Chapter17 The Cardiovascular System: Blood

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 defence, distribution of heat, and maintenance of homeostasis.

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 RBCs, 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 17.1). Because the heaviest elements in blood are the erythrocytes, these settle at the very bottom of the hematocrit tube. Located above the erythrocytes is a pale, thin layer composed of the remaining formed elements of blood. These are the WBCs, 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 percent 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 percent of a sample is erythrocytes. The hematocrit of any one sample can vary significantly, from about 36 to 50 percent, according to gender 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 WBCs and platelets, is extremely small, so it is not normally considered with the hematocrit. So the mean plasma percentage is the percentage 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 duskier red. This is because hemoglobin is a pigment that changes colour depending on 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 the presence of the plasma proteins and formed elements 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, compared to 37°C 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; however, it 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 actually help regulate pH.

Blood constitutes approximately 8 percent of adult body weight. Adult males typically average about 5 to 6 L of blood. Females average 4–5 L.

Blood Plasma

Like other fluids in the body, plasma is composed primarily of water: In fact, it is about 92 percent 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.

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.

Throughout adulthood, the liver and spleen maintain their ability to generate the formed elements. This process is referred to as extramedullary hemopoiesis (meaning hemopoiesis outside the medullary cavity of adult bones).

When a disease such as bone cancer destroys the bone marrow, causing hemopoiesis to fail, extramedullary hemopoiesis may be initiated.

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. Stem cells may be viewed as occupying a hierarchal system, with some loss of the ability to diversify at each step. The totipotent stem cell is the zygote, or fertilized egg. The totipotent (multipotent) stem cell gives rise to all cells of the human body. The next level is the pluripotent stem cell, which gives rise to multiple types of cells of the body and some of the supporting fetal membranes.

Beneath this level, the mesenchymal cell is a stem cell that develops only into types of connective tissue, including fibrous connective tissue, bone, cartilage, and blood, but not epithelium, muscle, and nervous tissue. One step lower on the hierarchy of stem cells is the hematopoietic stem cell, or hemocytoblast. All of the formed elements of blood originate from this specific type of cell.

Hemopoiesis begins when the hematopoietic stem cell is exposed to appropriate chemical stimuli collectively called hemopoietic growth factors, which prompt it to divide and differentiate. One daughter cell remains a hematopoietic stem cell, allowing hemopoiesis to continue. The other daughter cell becomes either of two types of more specialized stem cells (Figure 17.2):

• • Lymphoid stem cells give rise to a class of leukocytes known as lymphocytes, which include the various T cells, B cells, and natural killer (NK) cells, all of which function in immunity. However, hemopoiesis of lymphocytes progresses somewhat differently from the process for the other formed elements. In brief, lymphoid stem cells quickly migrate from the bone marrow to lymphatic tissues, including the lymph nodes, spleen, and thymus, where their production and differentiation continues. B cells are so named because they mature in the bone marrow, while T cells mature in the thymus.
• • Myeloid stem cells give rise to all the other formed elements, including the erythrocytes; megakaryocytes that produce platelets; and a myeloblast lineage that gives rise to monocytes and three forms of granular leukocytes: neutrophils, eosinophils, and basophils.

Lymphoid and myeloid stem cells do not immediately divide and differentiate into mature formed elements. As you can see in Figure 17.2, there are several intermediate stages of precursor cells (literally, forerunner cells), many of which can be recognized by their names, which have the suffix -blast. For instance, megakaryoblasts are the precursors of megakaryocytes, and proerythroblasts become reticulocytes, which eject their nucleus and most other organelles before maturing into erythrocytes.

