Hematology and Immunology Systems


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HEMATOLOGY AND IMMUNOLOGY SYSTEMS


Jessica L. Spruit






DEVELOPMENTAL ANATOMY AND PHYSIOLOGY



A.    Hematopoiesis



1.    Hematopoiesis is the process by which blood cells are formed.



2.    Anatomic sites of hematopoiesis vary with age.



a.    During embryonic and fetal life, the yolk sac, liver, spleen, thymus, lymph nodes, and bone marrow are all involved (Fernández & de Alarcón, 2013; Sieff, Daley, & Zon, 2015).



b.    At birth, hematopoiesis takes place in the bone marrow, called red marrow, of all bones.



c.    After birth, the red (blood-forming) marrow is gradually replaced by yellow (fatty) marrow. By adulthood, red marrow exists only in the pelvis, vertebrae, cranium, and sternum.



3.    Mature blood cells arise through a developmental process called differentiation.



a.    Pluripotent hematopoietic stem cells give rise to many differentiated blood cells and also replenish themselves.



b.    Pluripotent hematopoietic stem cells differentiate into committed stem cells. These cells are committed to develop and differentiate into a certain cell type (i.e., red blood cells [RBCs], platelets, white blood cells [WBCs]).



c.    The process of development and differentiation is guided and stimulated by a variety of important growth factors and cytokines: erythropoietin (EPO; stimulates red cells), thrombopoetin (platelets), and granulocyte colony-stimulating factor (G-CSF) stimulates white cells.



4.    Five types of cells arise from the stem cell. Each of these cells end with “-blast,” which refers to a nucleated precursor cell (Porth, 2015).



a.    Proerythroblasts form the mature erythrocyte (RBCs).



b.    Megakaryoblasts form the mature thrombocytes (platelets).



c.    Myeloblasts form the mature neutrophils, eosinophils, and basophils (each a type of WBC).



d.    Monoblasts form the mature monocytes (a type of WBC).



e.    Lymphoblasts form the mature lymphocytes (a type of WBC; Fernández & de Alarcón, 2013; Figure 8.1).



5.    Development of the pluripotential stem cell into a mature hematopoietic cell (RBC, WBC, or platelet) occurs in approximately 1 to 2 weeks.



6.    Alterations in the development of blood cell lines include aplasia, in which the bone marrow completely fails to develop stem cells, and hypoplasia, in which the bone marrow develops an abnormally low number of stem cells.


B.    Immune System



1.    Functionally and anatomically, there is overlap with the hematopoietic system and hematopoiesis.



2.    Lymphocytes are a type of WBC whose role is to provide protection to the organ via development of various types of immunity. There are two main types of lymphocytes: B cells (involved with humoral immunity (HI), the production of antibodies), and T cells (involved with cellular immunity; Pai & Reinherz, 2015).



3.    The primary lymphocytic tissue organs describe the key sites of development of lymphocytes. B lymphocytes develop in the bone marrow. T lymphocytes develop in the thymus, which is located in the anterior mediastinum, behind the sternum (Pai & Reinherz, 2015).



4.    Secondary lymphoid tissue or organs are sites for storage, division, and activation of lymphocytes.



a.    The spleen is important for HI and for cellular immunity as well. It is also rich in macrophages (phagocytic cells) and serves as a normal site for destruction of old or damaged red cells.








586image


FIGURE 8.1    Cell differentiation from stem cells.


G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; M-CSF, macrophage colony-stimulating factor.







b.    Lymphatic channels transport fluid from the interstitium around the cells in the body, through lymph nodes, and eventually empty into a large lymphatic vessel called the thoracic duct.



c.    Lymph nodes are bean-shaped structures located along the length of the lymphatic vessels. Lymph nodes are distributed throughout the body and clustered in groups, both superficial and deep. Lymph nodes function as filters and are important sites of lymphocyte activation and differentiation. Lymph nodes of the head and neck are illustrated in Figure 8.2. Epitrochlear and inguinal lymph nodes should also be assessed.








587image


FIGURE 8.2    Lymph nodes of the head and neck.







d.    Mucosa-associated lymph tissues (MALT) are dispersed throughout the body and line mucosal surfaces (i.e., the gastrointestinal [GI] tract, lungs, skin). They are located within or close to sites of potential invasion by bacteria or foreign substances.



e.    The liver is rich in a particular type of macrophage called Kupffer’s cells. These have filtering functions similar to the spleen although they are less effective.


C.    Committed Hematologic Lines



1.    RBCs, or erythrocytes, develop from erythroid precursor cells under the influence of EPO.



a.    Reticulocytes represent the stage of maturation that occurs just before the erythrocyte matures. Reticulocytes are normally present in small numbers in the peripheral blood and are increased during states of erythroid stimulation. They quickly (in 24–48 hours) mature into RBCs.



b.    Mature RBCs have a life span of 120 days. Their main function is to pick up oxygen as they move through the pulmonary capillaries and deliver that oxygen to the tissues.



c.    Hemoglobin is a large, complex, iron-containing protein that fills RBCs and is responsible for the RBCs’ oxygen-carrying abilities.



i.    Normal adult hemoglobin is called Hgb A.



ii.    Hemoglobin F (fetal Hgb) is present in large concentrations in the fetus, but it rapidly declines after birth and is present in only minimal amounts in children and adults.



d.    Normal RBC production requires adequate amounts of iron, folic acid, and vitamin B12.



e.    Anemia represents a decreased number of red cells or hemoglobin, with a resultant decrease in oxygen-carrying capacity. Anemia can result from decreased production of red cells, increased destruction of RBCs, or blood loss. Anemia is measured as a decrease in hematocrit and hemoglobin; it is usually defined as two standard deviations below the mean for the normal population (Brugnara, Oski, & Nathan, 2015).



f.    The RBCs carry a variety of important surface antigens that are important in transfusion medicine. The most important antigens are A and B. The presence or absence of these determine one’s blood group. Other antigen groups are also important; the Rh system is of considerable significance in pediatrics, where maternal sensitization to the D antigen can lead to hemolytic disease of the newborn.



2.    Leukocytes (WBCs) are a heterogeneous group of cells that serve in a variety of ways to protect the organism. Phagocytosis, humoral and cellular immunity, and mediators of the inflammatory response are all important components of host defense. Granulocytes (neutrophils), lymphocytes (discussed separately), monocytes, eosinophils, and basophils are the different types of WBCs.



a.    Neutrophils account for the largest component of total circulating WBCs, approximately 55% (age related). Neutrophils are the most active in phagocytosis (Moriber, 2014).



i.    Neutrophils originate and mature in the bone marrow and can be found in blood vessel walls, intravascular spaces, tissues, and bone marrow.



ii.    The mature form of the neutrophil is polymorphonucleated (PMNs or “poly”). PMNs normally constitute the majority of the circulating neutrophils and are phagocytic and active in inflammation and tissue damage. PMNs are the first WBCs to respond to infection and the most numerous WBCs at the site of infection.



iii.    The immature form of the neutrophil has an unsegmented-appearing nucleus and is referred to as a band. The immature form lacks complete phagocytic ability and 588normally constitutes less than 10% of the circulating neutrophils.



