the least common white blood cell; plays a role in allergic reactions.
cells formed from stem cells during the differentiation process that will, in turn, produce mature blood cells.
the complex series of reactions that must take place before fibrin can be produced.
the proteins that make up the clotting cascade, identified by roman numerals.
the process of forming a blood clot.
Complete blood count (CBC)
a laboratory test that evaluates the number of cells and level of hemoglobin in the blood.
the process of stem and precursor cells developing into mature cells.
white blood cells that play a role in allergic reactions and parasitic infections.
mature red blood cells.
the process of producing red blood cells.
hematopoietic growth factor that controls the production of red blood cells.
the storage form of iron in the blood.
certain white blood cells, including neutrophils, basophils, and eosinophils.
the development of blood cells.
Hematopoietic stem cell
a cell in the bone marrow that is capable of differentiating into many different blood cell types.
a protein in red blood cells consisting of heme, globin, and iron that is responsible for carrying oxygen.
the process of stopping blood loss.
white blood cells.
an increase in the number of white blood cells.
a decrease in the number of white blood cells.
white blood cells, categorized as T or B lymphocytes that attack viruses and tumor cells, and produce antibodies.
Myeloid stem cell
a cell that can differentiate into a number of blood cells depending on the growth factor that acts on it.
white blood cells that serve as the first response to infection.
the liquid component of blood.
mature B lymphocytes that produce antibodies.
an enzyme that dissolves blood clots.
blood cells responsible for forming clots to stop bleeding.
Polymorphonuclear cells (PMNs)
Red blood cells (RBCs)
a blood cell containing hemoglobin that carries oxygen throughout the body.
immature red blood cells.
White blood cells (WBCs)
a group of six blood cells that contribute to allergic reactions, fight infections, and attack tumor cells.
After completing this chapter, you should be able to
Describe the developmental process of red blood cells, white blood cells, and platelets.
List nutritional requirements for the proper development of red blood cells.
Explain the structure and function of red blood cells, white blood cells, and platelets.
Describe the processes the body uses to achieve hemostasis: vasoconstriction, platelet plug formation, and the clotting cascade.
List the utility of the most common laboratory tests of the blood.
The blood being pumped throughout the circulatory system is the foundation for virtually every system in the body. Blood vessels act as the equivalent of a vast highway, and blood, in its travels over this highway, transports oxygen, nutrients, and hormones to the tiniest of capillaries while carrying away carbon dioxide, cellular debris, and harmful chemicals. The volume of blood in the body depends on a number of factors, including age, gender, and body type. Blood consists of fluid or plasma, formed elements or cells, and cell fragments called platelets. The cells are suspended within the plasma and move along the blood vessel highway to the various body systems like cars on the interstate. The formed elements of blood consist of red blood cells (RBCs) or erythrocytes, white blood cells (WBCs) or leukocytes, and platelets (thrombocytes).
Plasma or whole blood contains varying amounts of each of the formed elements. The volume percentage of RBCs in whole blood is called the packed cell volume (PCV) or hematocrit. A normal range of hematocrit is between 37% and 49% dependent on gender and age. WBCs make up less than 1% of blood volume, and plasma constitutes the remainder of the blood volume. When the percentages of these elements are outside of the normal range, changes can occur within the body that can lead to health concerns. For example, a decreased number of RBCs can lead to a disease such as anemia (discussed later in the chapter), and too few WBCs can compromise the immune system. In this chapter, the development of the blood elements is explained, and the role each plays in the maintenance of the overall health of the human body is explored.
Hematopoiesis: The Development of Blood Cells
Hematopoiesis, the development of blood cells, begins deep in the bone marrow in the hollow center of bones. Though there are many different blood cells with numerous functions, they all originate from the same hematopoietic stem cells located in the bone marrow. Hematopoietic stem cells have the potential to mature into many different cell types, including RBCs, WBCs, and platelets. The process of maturing into a particular type of cell is known as differentiation. The final cell type formed by differentiation depends on the signals stem cells receive. Figure 25-1 summarizes the complex developmental process of blood cells.
