effects.
IV. Specify the two main components of blood that give blood its viscosity, and describe the importance of each to the blood.
- What factors contribute to the viscosity of blood?
- Describe in general terms how each factor is normally regulated by the body.
V. Define hemostasis and describe the mechanisms involved in achieving hemostasis: vascular spasm, platelet plug formation, blood clotting.
- Define “hemostasis” and describe why hemostasis is vital to maintaining homeostasis in the human body.
- What is the specific chemical stimulus that causes the smooth muscle of blood vessels walls to contract when they are damaged, and what is the functional purpose of this contraction?
- Describe in detail the formation of a platelet plug. Include in your description references to the specific stimulus that initially activates platelets, a definition of ‘platelet activation’, and a description of how activated platelets recruit additional platelets to a damaged site.
- Compare and contrast the stimuli, events, and end result of the intrinsic and extrinsic pathways of blood clotting.
- Is it possible to stimulate either the intrinsic or extrinsic pathway of blood clotting, without stimulating the other one? Explain your reasoning.
- Describe the common pathway of clotting, including the activation of prothrombin and fibrinogen, and the end result.
- Describe the following disorders of hemostasis, including common cause(s) and danger to physiology: thrombus, hemophilia.
VI. Describe how the process of blood clotting is regulated, particularly with respect to prevention of blood clotting when it is not required, rapid initiation and progression of blood clotting when damage occurs, localization of blood clotting to the damaged region, and the dissolution of blood clots (fibrinolysis).
- Describe the mechanisms in place that both allow rapid production of a blood clot when needed, and prevention of blood clot formation when there is no damage to a blood vessel.
- How are blood clots normally dissolved when they are no longer needed?
- Describe the meaning and importance of anticoagulants and thrombolytic agents. Give one example of each.
- Describe how vitamin K affects blood clotting.
Part 1: An Overview of Blood
Single-celled organisms do not need blood. They obtain nutrients directly from and excrete wastes directly into their environment. The human organism cannot do that. Our large, complex bodies need blood to deliver nutrients to and remove wastes from our trillions of cells. The heart pumps blood throughout the body in a network of blood vessels. Together, these three components—blood, heart, and vessels—makes up the cardiovascular system.
Recall that blood is a connective tissue. Like all connective tissues, it is made up of cellular elements and an extracellular matrix. The cellular elements—referred to as the formed elements—include erythrocytes (red blood cells, or RBCs), leukocytes (white blood cells, or WBCs), and cell fragments called platelets. The extracellular matrix, called plasma, makes blood unique among connective tissues because it is fluid. This fluid, which is mostly water, perpetually suspends the formed elements and enables them to circulate throughout the body within the cardiovascular system.
Functions of Blood
The primary function of blood is to deliver oxygen and nutrients to and remove wastes from body cells, but that is only the beginning of the story. The specific functions of blood also include defense, distribution of heat, and maintenance of homeostasis.
Transportation: Nutrients from the foods you eat are absorbed in the digestive tract. Most of these travel in the bloodstream directly to the liver, where they are processed and released back into the bloodstream for delivery to body cells. Oxygen from the air you breathe diffuses into the blood, which moves from the lungs to the heart, which then pumps it out to the rest of the body. Moreover, endocrine glands scattered throughout the body release their products, called hormones, into the bloodstream, which carries them to distant target cells. Blood also picks up cellular wastes and by products, and transports them to various organs for removal. For instance, blood moves carbon dioxide to the lungs for exhalation from the body, and various waste products are transported to the kidneys and liver for excretion from the body in the form of urine or bile.
Defense: Many types of leukocytes protect the body from external threats, such as disease-causing bacteria that have entered the bloodstream in a wound. Other leukocytes seek out and destroy internal threats, such as cells with mutated DNA that could multiply to become cancerous, or body cells infected with viruses.
When damage to the vessels results in bleeding, blood platelets and certain proteins dissolved in the plasma, the fluid portion of the blood, interact to block the ruptured areas of the blood vessels involved. This protects the body from further blood loss.
Maintenance of Homeostasis: Recall that body temperature is regulated via a classic negative-feedback loop. If you were exercising on a warm day, your rising core body temperature would trigger several homeostatic mechanisms, including increased transport of blood from your core to your body periphery, which is typically cooler. As blood passes through the vessels of the skin, heat would be dissipated to the environment, and the blood returning to your body core would be cooler. In contrast, on a cold day, blood is diverted away from the skin to maintain a warmer body core. In extreme cases, this may result in frostbite.
Blood also helps to maintain the chemical balance of the body. Proteins and other compounds in blood act as buffers, which thereby help to regulate the pH of body tissues. Blood also helps to regulate the water content of body cells.
Composition of Blood
You have probably had blood drawn from a superficial vein in your arm, which was then sent to a lab for analysis. Some of the most common blood tests—for instance, those measuring lipid or glucose levels in plasma—determine which substances are present within blood and in what quantities. Other blood tests check for the composition of the blood itself, including the quantities and types of formed elements. One such test, called a hematocrit, measures the percentage of red blood cells, clinically known as erythrocytes, in a blood sample. It is performed by spinning the blood sample in a specialized centrifuge, a process that causes the heavier elements suspended within the blood sample to separate from the lightweight, liquid plasma (Figure 1). Because the heaviest elements in blood are the erythrocytes, these settle at the bottom of the hematocrit tube. Located above the erythrocytes is pale, thin layer composed of the remaining formed elements of blood.