iv.    Neutrophilia is an increased number of circulating neutrophils, often accompanied by an increase in the number of immature neutrophils (bands). Neutrophilia is associated with infections; situations that increase cardiac output (stress response associated with surgery, hemorrhage, or emotional distress such as intense crying); or increased release of epinephrine, adrenocorticotropic hormone (ACTH), or adrenal corticosteroids. Neutrophilia is also sometimes seen following administration of granulocyte colony-stimulating factor (G-CSF).



v.    Neutropenia refers to a decreased number of circulating neutrophils with the understanding that normal values are based on age, race, and other factors (Dinauer, Newburger, & Borregaard, 2015); it is often associated with malignant conditions and marrow hypoplasia or aplasia.



vi.    WBCs mature in the bone marrow for approximately 10 days. WBCs then are released into the circulation, circulate in the blood for 4 to 8 hours, and then circulate another 4 to 5 days in the tissues. The life span of WBCs is shortened in the presence of an infection (Porth, 2015).



b.    Eosinophils normally account for 2% to 5% of the circulating WBCs and have weak phagocytic activity (Porth, 2015). Eosinophils may have a role in “turning off” the immune response because the eosinophil is the last to arrive at the site of infection. Cytoplasmic granules contain chemical substances that destroy parasitic worms and act on immune complexes involved in allergic responses.



i.    Eosinophilia refers to an increased number of eosinophils that is greater than normally present. The eosinophil count may rise as high as 50% of the circulating WBCs with parasitic infection and less often with allergic conditions.



ii.    Eosinopenia refers to a decreased number of eosinophils; this decrease is not clinically significant and is rarely recognized clinically, as it requires an absolute eosinophil count. There are at least two known mechanisms that produce eosinopenia: primary elevation of adrenal corticosteroids or epinephrine and acute inflammation or stress causing release of adrenal corticoids and/or epinephrine (Dinauer et al., 2015).



iii.    From the bone marrow, eosinophils are released into the circulation and migrate to tissues. Unlike other granulocytes, eosinophils may recirculate back and forth between the circulation and the tissues.



c.    Basophils represent the smallest proportion of granulocytes, accounting for fewer than 1% of circulating WBCs. Cytoplasmic granules contain chemical substances (e.g., histamine, heparin, and probably serotonin) that are released and participate in inflammation and allergic responses.



i.    Production and life span of the basophil are not thoroughly understood.



ii.    Basophilia is an increased number of circulating basophils, often associated with allergic responses, infections, and chronic inflammatory diseases (Dinauer et al., 2015).



iii.    Basophilopenia is a decreased number of circulating basophils, and may occur in thyrotoxicosis and after treatment with thyroid hormones (Dinauer et al., 2015).



d.    Mononuclear phagocytes (monocytes and macrophages) normally constitute 3% to 8% of circulating WBCs. Produced in the bone marrow and spending only a brief time in the circulation, most monocytes migrate into the tissues and differentiate into macrophages (Porth, 2015).



i.    Monocytosis, an increase in the number of circulating monocytes, is observed in patients with bacterial, protozoan, parasitic, or rickettsial infections. It is also a hallmark finding in juvenile myelomonocytic leukemia and may be observed in other oncologic disorders (Dinauer et al., 2015).



ii.    Monocytopenia is a decrease in the number of circulating monocytes. It may be observed after glucocorticoid administration and infections with endotoxemia. In addition, monocytopenia is described as a primary feature of MonoMAC syndrome, which predisposes patients to infections and certain malignancies (Dinauer et al., 2015).



iii.    Macrophages are not quantified in the serum and have a long life span; some live for years. Macrophages commonly reside in a specific tissue, although a small percentage may wander. Examples of fixed macrophages include alveolar macrophage, Kupffer’s cells in the liver, microglial cells of the brain, and spleenic macrophages. Macrophages play a primary role in nonspecific defenses through the ability to phagocytose. They are capable of phagocytosing larger and 589greater numbers of particles than the neutrophil or the monocyte. Macrophages also play a primary role in specific defense through processing and presentation of the antigen to the helper T cell (Dinauer et al., 2015).



3.    Lymphocytes (lymphoid lineage) are the primary immune cells associated with humoral and cell-mediated immunity (CMI), although a small portion of lymphocytes (natural killer [NK] cells) are nonspecific in nature.



a.    Lymphocytes account for 10% to 40% of the circulating WBCs. They are produced in the bone marrow and then migrate to other parts of the body to differentiate and mature into several distinct subsets.



i.    Cells that migrate to the thymus differentiate into T lymphocytes (T cells) and mediate CMI.



ii.    Cells that migrate to the bursa equivalent in the human (thought to be the bone marrow) differentiate into B lymphocytes (B cells) and mediate HI (involving antibody production).



iii.    NK cells constitute a subset of lymphocytes that is nonspecific in nature, and attack infectious microbes and tumor cells (Tortora & Derrickson, 2014).



b.    Lymphocytosis, an increase in the number of circulating lymphocytes, is often noted in patients with viral infections (such as infectious mononucleosis or infectious hepatitis) or lymphocytic leukemia or lymphoma.



c.    Lymphopenia, a decrease in the number of circulating lymphocytes, is often noted in patients with congenital immunodeficiency, AIDS, uremia, or following administration of corticosteroids or ACTH.



d.    T lymphocytes, or T cells, normally constitute 65% to 85% of all lymphocytes. T cells mediate CMI, which confers a component of specific, acquired immunity and protects from infections with intracellular organisms, such as viruses, fungi, protozoa, and helminthic parasites. T cells are involved in the elimination of mutated or tumor cells and the immune response triggered during tissue graft or organ transplantation.



i.    Subsets of T lymphocytes have been identified through the identification of specialized molecules of the cell membrane surfaces, referred to as clusters of differentiation (CD).



ii.    Helper T cells (CD4) send chemical signals (via lymphokines) to the cytotoxic T cells, macrophages, and NK cells. They have an important role in the activation of B cells.



iii.    Suppressor T cells (CD8) send a signal to inhibit actions of B cells, helper T cells, and killer T cells.



iv.    Cytotoxic or killer T cells (CD8) eliminate targets directly by chemical destruction and play a role in the rejection of tissue transplantation.



e.    B lymphocytes, or B cells, normally constitute up to 35% of circulating lymphocytes. B cells mediate HI through transformation into a plasma cell, which then secretes immunoglobulin (Ig). HI confers a component of specific, acquired immunity and protects the host from bacterial infection and viral invasion.



f.    NK cells normally constitute 5% to 10% of the total lymphocyte count. NK cells have neither B-nor T-cell markers and are referred to by many other names (e.g., non-B cells, non-T cells, null cells). The target for the NK cell is the tumor cell or microbe-infected cell. The NK cells’ cytotoxic abilities are nonspecific in nature because they can destroy the target without prior sensitization (Tortora & Derrickson, 2014).



g.    Memory cells have CD according to the various distinct cell types (helper, suppressor, or cytotoxic T or B cell). They are programed to recognize the original invading microorganism on subsequent invasions. Memory cells initiate a secondary response and may result in elimination before any signs or symptoms of infection are seen.



