Briefly describe hematopoietic and immune functions.

  Identify common clinical manifestations of inadequate erythropoiesis and diminished host defense mechanisms.

  Discuss characteristics of hematopoietic drugs in terms of the prototype, mechanism of action, indications for use, adverse effects, principles of therapy, and nursing implications.

  Describe the characteristics of colony-stimulating factors in terms of the prototype, mechanism of action, indications for use, adverse effects, principles of therapy, and nursing implications.

  Discuss interferons in terms of the prototype, mechanism of action, indications for use, adverse effects, principles of therapy, and nursing implications.

  Implement the nursing process in the care of patients who take drugs to enhance hematopoietic and immune system function.

KEY TERMS

Biologic response modifiers: intrinsic and extrinsic substances in the body that enhance the body’s response to infection, for example, interferons

Cytokines: small proteins released by cells that specifically affect cell-to-cell communication; these include colony-stimulating factors, interleukins, and interferons

Erythropoiesis: production of red blood cells

Erythropoietin: hormone secreted by the kidneys that stimulates bone marrow production of red blood cells

Hematopoiesis: formation of blood cells

Immunostimulants: drugs that stimulate immune function to fight infection and disease

Neutropenia: low neutrophil count

Pegylation: process of modifying a protein drug by treatment with polyethylene glycol

Introduction

Adequate blood cell production, or hematopoiesis, and normal immune system function, or immunocompetence, are vital processes in the human body’s ability to fight harmful invaders. Inadequate or impaired hematopoiesis or immune function (immunodeficiency) leads to high risks of infection and cancer. Efforts to enhance a person’s own body systems to fight disease include the development of drugs to stimulate hematopoiesis and immune function. People take these drugs to restore normal function or to increase the ability of the immune system to eliminate potentially harmful invaders. This chapter discusses several drugs that affect hematopoietic function and the immune system.

Overview of Hematopoiesis and Immune Function

Hematopoietic and immune blood cells originate in bone marrow in stem cells, which are often called pluripotent stem cells because they are capable of becoming different types of cells. As these stem cells reproduce, some cells are exactly like the original cells and are retained in the bone marrow to maintain a continuing supply. However, most reproduced stem cells differentiate to form other types of cells. The early offspring are committed to become a particular type of cell, and a committed stem cell that produces a cell type in a specific cell line is called a colony-forming unit (CFU). Figure 9.1 illustrates the process of hematopoiesis in red and white cells. Hematopoietic growth factors or cytokines control the reproduction, growth, and differentiation of stem cells and CFUs. They also initiate the processes required to produce fully mature cells. Overall, cytokines are involved in numerous physiologic responses, including hematopoiesis, cellular proliferation and differentiation, inflammation, wound healing, and cellular and humoral immunity.

Physiology

Hematopoietic Cytokines

To understand the effects of drug therapy to enhance hematopoiesis or immune function, it is necessary to appreciate the physiologic effects of the endogenous hematopoietic cytokines. The following section discusses the three major groups of cytokines, and it briefly considers erythropoiesis and immune function as well.

Hematopoietic cytokines are diverse substances produced mainly by bone marrow and white blood cells (WBCs). They regulate many cellular activities by acting as chemical messengers among cells and as growth factors for blood cells. Cytokines act by binding to receptors on target cells. After binding, the cytokine–receptor complexes trigger signal-transduction pathways that alter gene expression in the target cells.

Several factors affect cytokine actions and functions. First, cytokines affect any cells they encounter that have cytokine receptors and are able to respond; they do not act in response to specific antigens. However, cytokine receptors are often expressed on a cell only after that cell has interacted with an antigen, so that cytokine activation is limited to antigen-activated lymphocytes. Second, researchers have determined the actions of most cytokines in laboratories by analyzing the effects of recombinant cytokines, often at nonphysiologic concentrations, and then adding them individually to in vitro systems. Within the human body, however, cytokines rarely, if ever, act alone. Several cytokines, which may have synergistic or antagonistic effects on each other, may affect a target cell. Third, cytokines often induce the synthesis of other cytokines. The resulting interactions may profoundly alter physiologic responses. Fourth, proteins that act as cytokine antagonists are found in the bloodstream and other extracellular fluids. These proteins may bind directly to a cytokine and inhibit its activity or bind to a cytokine receptor but fail to activate the cell.