This pale, thin layer of centrifuged blood sample consists of the white blood cells, clinically known as leukocytes, and the platelets, cell fragments also called thrombocytes. This layer is referred to as the buffy coat because of its colour; it normally constitutes less than 1% of a blood sample. Above the buffy coat is the blood plasma, normally a pale, straw-coloured fluid, which constitutes the remainder of the sample.
The volume of erythrocytes after centrifugation is also commonly referred to as packed cell volume (PCV). In normal blood, about 45% of a sample is erythrocytes. The hematocrit of any one sample can vary significantly, and may be 36-50%, depending on sex and other factors. Normal hematocrit values for females range from 37 to 47%, with a mean value of 41%; for males, hematocrit ranges from 42 to 52%, with a mean of 47%. The percentage of other formed elements, the leukocytes and platelets, is extremely small so it is not normally considered with the hematocrit. The mean plasma percentage is the percent of blood that is not erythrocytes: for females, it is approximately 59% (or 100 minus 41), and for males, it is approximately 53% (or 100 minus 47).
Characteristics of Blood
When you think about blood, the first characteristic that probably comes to mind is its colour. Blood that has just taken up oxygen in the lungs is bright red, and blood that has released oxygen in the tissues is a more dusky red. This is because hemoglobin is a pigment that changes colour, depending upon the degree of oxygen saturation.
Blood is viscous and somewhat sticky to the touch. It has a viscosity approximately five times greater than water. Viscosity is a measure of a fluid’s thickness or resistance to flow, and is influenced by plasma proteins and formed elements (usually albumin concentration and the number of erythrocytes) within the blood. The viscosity of blood has a dramatic impact on blood pressure and flow. Consider the difference in flow between water and honey. The more viscous honey would demonstrate a greater resistance to flow than the less viscous water. The same principle applies to blood.
The normal temperature of blood is slightly higher than normal body temperature—about 38 °C (or 100.4 F), compared to 37 °C (or 98.6 F) for an internal body temperature reading, although daily variations of 0.5 °C are normal. Although the surface of blood vessels is relatively smooth, as blood flows through them, it experiences some friction and resistance, especially as vessels age and lose their elasticity, thereby producing heat. This accounts for its slightly higher temperature.
The pH of blood averages about 7.4, but can range from 7.35 to 7.45 in a healthy person. Blood is therefore somewhat more basic (alkaline) on a chemical scale than pure water, which has a pH of 7.0. Blood contains numerous buffers that help to regulate pH.
Blood constitutes approximately 8% of adult body weight. Adult males typically average about 5-6 litres of blood; adult females average 4-5 litres.
Blood Plasma
Like other fluids in the body, plasma is composed primarily of water, and is about 92% water. Dissolved or suspended within this water is a mixture of substances, most of which are proteins. There are literally hundreds of substances dissolved or suspended in the plasma, although many of them are found only in very small quantities.
Plasma Proteins: About 7% of the volume of plasma – nearly all that is not water – is made of proteins. These include several plasma proteins (proteins that are unique to the plasma), plus a much smaller number of regulatory proteins, including enzymes and some hormones (Table 1).
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- Albumin is the most abundant of the plasma proteins. Manufactured by the liver, albumin molecules serve as binding proteins—transport vehicles for fatty acids and steroid hormones. Recall that lipids are hydrophobic; however, their binding to albumin enables their transport in the watery plasma. Albumin is also the most significant contributor to the osmotic pressure of blood; that is, its presence holds water inside the blood vessels and draws water from the tissues, across blood vessel walls, and into the bloodstream. This in turn helps to maintain both blood volume and blood pressure. Albumin normally accounts for approximately 54% of the total plasma protein content, in clinical levels of 3.5–5.0 g/dL blood.
- The second most common plasma proteins are the globulins. A heterogeneous group, there are three main subgroups known as alpha, beta, and gamma globulins. The alpha and beta globulins transport iron, lipids, and the fat-soluble vitamins A, D, E, and K to the cells; like albumin, they also contribute to osmotic pressure. The gamma globulins are proteins involved in immunity and are better known as antibodies or immunoglobulins. Although other plasma proteins are produced by the liver, immunoglobulins are produced by specialized leukocytes known as plasma cells. Globulins make up approximately 38% of the total plasma protein volume, in clinical levels of 1.0–1.5 g/dL blood.
- The least abundant plasma protein is fibrinogen. Like albumin and the alpha and beta globulins, fibrinogen is produced by the liver. It is essential for blood clotting, a process described later in this chapter. Fibrinogen accounts for about 7% of the total plasma protein volume, in clinical levels of 0.2–0.45 g/dL blood.