4.    Platelets (Thrombocytes). Megakaryoblasts mature into megakaryocytes.



a.    Megakaryocytes break into pieces (budding) forming platelets, which are released into the bloodstream. Granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor, and interleukin-3 (IL-3) have been shown to stimulate the growth of megakaryocytes but are ineffective clinically. Thrombopoietin receptor agonists have recently been approved for certain indications in children and may also be helpful.



b.    Two thirds of mature platelets circulate in the bloodstream, and one third are stored in the spleen but are released if needed to maintain hemostasis. The life span of platelets produced in vivo is 7 to 10 days; transfused platelets have a shorter life span, usually 3 to 4 days. Thrombocytes usually are removed by the spleen or incorporated into a clot.



c.    Thrombocytes are minute round or oval discs. Platelet performance depends on the quantity of platelets (platelet count: 150,000–400,000 cells/mm3) and the quality of function. Adhesiveness is stickiness, the ability to attach to blood vessel walls 590and surfaces. Aggregation is the process in which the first-arriving platelets release substances that further recruit platelets so a platelet plug is formed.



d.    Aggregation is increased with secretion of epinephrine and serotonin, substances found on the surface of platelets. Functions are decreased in the presence of antiprostaglandins such as aspirin (see “Hematologic and Immunologic Pharmacology” section, Platelet Suppressor Agents).



e.    Newly produced platelets are more effective than those that have been in the circulation for a few days.


D.    Plasma Factors


Plasma factors describe more than 40 substances or protein molecules in blood and tissues that are involved in the clotting cascade.



1.    Procoagulants, also known as plasma clotting factors, promote coagulation. Clotting factors lead to the formation of a fibrin clot. They are referred to by Roman numerals and the name of the substance. Anticoagulants are produced in the liver except for factor VIII (formation site unknown). Vitamin K is required for the production of factors II, VII, IX, and X. Factors are circulated in inactive form until stimulated to initiate clotting (see “Plasma Factors” section). All factors act in concert in vivo to respond to tissue or blood cell injury. Consumption of the procoagulants results in their destruction.


TABLE 8.1    Nomenclature for Coagulation Factors














































Factor


Synonym


I


Fibrinogen


II


Prothrombin


III


Tissue thromboplastin


IV


Calcium


V


Proaccelerin


VI


Not assigned


VII


Proconvertin


VIII


AHF


IX


Plasma thromboplastin component (Christmas factor)


X


Stuart factor (Stuart-Prower factor)


XI


PTA


XII


Hageman factor


XIII


FSF


AHF, antihemophilic factor; FSF, fibrin-stabilizing factor; PTA, plasma thromboplastin antecedent.


Note: The antithrombin system involves a plasma protein that inactivates thrombin and active clotting.


Source: Modified from Gordon, J. B., Bernstein, M. L., Rogers, M. C. (1992). Hematologic disorders in the pediatric intensive care unit. In M. Rogers (Ed.). Textbook of pediatric intensive care (2nd ed.). Baltimore, MD: Williams & Wilkins.



2.    Anticoagulants Inhibit Coagulation



a.    Circulating anticoagulants are antithrombin III, protein C, and protein S. Antithrombin III inactivates thrombin and inhibits factor X. Protein C inactivates factors V and VIII, stimulates fibrinolysis, and elevates levels of tissue plasminogen activator (tPA). Protein activates protein C.



b.    The fibrinolytic system’s major component is plasminogen. Plasminogen is produced in the liver and circulated in the plasma. Concentrations increase in response to inflammatory states. Plasminogen is converted to plasmin, which has the ability to digest fibrinogen and fibrin. A by-product is D-dimer, an indicator of the breakdown of cross-linked fibrin. tPA further stimulates the conversion of plasminogen to plasmin. It is synthesized by endothelial cells of the vessels and is stimulated by tissue anoxia or damage to the endothelial lining of vessels. tPA will not activate plasminogen in the absence of fibrin.



c.    The antithrombin system involves a plasma protein that inactivates thrombin, and active clotting factors not used in the clotting process.



3.    Coagulation depends on a balance between the procoagulants and the anticoagulants. A balance is needed to maintain blood as a fluid when the vasculature is intact and uninjured. Anticoagulants usually predominate until a blood vessel or tissue is injured (Table 8.1).


591FUNCTIONS AND PHYSIOLOGIC MECHANISMS



A.    Red Blood Cells


The RBC function is to transport oxygen from the lungs to the tissues. Oxygen-carrying capacity is determined by the amount of hemoglobin available, the amount of dissolved arterial oxygen, and cardiac output.


B.    White Blood Cells



1.    Functions



a.    Defense. WBCs protect the body’s internal environment from “nonself” antigens or microorganism invasion by inactivating, destroying, or eliminating “nonself” antigens (Pai & Reinherz, 2015).



b.    A DNA code at the molecular level assists the immune system in discriminating “self” from “nonself” or “altered self.” Nonself is composed of foreign or alien molecular structures and is referred to as antigenic or as an antigen. Antigens are identified by characteristic shapes on their cell surfaces, referred to as epitopes. Antigens may carry several epitopes on their cell surface, making them capable of stimulating several different T and B lymphocytes (Moriber, 2014).



c.    Major histocompatibility complex (MHC) molecules serve as the genetic blueprint and allow lymphocytes to ignore self-antigens expressed on tissues (Moriber, 2014). The MHC molecules specific to the human species are human leukocyte antigens (HLAs) and are located on chromosome 6. HLA antigens are located on the surfaces of most nucleated cells in the body as well as on platelets. HLA antigens are inherited according to Mendelian laws, with an individual’s genotype determined by one paternal and one maternal haplotype. Close relatives share some of these antigens, whereas identical twins share all these antigens.



d.    HLAs of the MHC are divided into three classes (I, II, and III) based on function, types of cell antigens expressed on the cell membrane surfaces, and structure.



i.    Class I includes HLA-A, -B, and -C antigens and are found on all nucleated cell surfaces and platelets. Class I antigens serve as identification markers of self, assist in the elimination of cells infected with intracellular microorganisms and of mutated or malignant cells, and are involved in the rejection of tissue grafts. Class I antigens are the target antigens recognized by the cytotoxic T cells.



ii.    Class II includes HLA-DR, HLA-DQ, and HLA-DP in humans. Class II antigens serve as identification markers of exogenous antigens and assist in the elimination of extracellular microorganisms. Class II molecules are expressed on B cells, monocyte–macrophages, and dendritic cells. Expression may also be induced by inflammatory mediators and cytokines on T lymphocytes (Pai & Reinherz, 2015).



iii.    Class III plays an important role in the innate immune system and encodes many elements of the complement system (Moriber, 2014).



e.    Homeostasis. WBCs remove old or damaged debris from the circulation.



f.    Surveillance. WBCs recognize and guard against the development, growth, and dissemination of abnormal cells.