Hemopoietic Growth Factors

Development from stem cells to precursor cells to mature cells is again initiated by hemopoietic growth factors. These include the following:

• • Erythropoietin (EPO) is a glycoprotein hormone secreted by the interstitial fibroblast cells of the kidneys in response to low oxygen levels. It prompts the production of erythrocytes. 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.
• • Thrombopoietin, another glycoprotein hormone, is produced by the liver and kidneys. It triggers the development of megakaryocytes into platelets.
• • Cytokines are glycoproteins secreted by a wide variety of cells, including red bone marrow, leukocytes, macrophages, fibroblasts, and endothelial cells. They act locally as autocrine or paracrine factors, stimulating the proliferation of progenitor cells and helping stimulate both nonspecific and specific resistance to disease. There are two major subtypes of cytokines known as colony-stimulating factors and interleukins.
  • ◦ Colony-stimulating factors (CSFs) are glycoproteins that act locally, as autocrine or paracrine factors. Some trigger the differentiation of myeloblasts into granular leukocytes—namely, neutrophils, eosinophils, and basophils. These are referred to as granulocyte CSFs. A different CSF induces the production of monocytes, called monocyte CSFs. Both granulocytes and monocytes are stimulated by GM-CSF; granulocytes, monocytes, platelets, and erythrocytes are stimulated by multi-CSF. Synthetic forms of these hormones are often administered to patients with various forms of cancer who are receiving chemotherapy to revive their WBC counts.
  • ◦ Interleukins are another class of cytokine signalling molecules important in hemopoiesis. They were initially thought to be secreted uniquely by leukocytes and to communicate only with other leukocytes and were named accordingly but are now known to be produced by a variety of cells including bone marrow and endothelium. Researchers now suspect that interleukins may play other roles in body functioning, including differentiation and maturation of cells, producing immunity and inflammation. To date, more than a dozen interleukins have been identified, with others likely to follow. They are generally numbered IL-1, IL-2, IL-3, and so on.

Shape and Structure of Erythrocytes

As an erythrocyte matures in the red bone marrow, it extrudes its nucleus and most of its other organelles. During the first day or two that it is in the circulation, an immature erythrocyte, known as a reticulocyte, will still typically contain remnants of organelles. Reticulocytes should comprise approximately 1 to 2 percent of the erythrocyte count and provide a rough estimate of the rate of RBC production, with abnormally low or high rates indicating deviations in the production of these cells. These remnants, primarily of networks (reticulum) of ribosomes, are quickly shed, however, and mature, circulating erythrocytes have few internal cellular structural components. Lacking mitochondria, for example, they rely on anaerobic respiration. This means that they do not utilize any of the oxygen they are transporting, so they can deliver it all to the tissues. They also lack endoplasmic reticula and do not synthesize proteins. Erythrocytes do, however, contain some structural proteins that help the blood cells maintain their unique structure and enable them to change their shape to squeeze through capillaries. This includes the protein spectrin, a cytoskeletal protein element.

Erythrocytes are biconcave disks; that is, they are plump at their periphery and very thin in the centre (Figure 17.3). Since they lack most organelles, there is more interior space for the presence of the hemoglobin molecules that, as you will see shortly, 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 ratio of surface area to volume. 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. Fortunately, their structural proteins like spectrin are flexible, allowing them to bend over themselves to a surprising degree, then spring back again when they enter a wider vessel. In wider vessels, erythrocytes may stack up much like a roll of coins, forming a rouleaux.

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 17.4a). Each of these globin molecules is bound to a red pigment molecule called heme, which contains an ion of iron (Fe²⁺; Figure 17.4b).

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 (see Figure 17.4b).

In the lungs, hemoglobin picks up oxygen, which binds to the iron ions, forming oxyhemoglobin. The bright-red, oxygenated hemoglobin travels to the body tissues, where it releases some of the oxygen molecules, becoming darker-red deoxyhemoglobin, sometimes referred to as reduced hemoglobin. Oxygen release depends on the need for oxygen in the surrounding tissues, so hemoglobin rarely, if ever, leaves all of its oxygen behind. In the capillaries, carbon dioxide enters the bloodstream. About 76 percent dissolves in the plasma, some of it remaining as dissolved CO₂ and the remainder forming bicarbonate ion. About 23 to 24 percent of it binds to the amino acids in hemoglobin, forming a molecule known as carbaminohemoglobin. From the capillaries, the hemoglobin carries carbon dioxide back to the lungs, where it releases it in exchange for oxygen.

Changes in the levels of RBCs can have significant effects on the body’s ability to effectively deliver oxygen to the tissues. Ineffective hematopoiesis results in insufficient numbers of RBCs and results in one of several forms of anemia. An overproduction of RBCs produces a condition called polycythemia. 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.