Other Plasma Solutes: In addition to proteins, plasma contains a wide variety of other substances. These include various hormones such as insulin and oxytocin; electrolytes, such as sodium, potassium, and calcium ions; dissolved gases, such as oxygen, carbon dioxide, and nitrogen; various organic nutrients, such as vitamins, lipids, glucose, and amino acids; and metabolic wastes, such as carbon dioxide and urea. All of these non-protein solutes combined contribute approximately 1% to the total volume of plasma.
| Component and % of blood | Subcomponent and % of component | Type and % (where appropriate) | Site of production | Major function(s) |
|---|---|---|---|---|
| Plasma 46-63% | Water 92% | Fluid | Absorbed by intestinal tract or produced by metabolism | Transport medium |
| Plasma proteins 7% | Albumin 54-60% | Liver | Maintain osmotic concentration, transport lipid molecules | |
| Globulins 35-38% | Alpha globulins: liver | Transport, maintain osmotic concentration | ||
| Beta globulins: liver | Transport, maintain osmotic concentration | |||
| Gamma globulins (immunoglobulins): plasma cells | Immune responses | |||
| Fibrinogen 4-7% | Liver | Blood clotting in hemostasis | ||
| Regulatory proteins <1% | Hormones and enzymes | Various sources | Regulate various body functions | |
| Other solutes 1% | Nutrients, gases, and wastes | Absorbed by intestinal tract, exchanged in respiratory system, or produced by cells | Numerous and varied | |
| Formed elements 37-54% | Erythrocytes 99% | Erythrocytes | Red bone marrow | Transport gases (primarily O2, some CO2) |
| Leukocytes <1% | Granular leukocytes: neutrophils, eosinophils, basophils | Red bone marrow | Nonspecific immunity | |
| Agranular leukocytes: lymphocytes, monocytes | Lymphocytes: red bone marrow and lymphatic tissue | Lymphocytes: specific immunity | ||
| Monocytes: red bone marrow | Monocytes: nonspecific immunity | |||
| Platelets <1% | Megakaryocytes in red bone marrow | Hemostasis |
Part 2: Production of the Formed Elements
The lifespan of the formed elements is very brief. Although one type of leukocyte called memory cells can survive for years, most erythrocytes, leukocytes, and platelets normally live only a few hours to a few weeks. Thus, the body must form new blood cells and platelets quickly and continuously. When you donate a unit of blood during a blood drive (approximately 475 mL, or about 1 pint), your body typically replaces the donated plasma within 24 hours, but it takes about 4 to 6 weeks to replace the blood cells. This restricts the frequency with which donors can contribute their blood. The process by which this replacement occurs is called hemopoiesis, or hematopoiesis (from the Greek root haima- = “blood”; -poiesis = “production”).
Sites of Hemopoiesis
Prior to birth, hemopoiesis occurs in a number of tissues, beginning with the yolk sac of the developing embryo, and continuing in the fetal liver, spleen, lymphatic tissue, and eventually the red bone marrow. Following birth, most hemopoiesis occurs in the red marrow, a connective tissue within the spaces of spongy (cancellous) bone tissue. In children, hemopoiesis can occur in the medullary cavity of long bones; in adults, the process is largely restricted to the cranial and pelvic bones, the vertebrae, the sternum, and the proximal epiphyses of the femur and humerus.
Differentiation of Formed Elements from Stem Cells
All formed elements arise from stem cells of the red bone marrow. Recall that stem cells undergo mitosis plus cytokinesis (cellular division) to give rise to new daughter cells: One of these remains a stem cell and the other differentiates into one of any number of diverse cell types.
Hemopoietic Growth Factors
Development from stem cells to precursor cells to mature cells is again initiated by hemopoietic growth factors. The growth factor responsible for the production of erythrocytes is erythropoietin (EPO). Erythropoietin is a hormone secreted by the kidneys in response to low oxygen levels. Some athletes use synthetic EPO as a performance-enhancing drug (called blood doping) to increase RBC counts and subsequently increase oxygen delivery to tissues throughout the body. EPO is a banned substance in most organized sports, but it is also used medically in the treatment of certain anemia, specifically those triggered by certain types of cancer, and other disorders in which increased erythrocyte counts and oxygen levels are desirable.
Part 3: Erythrocytes
Erythrocytes
The erythrocyte, commonly known as a red blood cell (or RBC), is by far the most common formed element: A single drop of blood contains millions of erythrocytes and just thousands of leukocytes. Specifically, males have about 5.4 million erythrocytes per microlitre (µL) of blood, and females have approximately 4.8 million per µL. In fact, erythrocytes are estimated to make up about 25% of all cells in the body. As you can imagine, they are quite small cells, with a mean diameter of only about 7–8 micrometres (µm) (Table 2). The primary functions of erythrocytes are to pick up inhaled oxygen from the lungs and transport it to the body’s tissues, and to pick up some (about 24%) of the carbon dioxide waste produced at the tissues and transport it to the lungs for exhalation. Erythrocytes remain within the vascular network. Although leukocytes typically leave the blood vessels to perform their defensive functions, movement of erythrocytes from the blood vessels is abnormal. Their unique structure enables them to change their shape to squeeze through capillaries.
Erythrocytes are biconcave disks; that is, they are plump at their periphery and very thin in the centre (Figure 3). Since they lack most organelles, there is more interior space for the presence of the hemoglobin molecules that transport gases. The biconcave shape also provides a greater surface area across which gas exchange can occur, relative to its volume; a sphere of a similar diameter would have a lower surface area-to-volume ratio. In the capillaries, the oxygen carried by the erythrocytes can diffuse into the plasma and then through the capillary walls to reach the cells, whereas some of the carbon dioxide produced by the cells as a waste product diffuses into the capillaries to be picked up by the erythrocytes. Capillary beds are extremely narrow, slowing the passage of the erythrocytes and providing an extended opportunity for gas exchange to occur. However, the space within capillaries can be so minute that, despite their own small size, erythrocytes may have to fold in on themselves if they are to make their way through.