Development of Red Blood Cells
The hematopoietic stem cell is the starting point for RBC production. The first step in the development of RBCs is the differentiation of myeloid stem cells into blasts or precursor cells, after being exposed to the hormone erythropoietin, or EPO. Precursor cells then mature into reticulocytes, immature RBCs that will enter the bloodstream via capillaries in the bone marrow to continue their maturation. After 24–48 hours in the circulation, reticulocytes become mature RBCs.
A reticulocyte count is a laboratory test that can be used to examine how well the body is producing RBCs.
Development of Platelets
When a myeloid stem cell is exposed to thrombopoietin, or TPO, the result is the formation of megakaryocytes, giant cells that are about 10 to 15 times the size of a typical RBC and made of up to 5,000 interconnected platelets. Under the influence of TPO, this large cell will begin to crumble, releasing platelets (or thrombocytes) into the bloodstream.
Development of White Blood Cells
There are actually six different cell types grouped together as WBCs: monocytes, neutrophils, basophils, eosinophils, B (β-) lymphocytes, and T lymphocytes. These cells are responsible for defending the body from outside attacks. The development of WBCs closely mirrors that of the RBCs, with a few important differences.
Granulocytes and Monocytes
Once again, the hematopoietic stem cells, which have differentiated into myeloid stem cells, serve as the starting point for the development of granulocytes (neutrophils, basophils, and eosinophils) and monocytes. In this case, however, they respond to colony stimulating factors (CSFs). Once produced, monocytes enter the bloodstream and travel to various tissues to differentiate into mature macrophages. The mature granulocytes, on the other hand, remain in the bloodstream to fend off invaders.
In contrast to RBCs, monocytes, and granulocytes, the lymphocytes begin their development as hematopoietic stem cells that differentiate into lymphoid stem cells. These stem cells mature directly into T and B lymphoblasts (immature cells). The T lymphoblasts travel through the bloodstream to an organ called the thymus, located behind the sternum. Here they mature to T lymphocytes. Mature T cells travel from the thymus to the spleen and peripheral lymph nodes, where they play a central role in fighting viral infections. T lymphocytes that do not survive to maturity are cleared from the thymus by macrophages.
The majority of mature T cells are produced before puberty. As a person ages, the thymus atrophies and its capacity for developing T cells decreases.
The B lymphoblasts remain in the bone marrow to develop into mature B lymphocytes. When an antigen (immune system stimulant, such as a microorganism fragment or byproduct) binds to the B cell receptor, the B cell is activated. Some activated B cells will enlarge and convert to plasma cells that secrete antibodies to help fight infections, while others will become memory B cells that lie in wait for future infections carrying the same antigen.
Structure and Function of the Components of Blood
Red Blood Cells
In each drop of blood, the normal range is 240–270 million RBCs. Mature RBCs have a characteristic biconcave shape (Figure 25-2) and a flexibility that allows them to safely travel through the turbulent circulatory system. They are relatively small, with a diameter of 7–8 μm (micrometer, or millionth of a meter), so about 10 RBCs can fit inside a single speck of dust. They are packed with hemoglobin to transport oxygen.
Hemoglobin is made of a protein called globin and four heme units. At the center of each heme is an iron ion that not only gives the RBC its distinctive red color but is also responsible for the ability to carry oxygen. Each RBC contains roughly 280 million hemoglobin molecules, making up about a third of the cell’s weight. If iron supplies cannot meet the demand of RBC production, small, pale RBCs will be formed that will not carry oxygen efficiently and may cause symptoms of an iron deficiency anemia. The recommended daily allowance (RDA) of iron varies by age, gender, and pregnancy status and is shown in Table 25-1.
Iron can be found in many foods such as meats, beans, eggs, and whole grains or can be replaced using iron supplements.