In patients with insufficient hemoglobin, the tissues may not receive sufficient oxygen, resulting in another form of anemia. In determining oxygenation of tissues, the value of greatest interest in health care is the percent saturation—that is, the percentage of hemoglobin sites occupied by oxygen in a patient’s blood. Clinically this value is commonly referred to simply as “percent sat.”

The kidneys filter about 180 L of blood in an average adult each day, or about 20 percent of the total resting volume, and thus serve as ideal sites for receptors that determine oxygen saturation. In response to hypoxemia, less oxygen will exit the vessels supplying the kidney, resulting in hypoxia (low oxygen concentration) in the tissue fluid of the kidney, where oxygen concentration is actually monitored. Interstitial fibroblasts within the kidney secrete EPO, thereby increasing erythrocyte production and restoring oxygen levels. In a classic negative-feedback loop, as oxygen saturation rises, EPO secretion falls, and vice versa, thereby maintaining homeostasis.

Populations dwelling at high elevations, with inherently lower levels of oxygen in the atmosphere, naturally maintain a hematocrit higher than people living at sea level. Consequently, people travelling to high elevations may experience symptoms of hypoxemia, such as fatigue, headache, and shortness of breath, for a few days after their arrival. In response to the hypoxemia, the kidneys secrete EPO to step up the production of erythrocytes until homeostasis is achieved once again. To avoid the symptoms of hypoxemia, or altitude sickness, mountain climbers typically rest for several days to a week or more at a series of camps situated at increasing elevations to allow EPO levels and, consequently, erythrocyte counts to rise. When climbing the tallest peaks, such as Mt. Everest and K2 in the Himalayas, many mountain climbers rely on bottled oxygen as they near the summit.

Life Cycle of Erythrocytes

Production of erythrocytes in the marrow occurs at the staggering rate of more than 2 million cells per second. For this production to occur, a number of raw materials must be present in adequate amounts. These include the same nutrients that are essential to the production and maintenance of any cell, such as glucose, lipids, and amino acids. However, erythrocyte production also requires several trace elements:

• • Iron. We have said that each heme group in a hemoglobin molecule contains an ion of the trace mineral iron. On average, less than 20 percent of the iron we consume is absorbed. Heme iron, from animal foods such as meat, poultry, and fish, is absorbed more efficiently than nonheme iron from plant foods. Upon absorption, iron becomes part of the body’s total iron pool. The bone marrow, liver, and spleen can store iron in the protein compounds ferritin and hemosiderin. Ferroportin transports the iron across the intestinal cell plasma membranes and from its storage sites into tissue fluid, where it enters the blood. When EPO stimulates the production of erythrocytes, iron is released from storage, bound to transferrin, and carried to the red marrow, where it attaches to erythrocyte precursors.
• • Copper. A trace mineral, copper is a component of two plasma proteins, hephaestin and ceruloplasmin. Without these, hemoglobin could not be adequately produced. Located in intestinal villi, hephaestin enables iron to be absorbed by intestinal cells. Ceruloplasmin transports copper. Both enable the oxidation of iron from Fe²⁺ to Fe³⁺, a form in which it can be bound to its transport protein, transferrin, for transport to body cells. In a state of copper deficiency, the transport of iron for heme synthesis decreases, and iron can accumulate in tissues, where it can eventually lead to organ damage.
• • Zinc. The trace mineral zinc functions as a coenzyme that facilitates the synthesis of the heme portion of hemoglobin.
• • B vitamins. The B vitamins folate and vitamin B₁₂ function as coenzymes that facilitate DNA synthesis. Thus, both are critical for the synthesis of new cells, including erythrocytes.

Erythrocytes live an average of 120 days in the circulation, after which the worn-out cells are removed by a type of myeloid phagocytic cell called a macrophage, located primarily within the bone marrow, liver, and spleen. The components of the degraded erythrocytes’ hemoglobin are further processed as follows:

• • Globin, the protein portion of hemoglobin, is broken down into amino acids, which can be sent back to the bone marrow to be used in the production of new erythrocytes. Hemoglobin that is not phagocytized is broken down in the circulation, releasing alpha and beta chains that are removed from circulation by the kidneys.
• • The iron contained in the heme portion of hemoglobin may be stored in the liver or spleen, primarily in the form of ferritin or hemosiderin, or carried through the bloodstream by transferrin to the red bone marrow for recycling into new erythrocytes.
• • The noniron portion of heme is degraded into the waste product biliverdin, a green pigment, and then into another waste product, bilirubin, a yellow pigment. Bilirubin binds to albumin and travels in the blood to the liver, which uses it in the manufacture of bile, a compound released into the intestines to help emulsify dietary fats. In the large intestine, bacteria break the bilirubin apart from the bile and convert it to urobilinogen and then into stercobilin. It is then eliminated from the body in the feces. Broad-spectrum antibiotics typically eliminate these bacteria as well and may alter the colour of feces. The kidneys also remove any circulating bilirubin and other related metabolic by-products such as urobilins and secrete them into the urine.

The breakdown pigments formed from the destruction of hemoglobin can be seen in a variety of situations. At the site of an injury, biliverdin from damaged RBCs produces some of the dramatic colours associated with a bruise. With a failing liver, bilirubin cannot be removed effectively from circulation and causes the body to assume a yellowish tinge associated with jaundice. Stercobilins within the feces produce the typical brown colour associated with this waste. And the yellow of urine is associated with the urobilins.

The erythrocyte life cycle is summarized in Figure 17.5.

Characteristics of Leukocytes

Although leukocytes and erythrocytes both originate from hematopoietic stem cells in the bone marrow, they are very different from each other in many significant ways. For instance, leukocytes are far less numerous than erythrocytes: Typically there are only 5,000 to 10,000 per µL. They are also larger than erythrocytes and are the only formed elements that are complete cells, possessing a nucleus and organelles. And although there is just one type of erythrocyte, there are many types of leukocytes. Most of these types 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. As shown in Figure 17.6, they leave the capillaries—the smallest blood vessels—or other small vessels through a process known as emigration or diapedesis in which they squeeze through adjacent cells in a blood vessel wall.

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 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 clinical medicine, the differential counts of the types and percentages of leukocytes present 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 (you can view their lineage from myeloid stem cells in Figure 17.2).
• • While granules are not totally lacking in agranular leukocytes, they are far fewer and less obvious. Agranular leukocytes include monocytes, which mature into macrophages that are phagocytic, and lymphocytes, which arise from the lymphoid stem cell line.

Life Cycle of Leukocytes

Most leukocytes have a relatively short lifespan, typically measured in hours or days. Production of all leukocytes begins in the bone marrow under the influence of CSFs and interleukins. Secondary production and maturation of lymphocytes occurs in specific regions of lymphatic tissue known as germinal centres. Lymphocytes are fully capable of mitosis and may produce clones of cells with identical properties. This capacity enables an individual to maintain immunity throughout life to many threats that have been encountered in the past.

Disorders of Leukocytes

Leukopenia is a condition in which too few leukocytes are produced. If this condition is pronounced, the individual may be unable to ward off disease. Excessive leukocyte proliferation is known as leukocytosis. Although leukocyte counts are high, the cells themselves are often nonfunctional, leaving the individual at increased risk for disease.

Leukemia is a cancer involving an abundance of leukocytes. It may involve only one specific type of leukocyte from either the myeloid line (myelocytic leukemia) or the lymphoid line (lymphocytic leukemia). In chronic leukemia, mature leukocytes accumulate and fail to die. In acute leukemia, there is an overproduction of young, immature leukocytes. In both conditions the cells do not function properly.

Lymphoma is a form of cancer in which masses of malignant T and/or B lymphocytes collect in lymph nodes, the spleen, the liver, and other tissues. As in leukemia, the malignant leukocytes do not function properly, and the patient is vulnerable to infection. Some forms of lymphoma tend to progress slowly and respond well to treatment. Others tend to progress quickly and require aggressive treatment, without which they are rapidly fatal.

Platelets

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 (see Figure 17.1) and are large, typically 50–100 µm in diameter, and contain an enlarged, lobed nucleus. As noted earlier, thrombopoietin, a glycoprotein secreted by the kidneys and liver, stimulates the proliferation of megakaryoblasts, which mature into megakaryocytes. These remain within bone marrow tissue (Figure 17.8) and ultimately form platelet-precursor extensions that extend through the walls of bone marrow capillaries to 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.