Hemoglobin
Hemoglobin is a large molecule made up of proteins and iron. It consists of four folded chains of a protein called globin, designated alpha 1 and 2, and beta 1 and 2 (Figure 4a). Each of these globin molecules is bound to a red pigment molecule called heme, which contains an ion of iron (Fe2+) (Figure 4b).
Each iron ion in the heme can bind to one oxygen molecule; therefore, each hemoglobin molecule can transport four oxygen molecules. An individual erythrocyte may contain about 300 million hemoglobin molecules, and therefore can bind to and transport up to 1.2 billion oxygen molecules. These oxygen molecules come from the air we breathe; they diffuse across the respiratory membrane in the lungs, then into erythrocytes where they can bind to hemoglobin and be carried back to the heart and then to the rest of the body.
Carbon dioxide enters the bloodstream at the tissue level, and (among other transport mechanisms) can bind to one end of a subunit of hemoglobin. From the capillaries, the carbon dioxide is carried back to the lungs, where it is released.
Changes in the levels of erythrocytes can have significant effects on the body’s ability to effectively deliver oxygen to the tissues. Ineffective hematopoiesis results in insufficient numbers of erythrocytes and results in one of several forms of anemia. In patients with insufficient hemoglobin, the tissues may not receive sufficient oxygen, resulting in another form of anemia An overproduction of erythrocytes produces a condition called polycythemia and is detected in a patient’s elevated hematocrit. The primary drawback with polycythemia is not a failure to directly deliver enough oxygen to the tissues, but rather the increased viscosity of the blood, which makes it more difficult for the heart to circulate the blood.
It can occur transiently in a person who is dehydrated; when water intake is inadequate or water losses are excessive, the plasma volume falls. As a result, the hematocrit rises. A mild form of polycythemia is chronic (but normal) in people living at high altitudes; the decreased oxygen availability at high altitudes causes erythropoietin release, resulting in increased erythrocyte production (discussed earlier in this chapter). Some elite athletes train at high elevations specifically to induce this phenomenon. Finally, a type of bone marrow disease called polycythemia vera (from the Greek vera = “true”) causes an excessive production of immature erythrocytes. Polycythemia vera can dangerously elevate the viscosity of blood, raising blood pressure and making it more difficult for the heart to pump blood throughout the body. It is a relatively rare disease that occurs more often in men than women and is more likely to be present in elderly patients those over 60 years of age.
Part 4: Leukocytes
The leukocyte, commonly known as a white blood cell (or WBC), is a major component of the body’s defenses against disease. Leukocytes protect the body against invading microorganisms as well as genetically transformed body cells that are potentially cancerous. They also clean up extracellular debris and can signal and enhance the healing and repair process.
Characteristics of Leukocytes
Although leukocytes and erythrocytes both originate from hematopoietic stem cells in the bone marrow (Figure 2), they are very different from each other in many significant ways. For instance, leukocytes are far less numerous than erythrocytes. Typically, there are only 5000 to 10,000 leukocytes per microlitre (µl) of blood compared to the roughly 5 million erythrocytes. They are also larger than erythrocytes, possessing a nucleus and organelles while erythrocytes expel these structures early in development. Although there is just one type of erythrocyte, there are many types of leukocytes. Most of these leukocytes have a much shorter lifespan than that of erythrocytes, some as short as a few hours or even a few minutes in the case of acute infection.
One of the most distinctive characteristics of leukocytes is their movement. Whereas erythrocytes spend their days circulating within the blood vessels, leukocytes routinely leave the bloodstream to perform their defensive functions in the body’s tissues. For leukocytes, the vascular network is simply a highway they travel and soon exit to reach their true destination. When they arrive, they are often given distinct names, such as macrophage or microglia, depending on their function.
Once they have exited the capillaries, some leukocytes will take up fixed positions in lymphatic tissue, bone marrow, the spleen, the thymus, or other organs. Others will move about through the tissue spaces (diapedesis), very much like amoebas, continuously extending their plasma membranes, sometimes wandering freely, and sometimes moving toward the direction in which they are drawn by chemical signals. This attracting of leukocytes occurs because of positive chemotaxis (literally “movement in response to chemicals”), a phenomenon in which injured or infected cells and nearby leukocytes emit the equivalent of a chemical “911” call, attracting more leukocytes to the site. In medicine, determining the quantity of the different leukocytes can provide pertinent clinical information. These differential counts of the types and percentages of leukocytes present in a sample are often key indicators in making a diagnosis and selecting a treatment.
Classification of Leukocytes
When scientists first began to observe stained blood slides, it quickly became evident that leukocytes could be divided into two groups, according to whether their cytoplasm contained highly visible granules:
- Granular leukocytes contain abundant granules within the cytoplasm. They include neutrophils, eosinophils, and basophils.
- While granules are not totally lacking in agranular leukocytes, they are far fewer and less obvious. Agranular leukocytes include monocytes, which mature into phagocytic macrophages, and lymphocytes, which arise from the lymphoid stem cell line.
Granular Leukocytes: We will consider the granular leukocytes in order from most common to least common. All of these are produced in the red bone marrow and have a short lifespan of hours to days. They typically have a lobed nucleus and are classified according to which type of stain best highlights their granules (Figure 5).