2.    Physiologic mechanisms of WBCs are usually categorized by three lines of defense, each representing increasingly more complex and sophisticated means of protection and methods of elimination.



a.    The first line of defense involves the child’s natural, innate barriers with unique physical, chemical, and mechanical capabilities. This provides a nonspecific or generic defense with immediate onset.



i.    Physical and mechanical barriers prevent or minimize entry and attachment of the antigen. These include the phenomenon of simple chemicals on the skin, which inhibit colonization and promote destruction of microorganisms, mucus traps in the respiratory and GI tract, hair and cilia traps, saliva, tears, and urine (dilution and washing away of antigens), defecation and vomiting (expulsion of invading organisms), and an intact GI lining (Moriber, 2014). Many factors associated with critical illnesses are thought to threaten the barrier role of the gut mucosa and increase the risk of translocation of gram-negative bacteria or endotoxins.



ii.    Chemical barriers deter attachment, survival, and replication of antigen. These include the acidic pH of the skin; lysozymes present in saliva, tears, and nasal secretions; gastric secretions; and unsaturated fatty acids in sweat and sebaceous glands.



592b.    The second line of defense involves the inflammatory response, phagocytosis, and complement activation. It is nonspecific or generic in nature with immediate onset once triggered, if the first line of defense is ineffective.



i.    The local inflammatory response is a sequential reaction to injury hallmarked by the release of numerous chemical mediators such as histamine, bradykinin (and other kinins), serotonin, and prostaglandins. The goals of inflammation include localization, dilution, and destruction of the offending antigen, maintenance of vascular integrity, minimization of tissue damage, and transportation of cells and substances to the area.



ii.    Vascular response is characterized by immediate vasoconstriction, which facilitates fibrin plug formation and WBC, RBC, and platelet margination. Vasodilation facilitates cell and cell products to move close to the area of injury. Capillary permeability assists in cell and cell-product movement from the vascular space into the tissues. Local increases in hydrostatic pressure and increased oncotic pressure of proteins in the interstitium leads to edema (Grossman, 2014d).



iii.    Cellular response involves margination or paving of the lining of cells along the capillary endothelium to prepare for movement from the intravascular space to the tissue. Margination is facilitated by the vascular response because fluid leakage into the interstitium results in an increased blood viscosity and a decreased blood flow. Following the leukocyte accumulation that occurs in margination, cytokines are released, causing the endothelial cells lining the vessels to express cell adhesion molecules. Adhesion allows the process of transmigration as the endothelial cells separate. Transmigration allows the leukocytes to move through the vessel wall and migrate into tissue spaces while influenced by chemotactic factors (Grossman, 2014d). Chemotaxis involves chemical signals to attract cells to the site of injury. Substances that serve as chemotactic chemicals include chemokines, protein fragments, and bacterial and cellular debris (Grossman, 2014d). The final phase of cellular response is phagocytosis, in which monocytes, neutrophils, and tissue macrophages engulf and degrade bacterial and cellular debris (Grossman, 2014d).



iv.    Other components of the inflammatory response, biochemical mediators, and plasma enzyme cascades facilitate the inflammatory response through diverse but complementary actions. Numerous biochemical mediators have been identified, such as prostaglandins, leukotrienes, endorphins, and histamine. The primary nonspecific plasma enzyme cascades include complement, coagulation (involved in the vascular response via hemostasis; see “Coagulation Factor” section, Coagulation Cascade), fibrinolysis (primary activity is the degradation of fibrin clot; see “Plasma Factors” section, Fibrinolytic System), and kallikrein or kinin (bradykinin; enhances inflammatory response by promoting vasodilation, increased capillary permeability, neutrophil chemotaxis, and other actions).



v.    Phagocytosis. Phagocytes include granulocytes (especially neutrophils) and monocytes or macrophages. The purpose of phagocytosis is to capture, engulf, and destroy the antigen. In addition, phagocytosis may eventually present the antigen to the helper T lymphocyte. The process of phagocytosis is complex and involves several mechanisms.



1)  Recognition of the antigen as nonself.



2)  Adherence or attachment of the phagocyte to the antigen or invader.



3)  Ingestion or engulfment is performed through the use of pseudopods. Eventually the antigen is taken into the phagocyte’s cytoplasm, where it is enveloped in a sac (phagosome).



4)  Killing and degradation occur when the antigen-containing sac is subjected to lysozyme and the process known as the respiratory (oxidative) burst, containing hydrogen peroxide, superoxide anion, and hydrochlorite anion. Some microorganisms are ingested but not necessarily killed. For instance, the toxins from staphylococci may in turn kill the phagocyte. Others, such as tubercule bacilli, may multiply within the phagosome and eventually destroy the phagocyte.



vi.    The complement system works through innate and adaptive immunity to localize and destroy microorganisms. Complement proteins C1 to C9 normally circulate in the plasma in the inactive form, making up approximately 10% to 15% of plasma proteins. 593Three independent pathways may lead to activation of the complement system in an innate response; these include the classical, lectin, and alternative pathways. The distinguishing features of these pathways are the proteins used in the early phases of activation. The reaction of each pathway is described in three phases: initiation or activation, amplification of inflammation, and membrane attack response.



1)  In the activation phase, the alternative pathway is activated by microbial cell surfaces in the absence of antibodies. The classical pathway is part of the HI, activated by antibodies bound to antigens. The lectin pathway is activated with plasma lectin binds to mannose on microbes and activates the classical system (Moriber, 2014).



2)  Activation of complement protein C3 is central to the inflammatory response. This leads to enzymatic cleavage into a larger C3b and smaller C3a fragment, which go on to attach to the microbe to initiate phagocytosis and to serve as a chemoattractant for neutrophils, respectively. C3b also works to cleave C5 into two fragments as part of an enzymatic response, leading to vasodilation, vascular permeability, and late-step membrane attack responses (Moriber, 2014).


TABLE 8.2    Acquired, Specific Immunity: Definition, Acquisition, and Characteristics




























Types of Acquired, Specific Immunity


Definition and Acquisition


Characteristics


Passive Immunity


Natural


Acquired through natural contact with antibody transplacentally or through colostrum and breast milk (e.g., IgG and IgA from mother to fetus or neonate)


No participation of the host; a transfer of preformed substances or sensitized cells from an immunized host to a nonimmunized host


Artificial


Acquired through the administration of antibody or antitoxin (e.g., gamma-globulin, tetanus)


Onset is immediate, but duration is temporary


Active Immunity


Natural


Acquired through natural infection; the body is exposed to an antigen and mounts an immune response to that antigen (e.g., chickenpox)


Active participation of the host following exposure to an antigen either naturally (subclinical or clinical disease) or artificially through immunization


Artificial


Acquired through inoculation with a variant antigen, but usually not the entire antigen (e.g., immunization, attenuated virus)


Provides slow antigen-specific development of antibody, but provides permanent or long-lived immunity to that antigen


IgA, immunoglobulin A; IgG, immunoglobulin G.


Source: Adapted from Mudge-Grout, C. L. (1992). Immunologic disorders. St Louis, MO: Mosby-Year Book.



3)  Late-step responses involve C3b as it binds to other complement proteins and stimulates additional responses through the influx of neutrophils and vascular phase of acute inflammation. Fluid and ions enter cells and cause lysis when complement C5b initiates C6, C7, C8, and C9 to form a membrane attack complex (MAC) protein.



c.    The third line of defense involves specific, acquired immunity and is triggered if the first and second lines of defense are ineffective in eliminating or containing the antigen. The immune response is a highly complex sequence of events that is triggered by an antigen and integrally associated with other physiologic events, including but not limited to complement activation and the clotting and fibrocytic systems (Moriber, 2014). Hallmarks of the third line of defense include specificity, the ability of a lymphocyte to respond to a single antigen for which it was designed, and memory (i.e., the ability of a lymphocyte to recall prior exposure to an antigen and respond in an accelerated, potentiated manner). Specific acquired immunity may be obtained either passively or actively and naturally or artificially (Table 8.2).