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.

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. This smooth muscle has both circular layers; larger vessels also have longitudinal layers. 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; and
• • prostaglandins and phospholipids, which also maintain vasoconstriction and help activate further clotting chemicals, as discussed next.

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 multilevel 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 fibrinogen, the plasma protein introduced earlier—in which platelets and blood cells are trapped. Figure 17.10 summarizes the three steps of hemostasis.

Fibrinolysis

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 (see Figure 17.10a). This process also wrings out of the clot a small amount of fluid called serum, which is blood plasma without its clotting factors.

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 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. As noted earlier, 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.

Antigens, Antibodies, and Transfusion Reactions

Antigens are substances that the body does not recognize as belonging to the “self” and that therefore trigger a defensive response from the leukocytes of the immune system. Here, we will focus on the role of immunity in blood transfusion reactions. With RBCs in particular, you may see the antigens referred to as isoantigens or agglutinogens (surface antigens) and the antibodies referred to as isoantibodies or agglutinins. In this chapter, we will use the more common terms antigens and antibodies.

Antigens are generally large proteins but may include other classes of organic molecules, including carbohydrates, lipids, and nucleic acids. Following an infusion of incompatible blood, erythrocytes with foreign antigens appear in the bloodstream and trigger an immune response. Proteins called antibodies (immunoglobulins), which are produced by certain B lymphocytes called plasma cells, attach to the antigens on the plasma membranes of the infused erythrocytes and cause them to adhere to one another.

• • Because the arms of the Y-shaped antibodies attach randomly to more than one nonself erythrocyte surface, they form clumps of erythrocytes. This process is called agglutination.
• • The clumps of erythrocytes block small blood vessels throughout the body, depriving tissues of oxygen and nutrients.
• • As the erythrocyte clumps are degraded, in a process called hemolysis, their hemoglobin is released into the bloodstream. This hemoglobin travels to the kidneys, which are responsible for filtration of the blood. However, the load of hemoglobin released can easily overwhelm the kidneys’ capacity to clear it, and the patient can quickly develop kidney failure.

More than 50 antigens have been identified on erythrocyte membranes, but the most significant in terms of their potential harm to patients are classified in two groups: the ABO blood group and the Rh blood group.

The ABO Blood Group

Although the ABO blood group name consists of three letters, ABO blood typing designates the presence or absence of just two antigens, A and B. Both are glycoproteins. People whose erythrocytes have A antigens on their erythrocyte membrane surfaces are designated blood type A, and those whose erythrocytes have B antigens are blood type B. People can also have both A and B antigens on their erythrocytes, in which case they are blood type AB. People with neither A nor B antigens are designated blood type O. ABO blood types are genetically determined.

The body must be exposed to a foreign antigen before an antibody can be produced. ABO blood group antigens are found in foods and microbes throughout nature. Thus, the human immune system is exposed to A and B antigens at an early age, and antibodies are formed naturally. Individuals with type A blood—without any prior exposure to incompatible blood—have naturally formed antibodies to the B antigen circulating in their blood plasma. These antibodies, referred to as anti-B antibodies, will cause agglutination and hemolysis if they ever encounter erythrocytes with B antigens. Similarly, an individual with type B blood has naturally formed anti-A antibodies.

Individuals with type AB blood, which has both antigens, do not have naturally formed antibodies to either of these. People with type O blood lack antigens A and B on their erythrocytes, but both anti-A and anti-B antibodies circulate in their blood plasma.

Rh Blood Groups

The Rh blood group is classified according to the presence or absence of a second erythrocyte antigen identified as Rh. (It was first discovered in a type of primate known as a rhesus macaque, which is often used in research, because its blood is similar to that of humans.) Although dozens of Rh antigens have been identified, only one, designated D, is clinically important. Those who have the Rh D antigen present on their erythrocytes—about 85 percent of Americans—are described as Rh positive (Rh⁺), and those who lack it are Rh negative (Rh⁻). Note that the Rh group is distinct from the ABO group, so any individual, no matter their ABO blood type, may have or lack this Rh antigen. When identifying a patient’s blood type, the Rh group is designated by adding the word positive or negative to the ABO type.