The most common of all the leukocytes, neutrophils will normally comprise 50–70 percent of total leukocyte count. They are called neutrophils because their granules show up most clearly with stains that are chemically neutral (neither acidic nor basic). The nucleus has a distinct lobed appearance and may have two to five lobes, the number increasing with the age of the cell.
Neutrophils are rapid responders to the site of infection and are efficient phagocytes with a preference for bacteria. Their granules include anti-microbial substances like lysozyme, an enzyme capable of lysing, or breaking down, bacterial cell walls, and defensins, proteins that bind to and puncture bacterial and fungal plasma membranes causing the cell contents to leak out. Abnormally high counts of neutrophils indicate infection and/or inflammation, particularly triggered by bacteria, but are also found in burn patients and others experiencing unusual stress. A burn injury increases the proliferation of neutrophils in order to fight off infection that can result from the destruction of the barrier of the skin. Low counts may be caused by drug toxicity and other disorders, and may increase an individual’s susceptibility to infection.
Eosinophils typically represent 2–4 percent of total leukocyte count. The granules of eosinophils stain best with an acidic stain known as eosin. The granules of eosinophils include antihistamine molecules, which counteract the activities of histamines, inflammatory chemicals produced by basophils and other inflammatory cells. Some eosinophil granules contain molecules toxic to parasitic worms, which can enter the body either through the skin or when an individual consumes raw or undercooked fish or meat. Eosinophils are also capable of phagocytosis. High counts of eosinophils are typical of patients experiencing allergies, parasitic worm infestations, and some autoimmune diseases. Low counts may be due to drug toxicity and stress.
Basophils are the least common leukocyte, typically comprising less than one percent of the total leukocyte count. The granules of basophils stain best with basic (alkaline) stains. In general, basophils intensify the inflammatory response. The granules of basophils release histamines, which contribute to inflammation, and heparin, which opposes blood clotting. High counts of basophils are associated with allergies, parasitic infections, and hypothyroidism. Low counts are associated with pregnancy, stress, and hyperthyroidism.
Agranular Leukocytes: Agranular leukocytes contain smaller, less-visible granules in their cytoplasm than do granular leukocytes. The nucleus is simple in shape, sometimes with an indentation but without distinct lobes. There are two major types of agranulocytes: lymphocytes and monocytes.
Lymphocytes are the primary cells of adaptive immune responses (Table 3). They are the only formed element of blood that arises from lymphoid stem cells. Although they initially form in the bone marrow, much of their subsequent development and reproduction occurs in the lymphatic tissues. Lymphocytes are the second most common type of leukocyte, accounting for about 20–30 percent of all leukocytes, and are essential for the immune response.
Abnormally high lymphocyte counts are characteristic of viral infections as well as some types of cancer. Abnormally low lymphocyte counts are characteristic of prolonged (chronic) illness or immunosuppression, including that caused by HIV infection and drug therapies that often involve steroids.
The two basic types of lymphocytes, B cells and T cells (also called B lymphocytes and T lymphocytes), are identical morphologically, with a large, often spherical, central nucleus surrounded by a thin layer of cytoplasm. They are distinguished from each other by their surface protein markers as well as by the molecules they secrete. B cells mature in red bone marrow and T cells mature in the thymus. B cells and T cells are found in many parts of the body, circulating in the bloodstream and lymph, and residing in secondary lymphoid organs, including the spleen and lymph nodes. The human body contains approximately 1012 lymphocytes. Both B cells and T cells play prominent roles in defending the body against specific pathogens (disease-causing microorganisms) and are involved in adaptive (specific) immunity (to be discussed in detail in the Lymphatic system and Immunity unit).
One form of B cells, when activated, become plasma cells. These cells differ in morphology from standard B and T cells in that they contain a large amount of cytoplasm packed with the protein-synthesizing machinery known as rough endoplasmic reticulum. A plasma cell forms from a naïve B cell with the purpose of producing antibodies or immunoglobulins. An antibody is any of the group of proteins that binds specifically to pathogen- associated molecules known as antigens. An antigen is a chemical structure on the surface of a pathogen, or the soluble product of a pathogen (ie. a toxin), that binds to T or B lymphocyte receptors. Once activated by binding to antigen, B cells differentiate into plasma cells and begin producing and secreting large quantities of antigen specific antibodies. These travel through the body targeting pathogens or toxins for destruction using mechanisms that will be discussed later in the chapter. This is also referred to as humoral (body fluid) immunity.
The T cell, on the other hand, does not secrete antibody but performs a variety of functions in the adaptive immune response. Different T cell types have the ability to either secrete soluble factors that communicate with and activate other cells of the adaptive immune response or destroy cells infected with intracellular pathogens. Therefore, T cells provide cell-mediated immunity by physically attacking foreign or diseased cells. Both B and T cells can differentiate to memory cells that form after exposure to a pathogen and mount rapid responses upon subsequent exposures. Unlike other leukocytes, memory cells live for many years. The roles of T and B lymphocytes in the adaptive immune response will be discussed further on.
| Type of Lymphocyte | Primary Function |
|---|---|
| B Lymphocyte | Generates diverse antibodies
Memory for subsequent infections |
| T Lymphocyte | Secretes chemical messengers
Cytotoxic activity Memory for subsequent infections |
| Natural Killer Cell | Destroys virally infected cells |
Another lymphocyte is the natural killer cell, which rather than participate in the adaptive immune response like B and T lymphocytes, forms part of the innate immune response. Further details about the function of NK cells are beyond the scope of this course.