594i.    Specific acquired immunity occurs in phases. Recognition and processing of the antigen are the primary responsibilities of the macrophage, although the B lymphocyte may participate. Once identified as nonself, or foreign, the macrophage ingests the antigen and, through an enzyme-mediated reaction, begins “antigen processing.” When “antigen processing” is complete, the macrophage reexpresses the processed antigen on its membrane surface in conjunction with HLA antigen. Antigen presentation to the B or T lymphocyte occurs (Moriber, 2014). Processing and presentation of the antigen trigger the immune response to facilitate elimination.



ii.    Acquired immunity comprises two different, but closely interrelated, antigen-specific immune responses (Figure 8.3):



1)  HI, which is mediated by B lymphocytes, results in the synthesis and secretion of immunoglobulins and indirectly eliminates or impedes the antigen. HI provides protection primarily from encapsulated pyogenic bacterial infections (Moriber, 2014).



2)  CMI, which is mediated by T lymphocytes, directly eliminates the antigen. CMI protects from viral, bacterial, and parasitic infections; plays a role in rejection of foreign grafts; and participates in delayed hypersensitivity reactions (Porth, 2015).



iii.    Humoral immunity. B lymphocytes can be activated without the help of the T lymphocyte, as in T-cell-independent antigen response, but most commonly are activated with the assistance of the T lymphocyte, as in the T-cell-dependent antigen response. B cells transform into plasma cells, which synthesize and secrete immunoglobulins and subsequently interact with the antigen for which it was made. Immunoglobulins (antibodies) are glycoproteins produced by plasma cells in response to an antigen (Moriber, 2014).



iv.    There are five major classes of immunoglobulins: IgG, IgA, IgM, IgD, and IgE (Moriber, 2014; Table 8.3).



1)  IgG makes up approximately 75% of total immunoglobulins and possesses antiviral, antitoxin, and antibacterial properties. This is the only type of IgG that crosses the placenta, and therefore, protects the newborn. IgG activates complement and binds to macrophages (Moriber, 2014).



2)  IgA comprises approximately 15% of the immunoglobulin present; it is found in secretions and protects the mucous membranes.



3)  IgM is prominent in early immune responses, responsible for activating complement, and forms natural antibodies such as ABO blood antigens. It makes up approximately 10% of immunoglobulins.



4)  IgD is found on B lymphocytes and is necessary for the maturation of mature B cells.



5)  IgE is involved in parasitic infections and allergic and hypersensitivity reactions.



v.    Outcomes of antigen–antibody interaction include neutralization (antibody binds the antigen, causing the antigen to be ineffective or to promote removal by phagocytes), agglutination (antibody combines with the antigen to form clumps), precipitation (antibody combines with the antigen to make an insoluble lattice formation that precipitates), opsonization (antibody coats the antigen, enhancing phagocytosis), complement (antibodies activate complement, thus causing target cell lysis), and antibody-dependent cytotoxicity (antibody facilitates lysis of the antigen by another immune cell).



vi.    Primary response. Antibody production occurs 2 to 10 days after the first exposure, and the response peaks in 1 to 3 weeks. Immunoglobulin M (IgM) is followed by an IgG response.



vii.    Secondary, or memory phase, response is the response that occurs with exposure to a previously encountered antigen. Memory cells are responsible for the rapid (in 1–2 days), prolific, sustained response to the familiar antigen. Antibody response is primarily IgG at much higher titers for a shorter period compared with the primary response (Moriber, 2014).



viii.    Cell-mediated immunity involves Tlymphocyte recognition and activation. T lymphocyte binds to the antigen and to a class I or class II protein on the surface of an antigen-presenting cell (usually the macrophage). Class I HLA antigens are required for cytotoxic T-lymphocyte activation. Class II HLA antigens are required for helper T-lymphocyte activation.








595image


FIGURE 8.3    The specific immune response consists of three distinct phases: (1) the recognition phase, which involves the recognition and processing of antigens; (2) the preparation phase, which focuses on activation, cloning, and differentiation of cells; and (3) the elimination phase, in which the target in the cell is destroyed. Through the interdependence of B and T cells, both humoral and cell-mediated immunity are initiated.


CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; CMI, cell-mediated immunity; HI, humoral (immunoglobulin) immunity. HLA, human leukocyte antigen; IL-1, interleukin-1; IL-2R, interleukin-2 receptor; TCR, T-cell receptor.







ix.    Communication among all the cells participating in the immune response is facilitated through the secretion of cytokines. Cytokines are hormone-like substances that function to upregulate and downregulate immunologic, inflammatory, and reparative host responses. Cytokines secreted by lymphocytes are referred to as lymphokines. Cytokines secreted by monocytes or macrophages are referred to as monokines. 596Cytokines are distinct from endocrine hormones in that they are produced by a number of cells rather than by a specialized gland, they do not usually present in the serum, and they act in a paracrine (locally near the producing cell) or autocrine (directly on the producing cell) fashion rather than on distant target cells. Selected cytokines are described in Table 8.4.


597image



x.    Developmental distinctions occur in the third line of defense. The infant’s B cells are deficient in producing comparable adult levels 598and subclasses of immunoglobulins. Serum immunoglobulin levels, the degree of synthesis at birth, and the age at which the levels are comparable to the adult are reflected in Table 8.5. The IgG level seems comparable between the newborn and the adult, but this level reflects the transplacental acquisition of maternal antibody during primarily the third trimester of gestation. The infant is lowest in immunoglobulin concentrations at about 4 to 5 months of age, when maternal IgG begins to decrease through natural catabolism and when infant synthesis of immunoglobulin is low. This period is referred to as physiologic hypogammaglobulinemia. During this time, the infant is most susceptible to infections caused by viruses, candida, and acute inflammatory bacteria (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis). This state can be prolonged to such an extent that the young child suffers from recurrent and severe infections.