Like iron, vitamin B12 and folate are two other important nutrients that play roles in the development of RBCs. If intake falls below the RDA of 2–3 mcg/day of vitamin B12 or 400 mcg/day of folate, cell division is delayed, resulting in a decreased production of RBCs. The RBCs that are produced tend to be larger than normal and are called macrocytes, causing a macrocytic anemia.
Iron supplements come in many different varieties. Each of the different iron salts contains a different amount of elemental iron; therefore, dosing is different for each type of iron supplement and the correct one must be chosen.
As RBCs enter areas of high oxygen concentration, such as the lungs, each iron ion located in the hemoglobin molecules can temporarily bond to a single molecule of oxygen. The RBC then leaves the lung and travels via the bloodstream to the farthest reaches of the circulatory system: the capillaries. Here, the oxygen concentration is low and the bonds holding the oxygen molecules to the hemoglobin are broken, allowing the free oxygen to diffuse into the tissue where it is needed most. On the return trip, the hemoglobin plays a role in bringing carbon dioxide away from the tissues and delivering it to the lungs for exhalation. While most carbon dioxide is simply dissolved in the plasma, 13% is transported on hemoglobin molecules.
Vitamin B12-rich foods include meats, dairy products, and fortified cereals. Folate can be found in spinach, beans, and rice, among other foods.
The average RBC will circulate for 120 days, traveling from the heart to the lungs to capillaries and back. A considerable amount of damage takes place as the cells race around the body in blood vessels and are crammed through tiny capillaries. RBCs at the end of the life cycle are cleared out by macrophages in the spleen and liver, but the important pieces that make up hemoglobin are conserved. The iron is stored in the blood as ferritin and is transferred to the bone marrow on transferrin molecules so that it can be recycled into new hemoglobin for newly formed RBCs.
To keep up with the rapid breakdown of RBCs, the bone marrow must produce 2 million RBCs per second. This process, called erythropoiesis, is regulated by the oxygen concentration in tissues throughout the body. When oxygen concentration drops for any number of reasons in a condition called hypoxia, the body sends signals to the kidneys to produce additional EPO. The hematopoietic growth factor then travels to the bone marrow to increase the production of RBCs, which will eventually lead to an increase in oxygen concentration. The same cycle is repeated in reverse when oxygen levels are high. Signals are sent to the kidneys to decrease EPO production, which will, in turn, decrease the number of RBCs produced in the bone marrow and decrease oxygen supply in the tissues. This type of regulation is known as a feedback loop and is commonly found in a number of body systems.
EPO can be made synthetically and used as a treatment for several anemias. Synthetic erythropoietins are discussed at length inChapter 26.
White Blood Cells
As mentioned in the previous section, there are six different WBCs found in the blood. Collectively, the neutrophils, basophils, and eosinophils are known as granulocytes because of the granules containing various substances found in each cell that fight infection, signal other WBCs, or cause allergic reactions. Slightly larger than RBCs, granulocytes are about 8–12 μm in diameter. At about 60% to 70%, the neutrophils are the most common of the WBCs and are also called polymorphonuclear cells (PMNs) due to their strangely shaped nuclei (see Figure 25-1). Neutrophils are often the first responders to outside invaders and leave the bloodstream to attack pathogens head on. Eosinophils, the WBCs usually linked with allergic reactions and fighting parasites, are much less common than neutrophils, accounting for only 2% to 4% of all WBCs. Basophils, however, are even rarer, making up only 0.5% to 1% of the WBCs.
Lymphocytes come in a variety of sizes ranging from 6–14 μm in diameter. They are the second most common WBC at 20% to 25%. The T lymphocytes are responsible for fending off viral infections and destroying human cells that have become cancerous. By using special receptors found on the outside surface of cells, T lymphocytes can differentiate self from nonself and launch attacks on anything that is seen as a foreign body.
Unfortunately, the process by which T lymphocytes discern self from nonself also results in attacks on organs that may be transplanted from other people or species.