Monocytes originate from myeloid stem cells. They normally represent 2–8 percent of the total leukocyte count. Macrophages are monocytes that have left the circulation and phagocytize debris, foreign pathogens, and many dead, worn out, or damaged cells, including red blood cells. Macrophages also release antimicrobial defensins and chemotactic chemicals that attract other leukocytes to the site of an infection. Some macrophages occupy fixed locations, whereas others wander through the tissue fluid.
Abnormally high counts of monocytes are associated with certain viral or fungal infections, tuberculosis, and some forms of leukemia and other chronic diseases. Abnormally low counts are typically caused by suppression of the bone marrow due to drugs or infiltration by tumor cells.
Part 5: Platelets
Platelets
Platelets are essential for the repair of blood vessels when damage to them has occurred; they also provide growth factors for healing and repair. You may occasionally see platelets referred to as thrombocytes, but because this name suggests they are a type of cell, it is not accurate. A platelet is not a cell but rather a fragment of the cytoplasm of a cell called a megakaryocyte that is surrounded by a plasma membrane. Megakaryocytes are descended from myeloid stem cells and are large, typically 50–100 µm in diameter, and contain an enlarged, lobed nucleus. These remain within bone marrow tissue (Figure 6) and ultimately release into the circulation thousands of cytoplasmic fragments, each enclosed by a bit of plasma membrane. These enclosed fragments are platelets. Each megakaryocyte releases 2000–3000 platelets during its lifespan. Following platelet release, megakaryocyte remnants, which are little more than a cell nucleus, are consumed by macrophages (macrophages are discussed further in the Immunity unit).
Platelets are relatively small, 2–4 µm in diameter, but numerous, with typically 150,000–160,000 per µL of blood. After entering the circulation, approximately one-third migrate to the spleen for storage for later release in response to any rupture in a blood vessel. They then become activated to perform their primary function, which is to limit blood loss. Platelets remain only about 10 days, then are phagocytized by macrophages. Platelets are critical to hemostasis, the stoppage of blood flow following damage to a vessel. They also secrete a variety of growth factors essential for growth and repair of tissue, particularly connective tissue. Infusions of concentrated platelets are now being used in some therapies to stimulate healing.
Disorders of Platelets
Thrombocytosis is a condition in which there are too many platelets. This may trigger formation of unwanted blood clots (thrombosis), a potentially fatal disorder. If there is an insufficient number of platelets, called thrombocytopenia, blood may not clot properly, and excessive bleeding may result.
Part 6: Hemostasis
Platelets are key players in hemostasis, the process by which the body seals a ruptured blood vessel and prevents further loss of blood. Although rupture of larger vessels usually requires medical intervention, hemostasis is quite effective in dealing with small, simple wounds. There are three steps to the process: vascular spasm, the formation of a platelet plug, and coagulation (blood clotting) (Figure 7). Failure of any of these steps will result in hemorrhage – excessive bleeding.
Vascular Spasm
When a vessel is severed or punctured, or when the wall of a vessel is damaged, vascular spasm occurs. In vascular spasm, the smooth muscle in the walls of the vessel contracts dramatically. Small blood vessels have smooth muscle arranged in circular layers; larger vessels also have longitudinal layers of smooth muscle. The circular layers tend to constrict the flow of blood, whereas the longitudinal layers, when present, draw the vessel back into the surrounding tissue, often making it more difficult for a surgeon to locate, clamp, and tie off a severed vessel. The vascular spasm response is believed to be triggered by several chemicals called endothelins that are released by vessel-lining cells and by pain receptors in response to vessel injury. This phenomenon typically lasts for up to 30 minutes, although it can last for hours.
Formation of the Platelet Plug
In the second step, platelets, which normally float free in the plasma, encounter the area of vessel rupture with the exposed underlying connective tissue and collagenous fibres. The platelets begin to clump together, become spiked and sticky, and bind to the exposed collagen and endothelial lining. This process is assisted by a glycoprotein in the blood plasma called von Willebrand factor, which helps stabilize the growing platelet plug. As platelets collect, they simultaneously release chemicals from their granules into the plasma that further contribute to hemostasis. Among the substances released by the platelets are:
- Adenosine diphosphate (ADP), which helps additional platelets to adhere to the injury site, reinforcing and expanding the platelet plug
- Serotonin, which maintains vasoconstriction
- Prostaglandins and phospholipids, which also maintain vasoconstriction and help to activate further clotting chemicals
A platelet plug can temporarily seal a small opening in a blood vessel. Plug formation, in essence, buys the body time while more sophisticated and durable repairs are being made. In a similar manner, even modern naval warships still carry an assortment of wooden plugs to temporarily repair small breaches in their hulls until permanent repairs can be made.
Coagulation
Those more sophisticated and more durable repairs are collectively called coagulation, the formation of a blood clot. The process is sometimes characterized as a cascade, because one event prompts the next as in a multi-level waterfall. The result is the production of a gelatinous but robust clot made up of a mesh of fibrin – an insoluble filamentous protein derived from the blood plasma protein fibrinogen – in which platelets and blood cells are trapped.
