Unit 3: Blood

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.

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.

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.

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.

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).

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.

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.

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.

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.