Colony-Stimulating Factors

The name colony-stimulating factor (CSF) comes from the cluster pattern derived when hemopoietic stem cells are cultured. There are various types of CSFs based on the different types of colonies that grow in the presence of different factors. For example, the substance found to stimulate formation of colonies of granulocytes is called granulocyte colony-stimulating factor (G-CSF) and for macrophages, it is called macrophage colony-stimulating factor (M-CSF). The exposure of pluripotent (progenitor) cells to CSFs controls the production, growth, and differentiation of specific blood cell types. CSFs pertinent to this discussion include those related to the production of red blood cells (RBCs) and leukocyte stem cells.

Interferons

Interferons “interfere” with the ability of viruses in infected cells to replicate and spread to uninfected cells. They also inhibit reproduction and growth of other cells, including tumor cells, and activate natural killer (NK) cells. Interferons enhance communication between cells when antigens or tumors are identified. These antiproliferative and immunomodulatory activities are important in normal host defense mechanisms. Interferons also combat bacterial and parasitic infections.

Interleukins

Interleukins (ILs) initially received their name because scientists thought they were produced by and acted only on leukocytes. However, body cells other than leukocytes can produce them, and they can act on nonhematopoietic cells. Researchers have characterized 18 ILs and identified more. Especially important ILs are IL-3 (stimulates growth of stem-cell precursors of all blood cells), IL-2 (stimulates T and B lymphocytes), IL-12 (stimulates hematopoietic cells and lymphocytes), and IL-11 (stimulates platelets and other cells). ILs may act only in combination with another factor, may be suppressive rather than stimulatory (e.g., IL-10), or may involve a specific function (e.g., IL-8 mainly promotes movement of leukocytes into injured tissues as part of the inflammatory response).

Erythropoiesis

Erythropoietin, a hormone secreted by the kidneys, stimulates bone marrow production of RBCs, or erythropoiesis. The hormone travels through the circulation to the bone marrow, where it stimulates red cell differentiation, maturation, and proliferation. The major signal for erythropoietin production is a decreased oxygen level detected by the proximal tubule cells in the kidneys. Conditions that trigger erythropoietin production include hemorrhage, anemia, chronic obstructive pulmonary disease, and high altitude. Erythropoietin also promotes the production of hemoglobin, necessary for a functioning erythrocyte.

Parameters used to measure erythropoiesis include RBC count, hemoglobin concentration and hematocrit, and mean corpuscular volume. In addition, the reticulocyte count quantitatively measures the bone marrow’s production of new RBCs.

Immune Function

Immune cells are WBCs that circulate in the blood and lymphatic vessels or reside in lymphoid tissues. These cells are present in virtually all body tissues, and their ability to circulate throughout the body and to migrate between blood and lymphoid tissues makes them a major component of host defenses. The cells are activated by exposure to antigens (e.g., viruses, bacteria, parasites). Although all WBCs play a role in phagocytic and immune processes, neutrophils, monocytes, and lymphocytes are especially important.

Cytokines also provide defense support to the immune system. These protein substances secreted by specific cells of the immune system carry signals locally between cells and thus have an effect on the interactions between them. The cytokines include the CSFs, interferons, and ILs, as well as cell signal molecules, such as tumor necrosis factor (see previous discussion).