TABLE 8.4    Selected Cytokines: Source and Functions






























































Type


Source


Functions


IL


IL-1 (endogenous pyrogen)


T cell, B cell, macrophage, endothelium, tissue cell


Enhances T-cell growth and function; stimulates macrophages; immunoaugmentation


IL-2 (T-cell growth factor)


T cells


Promotes T-cell and B-cell growth; activates T cell; enhances NK activity


IL-3 (multi-CSF)


T cells, mast cells


Stimulates growth of immature hematopoietic precursor cells (e.g., granulocytes, macrophages, RBCs, platelets, and mast cells)


BCGF (IL-4)


T cells


Enhances B-cell growth and function


BCDF (IL-6)


T cells


Enhances B-cell growth and function


INTERFERONS


Interferon alfa


Lymphocytes, NK cells, macrophages, fibroblasts, epithelial cells


Enhances NK activity; provides antiviral protection; induces HLA-I expression; induces fever; generates cytotoxic T lymphocytes; induces macrophage killing of tumor cells


Interferon beta


Fibroblasts, macrophages, epithelial cells


Provides antiviral protection


Interferon gamma


T cells, NK cells


Activates macrophages; induces macrophage killing of microorganism and tumor cells; regulates action of certain cytokines; increases NK cell activity; increases expression of Fc receptor and HLA-I antigens


Tumor necrosis factor


Macrophages, T cells, and others


Enhances destruction of tumor cells


CSFs


G-CSF


Monocytes, macrophages, endothelial cells, and fibroblasts


Stimulates growth and activation of neutrophils


M-CSF


Monocytes, macrophages, endothelial cells, and fibroblasts


Stimulates growth and activation of monocytes


GM-CSF


T cells, endothelial cells, and fibroblasts


Stimulates growth and activation of neutrophils, eosinophils, and macrophages


CSF, colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; HLA, human leukocyte antigen; ; IL, interleukin; M-CSF, macrophage colony-stimulating factor; NK, natural killer; RBCs, red blood cells.


Sources: Data from Mudge-Grout, C. L. (1992). Immunologic disorders. St Louis, MO: Mosby–Year Book; Plaeger, S. F. (1996). Principal human cytokines. In E. R. Stiehm (Ed.), Immunologic disorders in infants and children (4th ed.). Philadelphia, PA: WB Saunders.


C.    Platelets



1.    Function. The function of platelets is to maintain normal hemostasis and vascular integrity when a blood vessel wall is injured.



2.    Hemostasis is a complex interaction among three responding systems (Grossman, 2014c).



a.    Vascular constriction: Injury to a vessel wall leads to the release of chemical signals, such as endothelin 1, and constriction of the injured vessel within seconds. This smooth muscle contraction reduces blood flow to the area.


image



b.    Formation of the platelet plug: Platelets rush to the area of injury where they are activated by cytokines and initiate the process of adhesion. The platelet surface changes, becoming “sticky” and attracting additional platelets (Figure 8.4).



c.    Blood coagulation: Two coagulation pathways, the intrinsic and extrinsic pathways, lead to the activation of factor X, converting prothrombin to thrombin, and converting fibrinogen to fibrin threads.



3.    Physiologic conditions influencing platelet response can be quantitative (increase or decrease in number) or qualitative (abnormal function).








image


FIGURE 8.4    Hemostatic response of platelets. Major mechanisms involved in primary hemostasis (a) through (c). Injury results in vessel wall constriction, platelet aggregation, and clot formation. Anticoagulation mechanisms (d) reestablish blood flow by lysing the clot.


Source: From Harvey, M. (1986). Study guide to core curriculum for critical care nursing (p. 162). Philadelphia, PA: W. B. Saunders.







599a.    An increase in the number of circulating platelets (platelet count) usually occurs after acute blood loss to enhance hemostasis.



b.    Thrombocytopenia, defined as a platelet count lower than 150,000/mm3, can result from decreased production, increased destruction, or increased trapping in the spleen (splenic sequestration). Causes of thrombocytopenia include medications (see “Therapeutic Modalities That Depress the Functions of the Hematologic and Immunologic Systems” section), renal or liver disease, cardiopulmonary bypass or hemodialysis, aplastic anemia, immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT), viral diseases, disseminated intravascular coagulation (DIC), radiation to the bones, and malignancies involving the bone marrow (displacement of normal stem cells with malignant cells). Thrombocytopenia may also result from congenital disorders, such as thrombocytopenic absent radii (TAR), congenital amegakaryocytic thrombocytopenia (CAMT), and Wiskott–Aldrich syndrome (WAS; Lambert & Poncz, 2015).



c.    Platelet function can be impaired by medications (e.g., aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs]; see “Therapeutic Modalities That Depress the Functions of the Hematologic and Immunologic Systems” section), renal disease, and inherited disorders such as Glanzmann thrombasthenia and platelet-type von Willebrand disease (Lambert & Poncz, 2015). Uremia causes reversible impairment of qualitative platelet function. Impaired platelet function results in bleeding in areas abundant in capillaries, such as the mucous membranes in the GI tract, the vagina, the bladder, and the nasopharynx, producing petechiae or ecchymosis or both.



d.    Most platelet problems in critical care are due to thrombocytopenia rather than to decreased function of the platelets. Hemostasis begins to be affected when the platelet count is below 80,000 to 100,000/mm3, but bleeding is unlikely until the platelet count is less than 25,000/mm3. If the platelet count is less than 50,000/mm3, easy bruising may occur. If the platelet count is less than 10,000 to 20,000/mm3, spontaneous bleeding may occur, especially if the child is anemic or febrile. If the platelet count is 10,000/mm3, severe spontaneous or intracranial bleeding may occur.



e.    Critically ill children may bleed as a result of sepsis, trauma, malignancy, toxins, and immunologic reactions. Correcting the underlying cause of the bleeding will often lead to resolution of bleeding. In addition, DIC, as described later in this chapter, is a frequent cause of excessive bleeding in the critically ill child (Lambert & Poncz, 2015).


D.    Plasma Factors



1.    Procoagulants contribute to the process of secondary hemostasis, which is represented by the formation of a fibrin clot and trapping of RBCs at the site of the initiating primary hemostatic plug.



2.    Enzymes and proteins amplify initial activation of a soft clot to an appropriately sized, fully developed clot.



3.    Factors play a role in initiating primary nonspecific plasma enzyme cascades.



4.    Coagulation cascade starts within the bloodstream itself (intrinsic) or outside the bloodstream (extrinsic). The process results in blood changing from a liquid to a gel state by the ultimate conversion of fibrinogen to insoluble fibrin polymers. Contraction of the fibrin network follows, causing the plug to retract, the walls of the damaged vessel to come together, and the injured vessel wall to seal shut.



a.    The intrinsic pathway is activated when platelets contact collagen or damaged endothelium. Its function is screened by partial thromboplastin time (PTT).



b.    The extrinsic pathway is activated when tissue factor is released from injured tissues, such as when tissues have been cut in surgery. Its function is screened by prothrombin time (PT).



c.    The common pathway is the part of the coagulation cascade that is activated by the intrinsic or extrinsic pathway. The final step is a fibrin mesh within the platelet plug. Thrombin stimulates the platelets to further aggregate. Fibrin is an essential portion of a clot, soluble until polymerized by factor XIII, which converts it to a stable (insoluble) clot. The function of the common pathway is screened by both the PT and PTT.



5.    Anticoagulant mechanisms function to maintain blood as a fluid to maintain vascular patency. The system must turn off the various coagulation pathways to reestablish blood flow through an injured vessel, maintain vascular patency, and modulate the balance between the clotting and lysing systems.



a.    The fibrinolytic system involves the process of lysing a clot. Plasminogen is the precursor to the active part, which is plasmin. It is produced in the liver and circulated in the plasma. 600The conversion to plasmin is increased in states such as inflammation and coagulation or in the presence of tPA. Plasmin lyses fibrin clots by digesting fibrin or fibrinogen. Plasmin splits fibrin into smaller elements called fibrin split products (FSPs) or fibrin degredation products (FDPs). FSPs impair platelet aggregation, reduce prothrombin, and interfere with polymerization of fibrin.



b.    The antithrombin system defends against excessive clotting and maintains blood as a fluid. The blood vessel wall has sites that allow thrombin to be inactivated by antithrombin III. Disorders of antithrombin mechanism include congenital thrombotic disorders (thrombophilia) and hepatic failure.


