Overview of the Hematologic System

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.

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.

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.

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Cellular components of the blood. Each has a characteristic form. Note the biconcave shape of the RBCs and the platelets, which are cellular fragments.

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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.

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.

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.

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.

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.

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.

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.

Plasma

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.

Vasoconstriction

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.

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The clotting cascade. TF = tissue factor.

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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.

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.