For example, A positive (A⁺) means ABO group A blood with the Rh antigen present, and AB negative (AB⁻) means ABO group AB blood without the Rh antigen.

In contrast to the ABO group antibodies, which are preformed, antibodies to the Rh antigen are produced only in Rh⁻ individuals after exposure to the antigen. This process, called sensitization, occurs following a transfusion with Rh-incompatible blood or, more commonly, with the birth of an Rh⁺ baby to an Rh⁻ person. Problems are rare in a first pregnancy, since the baby’s Rh⁺ cells rarely cross the placenta (the organ of gas and nutrient exchange between the fetus and the pregnant person). However, during or immediately after birth, the Rh⁻ parent can be exposed to the baby’s Rh⁺ cells (Figure 17.11).

Determining ABO Blood Types

Clinicians are able to determine a patient’s blood type quickly and easily using commercially prepared antibodies. An unknown blood sample is allocated into separate wells. Into one well a small amount of anti-A antibody is added, and to another a small amount of anti-B antibody. If the antigen is present, the antibodies will cause visible agglutination of the cells (Figure 17.12). The blood should also be tested for Rh antibodies.

ABO Transfusion Protocols

To avoid transfusion reactions, it is best to transfuse only matching blood types; that is, a type B⁺ recipient should ideally receive blood only from a type B⁺ donor and so on. That said, in emergency situations, when acute hemorrhage threatens the patient’s life, there may not be time for cross matching to identify blood type. In these cases, blood from a universal donor—an individual with type O⁻ blood—may be transfused. Recall that type O erythrocytes do not display A or B antigens. Thus, anti-A or anti-B antibodies that might be circulating in the patient’s blood plasma will not encounter any erythrocyte surface antigens on the donated blood and therefore will not be provoked into a response. One problem with this designation of universal donor is if the O⁻ individual had prior exposure to Rh antigen, Rh antibodies may be present in the donated blood. Also, introducing type O blood into an individual with type A, B, or AB blood will nevertheless introduce antibodies against both A and B antigens, as these are always circulating in the type O blood plasma. This may cause problems for the recipient, but because the volume of blood transfused is much lower than the volume of the patient’s own blood, the adverse effects of the relatively few infused plasma antibodies are typically limited. Rh factor also plays a role. If Rh⁻ individuals receiving blood have had prior exposure to Rh antigen, antibodies for this antigen may be present in the blood and trigger agglutination to some degree. Although it is always preferable to cross match a patient’s blood before transfusing, in a true life-threatening emergency situation, this is not always possible, and these procedures may be implemented.

A patient with blood type AB⁺ is known as the universal recipient. This patient can theoretically receive any type of blood because the patient’s own blood—having both A and B antigens on the erythrocyte surface—does not produce anti-A or anti-B antibodies. In addition, an Rh⁺ patient can receive both Rh⁺ and Rh⁻ blood. However, keep in mind that the donor’s blood will contain circulating antibodies, again with possible negative implications. Table 17.3 summarizes the blood types and compatibilities.

This chart summarizes the characteristics of the blood types in the ABO blood group. See the text for more on the concept of a universal donor or recipient.

17.1 An Overview of Blood

Blood is a fluid connective tissue critical to the transportation of nutrients, gases, and wastes throughout the body; to defend the body against infection and other threats; and to the homeostatic regulation of pH, temperature, and other internal conditions. Blood is composed of formed elements—erythrocytes, leukocytes, and cell fragments called platelets—and a fluid extracellular matrix called plasma. More than 90 percent of plasma is water. The remainder is mostly plasma proteins—mainly albumin, globulins, and fibrinogen—and other dissolved solutes such as glucose, lipids, electrolytes, and dissolved gases. Because of the formed elements and the plasma proteins and other solutes, blood is sticky and more viscous than water. It is also slightly alkaline, and its temperature is slightly higher-than-normal body temperature.

17.2 Production of the Formed Elements

Through the process of hemopoiesis, the formed elements of blood are continually produced, replacing the relatively short-lived erythrocytes, leukocytes, and platelets. Hemopoiesis begins in the red bone marrow, with hematopoietic stem cells that differentiate into myeloid and lymphoid lineages. Myeloid stem cells give rise to most of the formed elements. Lymphoid stem cells give rise only to the various lymphocytes designated as B and T cells and NK cells. Hemopoietic growth factors, including erythropoietin, thrombopoietin, colony-stimulating factors, and interleukins, promote the proliferation and differentiation of formed elements.