B lymphocytes, on the other hand, act as the memory bank of the immune system, creating antibodies that circulate in blood vessels and attach themselves to invading organisms. Some B lymphocytes mature into memory cells that can survive many years in the bloodstream, ready to unload countless antibodies when a known pathogen returns.
Memory B cells are also responsible for conferring long-term immunity when a vaccine is administered.
Monocytes and their counterparts in the tissues, the macrophages, make up 3% to 8% of all WBCs. They are roughly twice the size of RBCs at 12–20 μm in diameter, but they can grow many times that size in the face of an immune response. Though neutrophils are usually the first WBCs to respond to sites of infection, the macrophages tend to do most of the defending. The function of the macrophage is phagocytosis, or the swallowing of pathogens and cellular debris. Once it has ingested a pathogen, the macrophage will attempt to destroy or contain it while it sends out signaling chemicals, called cytokines, to call additional WBCs to the area.
Even though RBCs outnumber WBCs by a ratio of at least 500:1, 75% of the bone marrow is dedicated to the production of WBCs. These numbers show that the turnover rate for WBCs is high, particularly when an immune response is ongoing. For instance, a macrophage, which has a typical life span of 1–3 months in normal tissue, may only survive a few hours when it is battling an infection at full capacity. Similar to the effect of EPO on RBCs, the production of WBCs is increased by CSFs and cytokines released from cells at the site of infection and is decreased when the infection resolves.
The cells discussed above make up approximately 45% of the blood volume. Though they perform the bulk of the hematological processes, they could not function without the remaining 55%, made up of plasma. The largest component of plasma is water (more than 91%), which acts as the conduit through which all blood cells flow. Suspended in this water are numerous proteins, such as albumin, antibodies, and fibrinogen, along with dissolved nutrients, electrolytes, gases, and waste products. Also located in the plasma are the numerous enzymes that make up the clotting cascade, a complex system of checks and balances that lead to the production and breakdown of blood clots.
When significant damage occurs to a blood vessel, the body works quickly to minimize the loss of blood. This process, known as hemostasis, is made up of three important steps: a narrowing of the damaged blood vessel known as vasoconstriction, the formation of a platelet plug, and the formation of a blood clot through the clotting cascade. While the response must be quick and definitive, the body must also be careful to avoid an overreactive hemostatic response that could lead to thrombogenesis, the formation of an unwanted blood clot. When a thrombus is formed, the risk for heart attack, stroke, and other cardiovascular events is drastically increased. As in most body systems, there is a delicate balance between coagulation and anticoagulation to form clots in appropriate areas and dissolve those that are not needed.
One of the most common and most devastating results of thrombus formation is a stroke. There are many antiplatelet medications, such as aspirin or clopidogrel, which help decrease the risk of forming unwanted blood clots.
After an initial injury, damaged cells send a signal to the surrounding smooth muscle to contract immediately. This is an effort to decrease the size of the blood vessel and limit the amount of blood flowing through it. If the injury is significant, the vasoconstriction may even result in the complete closure of the blood vessel. While this is an effective short-term measure to decrease blood loss, it is usually temporary, buying time for platelets to congregate in the area and to initiate the clotting cascade.
Platelet Plug Formation
As discussed earlier, platelets are released from megakaryocytes in the bone marrow in response to TPO. These smallest of blood cells are only 2–4 μm in diameter and are essentially only fragments of the much larger megakaryocyte precursor cell. Once they enter the circulation, platelets live for an average of 5–9 days.
Circulating platelets are attracted to damaged areas of vessel walls. Once attached, the platelet is activated and releases signaling chemicals that cause additional vasoconstriction and attract other platelets to the area. As more platelets arrive, the normally disc-shaped cells spread out and become sticky. This change makes it easier for platelets to interact with one another and form the platelet plug to fill any gaps in the vessel wall.