CLINICAL ASSESSMENT



A.    History



1.    Chief complaint is noted in the patient’s or the primary caretaker’s own words.



2.    History of Present Illness



a.    Activity intolerance, fatigue, and weakness; shortness of breath and dyspnea; and “racing heart”



b.    Fever or chills, chronic or recurrent infection, lymphadenopathy, skin rash, and joint pain



c.    Petechiae, bruising, or abnormal bleeding (either prolonged after a minor injury or spontaneous)



3.    Patient Health History



a.    Record immunizations and previous immunologic testing.



b.    The patient’s diet and nutrition history is described, including recent weight gain or loss, dietary restrictions, food dislikes and intolerance, and routine dietary intake, including cultural adherence. All blood cell lines are dependent to some extent on adequate nutritional intake. In particular, iron, vitamin B12, and folic acid are needed for RBC development.



c.    Allergies and hypersensitivities are noted, including allergies to inhalants (e.g., animal dander, pollens), contactants (e.g., fibers, chemicals, latex), injectables (e.g., drugs, blood transfusions), or ingestants (e.g., foods, food additives, drugs) and the symptoms accompanying the allergic or hypersensitivity reaction.



d.    Previous surgeries that may impair hematologic or immunologic status are noted, including organ or tissue transplantation, thymectomy, or splenectomy.



e.    Inquire about medical conditions that might impair hematologic or immunologic status. Abnormalities of RBCs are seen with anemia or malabsorption syndromes. Liver or spleen disorders (functional splenectomy), chronic or recurrent infections, mononucleosis, or problems with wound healing may impact WBC function or numbers. Platelets may be abnormal with prolonged or excessive bleeding or menorrhagia. Plasma factors may be implicated in hemarthrosis. Cancer, bone marrow abnormalities, congenital blood disorders, and immunodeficiency all can affect hematologic and immune status.



f.    General symptoms include fatigue, change in level of activity, weakness, headache, chills, fever, weight loss, failure to thrive, night sweats, poor wound healing, malaise, pain, prolonged or excessive bleeding, excessive bleeding related to dental extractions, and menorrhagia.



g.    See Table 8.6 for specific symptoms of concern.



h.    Psychosocial history should include recent stresses or life-changing events, response to stress, and coping methods.



4.    Family history of RBC, WBC, platelet, and coagulation factor abnormalities is noted.



a.    RBC abnormalities include jaundice, anemia, and RBC dyscrasia, such as sickle cell anemia.



b.    WBC abnormalities include malignancies; frequent, recurrent, or chronic infections; congenital immunodeficiencies; acquired immunodeficiencies; and autoimmune disorders.



c.    Platelet abnormalities include any bleeding disorders or predisposition to bleeding or clotting.



d.    Congenital bleeding disorders include hemophilia, von Willebrand disease, and clotting disorders (thrombophilia).



e.    Any symptoms of blood disorders similar to the patient’s symptoms are noted.



5.    Medication History



a.    Prescription agents used to treat existing hematologic or immunologic conditions may include multivitamins, iron preparations (oral or parenteral), vitamin B12, folic acid, or EPO for RBC deficiencies. A wide variety of agents used to treat infection, autoimmune disorders, and malignancies affect WBC number and function and the ability of the body to mount an inflammatory response. Examples of such agents include antineoplastic agents, antibiotics, antivirals or antiretrovirals, antifungals, NSAIDs, and CSFs. Antiplatelet agents, such as aspirin, may compromise clotting functions. Anticoagulants affect plasma factors. Evaluate agents used to treat nonhematologic or immunologic conditions that adversely affect hemopoietic function (see “Therapeutic Modalities That Depress the Functions of the Hematologic and Immunologic Systems” section).


601TABLE 8.6    Symptoms of Concern





































System


Symptoms of Concern


Neurologic


         Confusion, restlessness, syncope, irritability, impaired consciousness or somnolence


         Deficits in sensory and/or motor function; altered cranial nerve function (cough, gag, swallow, blink)


Skin


         Prolonged bleeding, bruising easily, petechiae, jaundice, pallor, lesions, ulcers, decreased skin turgor, rhinitis, dermatitis, urticaria, eczema


Eyes


         Visual disturbances, retinal hemorrhages, pallor, erythema of conjunctivae


Nose and mouth


         Epistaxis, gingival bleeding, sore or ulcerated tongue, mucositis, candidiasis, vesicular crusting lesions


Lymph nodes


         Adenopathy (enlargement) or tenderness


         Tachypnea, respiratory tract infection, respiratory distress, dyspnea, orthopnea, cough, hemoptysis, sputum, chest pain


Respiratory


         Bleeding from nose or endotracheal tube


Cardiovascular


         Hemodynamic instability


         Oozing from venipuncture, intra-arterial, or intravenous sites


         Pale skin and mucous membranes, vasculitis


GI


         Frank or occult bleeding in GI contents


         Anorexia, altered bowel sounds, diarrhea, constipation, melena, vomiting, hematemesis, protuberant abdomen (not age-related), abdominal pain, masses, hepatosplenomegaly


GU


         Hematuria, menorrhagia, urinary tract infection


Mobility


         Ataxia, paresthesias


         Altered level of activity


         Muscle weakness


         Pain in joints, back, shoulders, bones


         Hemarthrosis


GI, gastrointestinal; GU, genitourinary.



b.    Nonprescription drugs include common agents such as aspirin, and also substances used as recreational drugs.



6.    Social–Cultural History



a.    Environmental exposures may include radiation, either inadvertent exposure or radiation therapies (total or localized), or inadvertent exposure to chemicals such as benzene, lead, and insecticides.



b.    Discuss recent travel, especially outside the United States.



c.    Determine whether the patient is sexually active (including nonconsensual sex). Evaluate sexual preference, safer sex practices, and multiple partners.



d.    Determine tobacco and alcohol use. Alcohol consumption reduces the intake of essential nutrients and vitamins and may affect RBC production, platelet function, and clotting mechanisms.



602e.    Evaluate the use of complementary therapies and other interventions used by the patient and family.


B.    Physical Examination of the Patient



1.    Inspection (see Table 8.6)



2.    Auscultation



a.    Heart sounds, including gallop, rhythm, and pericardial rubs (may indicate an inflammatory process)



b.    Lung sounds, including rales, rhonchi, and pleural rubs



3.    Palpation



a.    Palpate superficial lymph nodes for location, size, tenderness, fixation, and texture (see Figure 8.2). In pediatric patients between infancy and adolescence, palpable lymph nodes less than 3 mm are considered normal and those in the cervical and inguinal areas may be up to 1 cm in size. It is important to assess the texture, temperature, tenderness, and mobility of these nodes. If the nodes are discrete, easily mobile, and nontender, they may not always be of clinical significance. The increased incidence of infection in children means the frequency of inflammatory adenopathy is higher. Supraclavicular lymphadenopathy should be addressed with a high index of suspicion, as these nodes enlarge with Hodgkin’s lymphoma (Jarvis, 2016).



b.    Examine for sternal or rib tenderness, joint mobility and tenderness, and bone or abdominal tenderness.



c.    Palpate liver and spleen for size and tenderness. Tenderness may be indicative of an inflammatory process or an enlarged organ with stretching of the capsule secondary to bleeding or malignancy. Assess for complications of portal hypertension (hepatomegaly or splenomegaly). Hepatosplenomegaly may also be noted in patients with numerous hematologic and oncologic disorders (e.g., hemolytic anemia, immunodeficiency disorders, and cancer).