Clotting Factors Involved in Coagulation
In the coagulation cascade, chemicals called clotting factors (or coagulation factors) prompt reactions that activate still more coagulation factors (Figure 6b). The process is complex, but is initiated along two basic pathways: the extrinsic pathway which normally is triggered by tissue damage, and the intrinsic pathway which begins in the bloodstream and is triggered by damage to the wall of the vessel.
Both of these merge into a third pathway, referred to as the common pathway (Figure 6b). All three pathways are dependent upon the 12 known clotting factors, including Ca2+ and vitamin K. Clotting factors are secreted primarily by the liver and the platelets. The liver requires the fat-soluble vitamin K to produce many of them. Vitamin K (along with biotin and folate) is somewhat unusual among vitamins in that it is not only consumed in the diet but is also synthesized by bacteria residing in the large intestine. The 12 clotting factors are numbered I through XIII according to the order of their discovery. Factor VI was once believed to be a distinct clotting factor, but is now thought to be identical to factor V. Rather than renumber the other factors, factor VI was allowed to remain as a placeholder and also a reminder that knowledge changes over time.
Extrinsic Pathway: The quicker responding and more direct extrinsic pathway (also known as the tissue factor pathway) begins when damage occurs to the surrounding tissues, such as in a traumatic injury. Upon contact with blood plasma, the damaged extravascular cells, which are extrinsic to the bloodstream, sets off a cascade of clotting factors (Figure 6), culminating in the activation of Factor X which activates the common pathway discussed below. The events in the extrinsic pathway are completed in a matter of seconds.
Intrinsic Pathway: The intrinsic pathway (also known as the contact activation pathway) is longer and more complex. In this case, the clotting factors involved are all intrinsic to (present within) the bloodstream. The pathway can be prompted by damage to the tissues, or resulting from internal factors such as arterial disease. Like the extrinsic pathway, a series of clotting factors are activated, culminating with the activation of Factor X (Figure 6) which activates the common pathway. The events in the intrinsic pathway are completed in a few minutes.
Common Pathway: Both the intrinsic and extrinsic pathways lead to the common pathway, in which fibrin is produced to seal off the vessel. Once factor X has been activated by either the intrinsic or extrinsic pathway, the enzyme prothrombinase converts prothrombin into the active enzyme thrombin. (Note that if the enzyme thrombin were not normally in an inactive form, clots would form spontaneously, a condition not consistent with life.) Then, thrombin converts fibrinogen into insoluble fibrin protein strands. Factor XIII then stabilizes the fibrin clot.
The stabilized clot is acted upon by contractile proteins within the platelets. As these proteins contract, they pull on the fibrin threads, bringing the edges of the clot more tightly together, somewhat as we do when tightening loose shoelaces. This process also wrings out of the clot a small amount of fluid called serum, which is blood plasma without its clotting factors.
Fibrinolysis
To restore normal blood flow as the vessel heals, the clot must eventually be removed. Fibrinolysis is the gradual degradation of the clot. Again, there is a fairly complicated series of reactions that involves factor XII and protein-catabolizing enzymes. During this process, the inactive protein plasminogen is converted into the active plasmin, which gradually breaks down the fibrin of the clot. Additionally, bradykinin, a vasodilator, is released, reversing the effects of the serotonin and prostaglandins from the platelets. This allows the smooth muscle in the walls of the vessels to relax and helps to restore the circulation.
Plasma Anticoagulants
An anticoagulant is any substance that opposes coagulation. Several circulating plasma anticoagulants play a role in limiting the coagulation process to the region of injury and restoring a normal, clot-free condition of blood. For instance, a cluster of proteins collectively referred to as the protein C system inactivates clotting factors involved in the intrinsic pathway. Antithrombin inactivates factor X and opposes the conversion of prothrombin (factor II) to thrombin in the common pathway. Basophils release heparin, a short-acting anticoagulant that also opposes prothrombin. Heparin is also found on the surfaces of cells lining the blood vessels. A pharmaceutical form of heparin is often administered therapeutically, for example, in surgical patients at risk for blood clots.
Among the many known biochemical activities of aspirin is its role as an anticoagulant. Aspirin (acetylsalicylic acid) is very effective at inhibiting the aggregation of platelets. It is routinely administered during a heart attack or stroke to reduce the adverse effects. Physicians sometimes recommend that patients at risk for cardiovascular disease take a low dose of aspirin on a daily basis as a preventive measure. However, aspirin can also lead to serious side effects, including increasing the risk of ulcers. A patient is well advised to consult a physician before beginning any aspirin regimen.
Disorders of Clotting
Either an insufficient or an excessive production of platelets can lead to severe disease or death. As discussed earlier, an insufficient number of platelets, called thrombocytopenia, typically results in the inability of blood to form clots. This can lead to excessive bleeding, even from minor wounds.
Another reason for failure of the blood to clot is the inadequate production of functional amounts of one or more clotting factors. This is the case in the genetic disorder hemophilia, which is actually a group of related disorders, the most common of which is hemophilia A, accounting for approximately 80% of cases. This disorder results in the inability to synthesize sufficient quantities of factor VIII. Regular infusions of clotting factors isolated from healthy donors can help prevent bleeding in hemophiliac patients. At some point, genetic therapy may become a viable option.