17.3 Erythrocytes

The most abundant formed elements in blood, erythrocytes are red, biconcave disks packed with an oxygen-carrying compound called hemoglobin. The hemoglobin molecule contains four globin proteins bound to a pigment molecule called heme, which contains an ion of iron. In the bloodstream, iron picks up oxygen in the lungs and drops it off in the tissues; the amino acids in hemoglobin then transport carbon dioxide from the tissues back to the lungs.

Erythrocytes live only 120 days on average and thus must be continually replaced. Worn-out erythrocytes are phagocytized by macrophages, and their hemoglobin is broken down. The breakdown products are recycled or removed as wastes: Globin is broken down into amino acids for synthesis of new proteins, iron is stored in the liver or spleen or used by the bone marrow for production of new erythrocytes, and the remnants of heme are converted into bilirubin or other waste products that are taken up by the liver and excreted in the bile or removed by the kidneys. Anemia is a deficiency of RBCs or hemoglobin, whereas polycythemia is an excess of RBCs.

17.4 Leukocytes and Platelets

Leukocytes function in body defences. They squeeze out of the walls of blood vessels through emigration or diapedesis, then may move through tissue fluid or become attached to various organs, where they fight against pathogenic organisms, diseased cells, or other threats to health. Granular leukocytes, which include neutrophils, eosinophils, and basophils, originate with myeloid stem cells, as do the agranular monocytes.

The other agranular leukocytes—NK cells, B cells, and T cells—arise from the lymphoid stem cell line. The most abundant leukocytes are the neutrophils, which are first responders to infections, especially with bacteria. About 20–30 percent of all leukocytes are lymphocytes, which are critical to the body’s defence against specific threats. Leukemia and lymphoma are malignancies involving leukocytes. Platelets are fragments of cells known as megakaryocytes that dwell within the bone marrow. While many platelets are stored in the spleen, others enter the circulation and are essential for hemostasis; they also produce several growth factors important for repair and healing.

17.5 Hemostasis

Hemostasis is the physiological process by which bleeding ceases. Hemostasis involves three basic steps: vascular spasm, the formation of a platelet plug, and coagulation, in which clotting factors promote the formation of a fibrin clot. Fibrinolysis is the process in which a clot is degraded in a healing vessel.

Anticoagulants are substances that oppose coagulation. They are important in limiting the extent and duration of clotting. Inadequate clotting can result from too few platelets or inadequate production of clotting factors, for instance, in the genetic disorder hemophilia. Excessive clotting, called thrombosis, can be caused by an excessive number of platelets. A thrombus is a collection of fibrin, platelets, and erythrocytes that has accumulated along the lining of a blood vessel, whereas an embolus is a thrombus that has broken free from the vessel wall and is circulating in the bloodstream.

17.6 Blood Typing

Antigens are nonself molecules, usually large proteins, which provoke an immune response. In transfusion reactions, antibodies attach to antigens on the surfaces of erythrocytes and cause agglutination and hemolysis. ABO blood group antigens are designated A and B. People with type A blood have A antigens on their erythrocytes, whereas those with type B blood have B antigens. Those with AB blood have both A and B antigens, and those with type O blood have neither A nor B antigens. The blood plasma contains preformed antibodies against the antigens not present on a person’s erythrocytes.

A second group of blood antigens is the Rh group, the most important of which is Rh D. People with Rh⁻ blood do not have this antigen on their erythrocytes, whereas those who are Rh⁺ do. About 85 percent of Americans are Rh⁺. When a person who is Rh⁻ becomes pregnant with an Rh⁺ fetus, their body may begin to produce anti-Rh antibodies. If the person subsequently becomes pregnant with a second Rh⁺ fetus, the fetus will be at risk for an antigen-antibody reaction, including agglutination and hemolysis. This is known as hemolytic disease of the newborn. Cross matching to determine blood type is necessary before transfusing blood, unless the patient is experiencing a hemorrhage that is an immediate threat to life, in which case type O⁻ blood may be transfused.