The Clotting Cascade
The platelet plug, though an important step in hemostasis, usually cannot stop a bleed alone. It is a loose mass of platelets that can be dislodged from the area of injury unless strengthened by fibrin threads, which are the end products of the clotting cascade (see Figure 25-3). Made up of a series of reactions, the clotting cascade involves the sequential activation of clotting factors.
The cascade is divided into three parts: the intrinsic, extrinsic, and common pathways. As described above, when tissue damage is present, the body needs to respond quickly to repair the damaged site. The extrinsic pathway is designed to be a fast track to the development of a clot. In cases of severe damage, the extrinsic pathway can form a clot in seconds. For this pathway to be used, damaged tissue must supply the starting ingredient, a protein called tissue factor (TF). Even without obvious tissue damage, however, it is still possible for a clot to form. When no TF is released, the intrinsic pathway must be used to form a clot. This longer pathway requires multiple steps and could take several minutes to form a clot. The delay is a natural protection against unwanted clot formation, allowing time for the body’s anticoagulants to take effect, if necessary. The intrinsic and extrinsic pathways converge to form the common pathway. Here, the final steps in the conversion of fibrinogen (one of the soluble proteins found in the plasma) to active fibrin threads occur. Once formed, the fibrin threads interact with the platelet plug, interweaving between platelets and entangled RBCs and lending strength to the new clot. At this point, blood loss is contained and the body can begin to heal the damaged area, replacing the injured vessel wall with new cells.
The ability of the clotting cascade to function normally depends heavily on the body having enough vitamin K. This important nutrient is found in most green, leafy vegetables and is essential to the production of clotting factors II, VII, IX, and X. If the body’s stores are low, the production of these factors will decrease and clot formation will be more difficult to achieve, increasing the risk of bleeding. Conversely, some medications, such as warfarin, will intentionally interfere with vitamin K to anticoagulate a patient. These and other anticoagulants (commonly known as blood thinners) are discussed in Chapter 26.
When patients are stabilized on warfarin, it is important that their intake of vitamin K is relatively uniform from day to day. Large changes in the amount of vitamin K consumed can have a big impact on the effectiveness of the prescribed medication dose.
Regulation of Hemostasis
When clots are formed at inappropriate locations or appropriate clots are no longer needed, the fibrinolytic cascade works to undo the effects of the clotting cascade. Incorporated into each formed clot is an inactive enzyme called plasminogen. The inactive enzyme can be converted to plasmin, which acts to dissolve fibrin threads and inhibit many clot-forming substances. Circulating in the blood are the body’s own natural anticoagulants, such as heparin and others, working to block the clotting cascade at various points, as well. After these substances were discovered, many were developed into powerful medications, which are discussed in Chapter 26. In this, as in many other body systems, it is the interplay between these two opposing systems that allows the hemostatic system to function properly.
Common Blood Tests
A number of blood tests are available to healthcare providers to assess the status of the hematological and hemostatic systems. The most widely used is the complete blood count (CBC). In each CBC, the WBC count, platelet count, hemoglobin level, and hematocrit are measured. The WBC count is a useful tool to identify infections, check the health of the immune system, or screen for cancers of the bone marrow. Typical WBC counts range between 5,000 and 10,000 cells per microliter (µL, or 0.1 mL) of blood. When the number of WBCs is higher than expected, the patient is said to have a leukocytosis, while those that have low counts have a leukopenia. If a CBC is ordered with differential, the lab will also include counts of each individual type of WBC for comparison. See Table 25-2 for more details. Platelet counts can show the ability of the body to form clots. Normal platelet counts are between 150,000 and 450,000 cells per microliter of blood. These levels can be affected by certain platelet disorders, cancers, and medications. The hemoglobin and hematocrit levels are two of the most important laboratory tests to screen for anemias. Hemoglobin is usually between 13.1 and 17.3 g/dL in adults. Though the hemoglobin level is very useful in determining the presence of an anemia, it does little to describe the cause. Additional lab tests, such as the mean corpuscular volume (MCV), ferritin, total iron binding capacity (TIBC), vitamin B12 and folate levels, need to be ordered. These tests are discussed in greater detail in Chapter 26. Finally, when a patient’s hemostatic system is in need of closer examination, tests such as the international normalized ratio (INR) and activated partial thromboplastin time (aPTT) describe the ability of the body to form clots and helps keep the doses of powerful anticoagulants in the proper range. These tests are discussed in Chapter 26, as well.