Clinical Manifestations

As RBCs or WBCs decrease, conditions related to inadequate hematopoiesis or poor immune function develop. Clinical manifestations of inadequate erythropoiesis include anemia. This results in a decrease in the oxygen-carrying capacity of blood and consequently a decreased oxygen availability to the tissues. A compensatory increase in heart rate and cardiac output initially increases cardiac output, offsetting the lower oxygen-carrying capacity of the blood. However, the oxygen demand becomes greater than the supply, and clinical manifestations are directly attributable to tissue hypoxia. Muscle weakness and easy fatigability are common. In severe anemia, the skin is usually pale to a waxy pallor, and cyanosis is typically absent. Headache, irritability, light-headedness, slowed thought processes, and depression are common central nervous system effects. (However, children appear to have a remarkable ability to function quite well with low hemoglobin levels.)

Clinical manifestations of diminished host defense mechanisms demonstrate decreased resistance to infections, including frequent colds and flu symptoms, recurring parasitic infections, and opportunistic infections. Complete blood (cell) count (CBC) measurements include neutropenia (low neutrophil count). Specifically, the absolute neutrophil count (ANC) is the number of neutrophils in the blood, which can be used as a direct measurement of a person’s ability to combat infection. The ANC is determined by multiplying the total number of WBCs by the percentage of neutrophils.

Drug Therapy

The drugs described in this chapter stimulate the production of either erythrocytes or leukocytes. Hematopoietic growth factors enhance the erythrocyte production and oxygen-carrying capability. Immunostimulants are drugs that enhance immune function; they help a person fight disease. Health care providers use these drugs to restore normal function or to increase the ability of the immune system to eliminate potentially harmful invaders. Available drugs include erythrocyte hematopoietic drugs, CSFs, and several interferons. The following sections and Table 9.1 describe these drugs, which are the primary focus of this chapter. The section on Adjuvant Medications briefly discusses two ILs. Other chapters also discuss drugs with immunostimulant properties. These include traditional immunizing agents (see Chap. 10); levamisole (Ergamisol), which restores functions of macrophages and T cells and is used with fluorouracil in the treatment of intestinal cancer (see Chap. 12); and antiviral drugs used in the treatment of acquired immunodeficiency syndrome (AIDS; see Chap. 21).

Most hematopoietic and immunostimulant drugs are synthetic versions of endogenous cytokines. Manufacturers use molecular biology–associated techniques to delineate the type and sequence of amino acids and to identify the genes responsible for producing the substances. Technicians then insert these genes into bacteria (usually Escherichia coli) or yeasts capable of producing the substances exogenously. Exogenous drug preparations have the same mechanisms of action as the endogenous products. Thus, CSFs bind to receptors on the cell surfaces of immature blood cells in the bone marrow and increase the number, maturity, and functional ability of the cells.

In cancer, the exact mechanisms by which interferons and ILs exert antineoplastic effects are unknown. However, their immunostimulant effects are thought to enhance activities of immune cells (i.e., NK cells, T cells, B cells, and macrophages), induce tumor-cell antigens (which make tumor cells more easily recognized by immune cells), or alter the expression of oncogenes (genes that can cause a normal cell to change to a cancer cell).

All these drugs may produce adverse effects so that patients may not feel better when taking the drug. The combination of injections and adverse effects may lead to nonadherence in taking the drugs as prescribed.

Erythrocyte Hematopoietic Drugs

The hematopoietic growth factor epoetin alfa (Epogen, Procrit) is the prototype recombinant form of human erythropoietin that helps the body make more RBCs. The clinical benefit of erythropoiesis-stimulating drug therapy is to reduce the cost of blood transfusions, lessen the risk of infectious diseases from transfusions, and enhance the overall quality of life as anemia is relieved.

Pharmacokinetics

Both subcutaneous and intravenous (IV) administration lead to good absorption (digestive enzymes would destroy the drug if it were given orally). The distribution is unknown, and metabolism occurs in the plasma. Excretion of a small amount occurs in the kidneys. The onset of action is 11 to 14 days. Whether the drug crosses the placenta or is excreted in breast milk is not known.

Action

Epoetin induces erythropoiesis by stimulating erythroid progenitor cells. This causes the release of reticulocytes from the bone marrow, leading to an increase in hemoglobin and hematocrit levels.