A thrombus (plural = thrombi) is an aggregation of platelets, erythrocytes, and even WBCs typically trapped within a mass of fibrin strands. While the formation of a clot is normal following the hemostatic mechanism just described, thrombi can form within an intact or only slightly damaged blood vessel. A thrombus can seriously impede blood flow to or from a region and will cause a local increase in blood pressure. If flow is to be maintained, the heart will need to generate a greater pressure to overcome the resistance.
When a portion of a thrombus breaks free from the vessel wall and enters the circulation, it is referred to as an embolus. An embolus that is carried through the bloodstream can be large enough to block a vessel critical to a major organ. When it becomes trapped, an embolus is called an embolism. In the heart, brain, or lungs, an embolism may accordingly cause a heart attack, a stroke, or a pulmonary embolism. These are medical emergencies.
A class of drugs collectively known as thrombolytic agents can help speed up the degradation of an abnormal clot. If a thrombolytic agent is administered to a patient within 3 hours following a thrombotic stroke, the patient’s prognosis improves significantly. However, some strokes are not caused by thrombi, but by hemorrhage. Thus, the cause must be determined before treatment begins. Tissue plasminogen activator is an enzyme that catalyzes the conversion of plasminogen to plasmin, the primary enzyme that breaks down clots. It is released naturally by endothelial cells but is also used in clinical medicine as a thrombolytic agent. New research is progressing using compounds isolated from the venom of some species of snakes, particularly vipers and cobras, which may also have therapeutic value as thrombolytic agents.
Part 1: An Overview of Blood
Part 2: Production of the Formed Elements
Part 3: Erythrocytes
Part 4: Leukocytes
Part 5: Platelets
Part 6: Hemostasis
(Also, red blood cell) mature myeloid blood cell that is composed mostly of hemoglobin and functions primarily in the transportation of oxygen and carbon dioxide.
(also, white blood cell) colorless, nucleated blood cell, the chief function of which is to protect the body from disease.
(Also, thrombocytes) one of the formed elements of blood that consists of cell fragments broken off from megakaryocytes.
In blood, the liquid extracellular matrix composed mostly of water that circulates the formed elements and dissolved materials throughout the cardiovascular system.
Alkaline solution produced by the liver and important for the emulsification of lipids.
Steady, dynamic state of body systems (specifically of extracellular fluid) that living organisms maintain.
(also, packed cell volume) volume percentage of erythrocytes in a sample of centrifuged blood.
Oxygen-carrying compound in erythrocytes.
A measure of the acidity or alkalinity or a solution, measured as the negative logarithm of the hydrogen ion (H+) concentration of a solution.
Most abundant plasma protein, accounting for most of the osmotic pressure of plasma.
Heterogeneous group of plasma proteins that includes transport proteins, clotting factors, immune proteins, and others.
Plasma protein produced in the liver and involved in blood clotting.
(Also, hematopoiesis) production of the formed elements of blood.
(Also, cancellous bone) trabeculated osseous tissue that supports shifts in weight distribution.
Wide section at each end of a long bone; filled with spongy bone and red marrow (plural = epiphyses).
Bone in the upper leg.
Bone in the upper arm.
Connective tissue in the interior cavity of a bone where hematopoiesis takes place.
Glycoprotein that triggers the bone marrow to produce RBCs; secreted by the kidney in response to low oxygen levels.
Concave (dipping in) on both sides.
Deficiency of red blood cells or hemoglobin, often linked to iron deficiency.
Elevated level of hemoglobin, whether adaptive or pathological.
(In cells) cell’s central organelle; contains the cell’s DNA (plural= nuclei)
(Also, emigration) process by which leukocytes squeeze through adjacent cells in a blood vessel wall to enter tissues.
Digestive enzyme with bactericidal properties.
Antimicrobial proteins released from neutrophils and macrophages that create openings in the plasma membranes to kill cells.
Vasoactive (active on blood vessels) mediator in granules of mast cells and is the primary cause of allergies and anaphylactic shock.
Clinically abnormal, elevated level of thyroid hormone in the blood; characterized by an increased metabolic rate, excess body heat, sweating, diarrhea, weight loss, and increased heart rate.
Cell that is oligo-, multi-, or pleuripotent that has the ability to produce additional stem cells rather than becoming further specialized.
Lymphocytes that act by differentiating into an antibody-secreting plasma cell.
Lymphocyte that acts by secreting molecules that regulate the immune system or by causing the destruction of foreign cells, viruses, and cancer cells.
Cytotoxic lymphocyte of innate immune response.
Precursor to macrophages and dendritic cells seen in the blood.
Ameboid (irregular outline with peripheral projections) phagocyte found in several tissues throughout the body.
Initial step in hemostasis, in which the smooth muscle in the walls of the ruptured or damaged blood vessel contracts.
Hormones that cause vasoconstriction or release of NO.
Proteins with short polysaccharide chains attached.
Accumulation and adhesion of platelets at the site of blood vessel injury.
Formation of a blood clot; part of the process of hemostasis.
Insoluble, filamentous protein that forms the structure of a blood clot.
(Also, coagulation factors) group of 12 identified substances active in coagulation.
Protein thromboplastin, which initiates the extrinsic pathway when released in response to tissue damage.
Enzyme essential for the final steps in formation of a fibrin clot.
Blood plasma that does not contain clotting factors.
Gradual degradation of a blood clot.
Substance such as heparin that opposes coagulation.
Genetic disorder characterized by inadequate synthesis of clotting factors.