Components of a Complete Blood Count with Differential2
Reference ranges may vary depending on individual laboratory techniques used.
Blood is made up of a number of cells, proteins, and other substances that work together to transport substances, defend the body from invaders, and stop blood loss after an injury occurs. All blood cells begin as hematopoietic stem cells found in bone marrow. The stem cells differentiate into red blood cells (RBCs), white blood cells (WBCs), and platelets when influenced by hematopoietic growth factors, such as erythropoietin (EPO).
The RBCs are responsible for the transport of oxygen from the lungs to tissues all over the body. When hemoglobin in the RBCs is exposed to an oxygen-rich environment, the iron ions can bind to oxygen molecules. The blood is then pumped to distant capillaries where the oxygen supply is low. As the concentration drops, the oxygen molecules break free of the hemoglobin and diffuse into the tissue.
Neutrophils, eosinophils, basophils, monocytes, and lymphocytes are collectively known as the WBCs. The WBCs are responsible for defending the body from infection. When a pathogen enters the body, neutrophils are the first cells to respond. They attack the invader and try to engulf it while sending out signals to attract other WBCs. Monocytes and their counterparts in the tissues, the macrophages, arrive next and also swallow pathogens. Lymphocytes are broken down into two groups. The T lymphocyte helps the body fight viral infections and kills off tumor cells. B lymphocytes, once activated, produce antibodies against antigens. The eosinophils and basophils, the least common WBCs, are responsible for allergic reactions in the body.
The hemostatic system stops the loss of blood from damaged blood vessels. The initial reaction to injury at a blood vessel is vasoconstriction. This tightening of smooth muscles decreases the amount of blood flowing through the area of injury, buying time for the rest of the system to go into effect. Platelets are blood cells that form plugs to stop blood loss. When exposed to an area of blood vessel damage, platelets are activated, becoming sticky and larger in size. Activated platelets also send signals to other platelets to converge. As more platelets arrive, they form a loose mass called a platelet plug. On its own, the platelet plug cannot adequately stop blood loss. It needs to be strengthened by the addition of fibrin threads. Fibrin threads are formed when soluble fibrinogen is converted into fibrin at the end of the clotting cascade. For blood clots to form rapidly when tissue damage is present, the extrinsic pathway of the clotting cascade shortens the usually complex series of steps necessary to form clots. The intrinsic pathway, however, allows clots to form even in the absence of tissue damage. To minimize the inappropriate clotting of blood, this pathway requires many steps to occur in sequence for clot formation. Other natural checks and balances are in place in the body to keep blood clots where they are needed, such as the fibrinolytic cascade, a system of many enzymes and anticoagulants that regulate the process of thrombogenesis.
Healthcare providers have a number of tests at their disposal to evaluate the condition of the hematologic system. The most commonly used blood test is the complete blood count (CBC). WBC counts, platelet counts, hemoglobin, and hematocrit levels are typically reported in a CBC. A high WBC count, a condition called leukocytosis, is usually present in patients with an infection, cancer, or on certain medications. Platelet counts can show how well a person can form blood clots, and the hemoglobin and hematocrit levels are usually used to detect the presence of an anemia.
National Institutes of Health, Office of Dietary Supplements. Nutrient recommendations: Dietary Reference Intakes (DRIs). https://ods.od.nih.gov/Health_Information/Dietary_Reference_Intakes.aspx. Accessed April 5, 2022.