Use

Uses of epoetin include the prevention and treatment of anemia associated with chronic renal failure, hepatic impairment, or anticancer chemotherapy. Prescribers also may order the drug to reduce the need for blood transfusions in patients with anemia undergoing elective noncardiac, nonvascular surgery. Table 9.2 presents route and dosage information for the hematopoietic drugs.

Use in Children

The basis for epoetin dosing in children is body weight and hemoglobin level.

Premature infants should not receive epoetin; it contains benzyl alcohol, which can be fatal.

Use in Older Adults

In general, hematopoietic drugs have the same uses and responses in older adults as in younger adults. However, older adults may be at greater risk of adverse effects, especially if large doses are used.

Use in Patients With Critical Illness

Patients with cancer often take epoetin to prevent or treat anemia. Studies indicate that patients with cancer-related anemia feel better and require fewer blood transfusions when hemoglobin is maintained at 10 g/dL or less. Despite the benefits, evidence indicates that this drug may stimulate tumor growth, mainly when it is used to achieve normal hemoglobin levels of 12 to 14 g/dL. As a result, authorities warn prescribers to avoid dosages that increase hemoglobin to above 12 g/dL. In addition, because cancer-related anemia may have numerous causes, some experts recommend a return to the original indication for use of these drugs in cancer (i.e., for anemia induced by chemotherapy that depresses bone marrow function).

Use in Patients Receiving Home Care

Patients often take epoetin in the home, whether self-administered or given by a caregiver. The home health nurse may need to teach patients or caregivers how to accurately administer the drug and provide assistance in obtaining appropriate laboratory tests (e.g., CBC, platelet count, tests of renal or hepatic function) to monitor the responses to the drug.

Adverse Effects

The most common adverse effect of epoetin is hypertension; raising the hemoglobin slowly minimizes this. Other adverse effects include nausea, vomiting, diarrhea, and arthralgias.

Epoetin also increases risks of myocardial infarction and stroke, especially if it is used to achieve hemoglobin levels greater than 12 g/dL.

In addition, injection of epoetin alfa increases the risk of thrombus formation. The U.S. Food and Drug Administration (FDA) has issued a BLACK BOX WARNING ♦ advising prescribers to avoid using hematopoietic growth factors in patients with hemoglobin values of 12 g/dL or above. In addition, it is important to prescribe epoetin at the lowest dose effective in raising hemoglobin levels just enough to avoid the need for blood transfusion. Regular monitoring of hemoglobin levels is necessary until they stabilize.

Contraindications

Contraindications to epoetin include known hypersensitivity to the drug or to albumin (or other cell-derived products from mammals). Also, people with uncontrolled hypertension should not take epoetin because it may further increase blood pressure.

Nursing Implications

Preventing Interactions

No significant interactions with drugs or herbs with epoetin have been reported.

Administering the Medication

For patients with chronic renal failure on hemodialysis, the nurse gives epoetin by bolus injection at the end of dialysis. For other patients with an IV line, IV administration is appropriate. For patients without an IV line or who are ambulatory, subcutaneous administration is suitable. The nurse ensures that the remainder of a multidose vial is discarded 21 days after opening.

A multidose vial of epoetin is not appropriate for use in children due to the risk of medication error.

Assessing for Therapeutic Effects

The nurse observes for increased RBCs, hemoglobin, and hematocrit; increased energy and exercise capacity; and improved quality of life. Therapeutic effects depend on the dose and the patient’s underlying condition. The goal is usually to achieve and maintain a hemoglobin level of no more than 12 g/dL. With epoetin, it is necessary to measure iron stores (transferrin saturation and serum ferritin) before and periodically during treatment. The nurse ensures that hemoglobin levels are measured twice weekly until stabilized and maintenance drug doses are established.

Assessing for Adverse Effects

The nurse ascertains that blood pressure remains within a safe range and also assesses for nausea, vomiting, diarrhea, or joint pain. Because there is an increased risk of myocardial infarction and stroke, assessment of mental status changes and chest pain or decreased cardiac perfusion is necessary.