INVASIVE AND NONINVASIVE DIAGNOSTIC STUDIES



A.    Complete Blood Count (CBC)



1.    RBC Count



a.    Normal is approximately 4.5 to 6 × 106 million/mm3 (varies with age; Table 8.7)



b.    RBCs are reduced in anemia from any cause and will be relatively decreased in a patient experiencing fluid overload.



c.    RBCs are increased in chronic hypoxemia, high altitude, and polycythemia.



2.    Hemoglobin (Hgb) measures the oxygen-carrying capacity of the RBC and gives it the red color.



a.    Normal (see Table 8.7)



b.    Hgb × 3 is an approximation of the patient’s hematocrit.



c.    Hgb is reduced in anemia from any cause and relatively with fluid overload.



d.    Hgb is increased in polycythemia and relatively with severe dehydration.



3.    Hematocrit (Hct) compares the volume of RBCs with the volume of plasma; it is measured as percentage of total RBC volume.



a.    Normal (see Table 8.7)



b.    Hct is reduced in anemia from any cause and will be relatively decreased in a patient experiencing fluid overload.



c.    Hct is increased in polycythemia and relatively with severe dehydration.



4.    Peripheral smear enables a more exact evaluation of blood cell size, shape, and composition and is especially useful in evaluating anemia and confirmation of thrombocytopenia.



5.    Reticulocyte count is the number of young RBCs. It indicates the proportion of immature RBCs in the circulation and is helpful in determining the cause of anemia in some children. The reticulocyte count measures the responsiveness and potential of the bone marrow to respond to bleeding or hemolysis.



a.    Normal. 0.5% to 2% (may vary from one laboratory to another)



b.    The reticulocyte count is reduced after a blood transfusion, in aplastic conditions, or in nutritional anemias.



c.    The reticulocyte count is increased in hemolytic anemia, after blood loss, and with bone marrow recovery as a compensatory mechanism.



6.    Total WBC Count



a.    Normal WBC is approximately 5,000 to 10,000/mm3 (age specific; see Table 8.7).



b.    Variations in the total WBC count include leukocytosis, an elevation in WBC count above normal range, and leukopenia, a reduction in WBC count below normal range.


603image



604c.    Total WBC count reflects only those WBCs in the intravascular space (excluding the marginal pool). WBCs are also located in the following:



i.    Marginal pool. Cells are temporarily sequestered in small vessels or adhere to the walls of large blood vessels.



ii.    Tissues. Nearly twice as many neutrophils are found in the tissues as in the intravascular space.



iii.    Bone marrow. The bone marrow is the primary storage area for mature neutrophils.



7.    Differential WBC count measures the five subcategories of circulating WBCs and is reported as a percentage of the total WBC count. It evaluates the bone marrow’s ability to produce those particular cells (see Table 8.7) and indicates the type of cell that is excessively prominent. Neutrophil shifts are the number of “segs,” or “bands” as reported in the differential WBC count, which may be interpreted in two ways:



a.    As an indication of the cell’s maturity, a “shift to the left” indicates predominantly immature neutrophils (bands), as seen in acute infection, tissue injury, or use of CSFs (Grossman, 2014b).



b.    A “shift to the right” indicates an increased number of mature neutrophils, called “segs” because of their segmented nucleus, which can be observed in patients experiencing pernicious anemia (vitamin B12 deficiency), folate deficiency, stress, epinephrine, and corticosteroid therapy (Grossman, 2014b).



8.    Absolute cell counts specifically quantifiy a particular cell line and may be derived for any cell line. Following is an example calculation of an absolute neutrophil count (ANC):



a.    Obtain patient’s total WBC count (i.e., WBC = 5 k/mm3).



b.    Translate the total WBC count into an absolute number (k means 1,000 cells; therefore, 5 × 1,000 = 5,000 or an absolute WBC count of 5,000/mm3).



c.    Obtain WBC differential and add the percentages of “polys” plus “bands” (polys = 60% plus bands = 10%; therefore, 60% + 10% = 70%).



d.    Translate the percentage of “polys” plus “bands” into an absolute number by dividing by 100 (70% ÷ 100 = 0.7).



e.    Multiply the absolute WBC count by the absolute “polys” plus “band” count (5,000 × 0.7 = 3,500; therefore, ANC = 3,500/mm3).



9.    Absolute neutrophil count



a.    Normal. 1,500 to 7,200/mm3 (may vary in infants and with race)



b.    Interpretation:



i.    ANC less than 1,000. Moderate risk for infection



ii.    ANC less than 500. High risk for infection



10.  Absolute lymphocyte counts were once thought to be comparable across ages. Although total lymphocyte count and subsets of lymphocytes are equivalent percentages of the WBC count in all ages, the young child’s higher WBC count yields greater absolute numbers of lymphocytes and subsets of lymphocytes.



a.    A lymphocyte count of less than 15% to 20% of the differential WBC count is considered abnormal.



b.    Lymphocyte subset determinations are capable through monoclonal antibody technology. Quantifying lymphocyte subsets is useful in monitoring a patient’s response to immunosuppressive therapy during the organ transplant process, an infectious process or an immune disorder, and the effect of medications on the patient’s immune system.



i.    CD4 count (helper T lymphocyte). Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) may result in a transient decrease in CD4 helper cells (Lexicomp, 2004).



ii.    CD8 count (suppressor or cytotoxic T lymphocyte). Viral illnesses may result in a marked increase in CD8 suppressor or cytotoxic cells (Lexicomp, 2004).



iii.    CD4:CD8 (helper-to-suppressor or cytotoxic) lymphocyte ratio. Normally there are more helper than suppressor or cytotoxic T lymphocytes. The normal ratio is greater than 1.0 (Lexicomp, 2004). Patients initially diagnosed with AIDS commonly demonstrate an elevation of CD8 suppressor or cytotoxic cells below 400 and a decrease of CD4 helper cells, resulting in a low CD4:CD8 ratio (Lexicomp, 2004).


B.    Other Immune-Related Diagnostic Testing



1.    Erythrocyte sedimentation rate (ESR) is a nonspecific indicator of acute inflammatory response. In many cases, the ESR is so nonspecific that it has little clinical utility as a single value, but following trends is helpful to assess the effectiveness of therapies. In the 605immunocompromised child, it may be one of the few objective measurements of response to therapy or relapse.



a.    ESR measures the amount of RBCs that settle in 1 hour. Normal values for the modified Westergren technique range from 4 to 20 mm/hr for a child, 0 to 15 mm/hr for adult males, and 1 to 20 mm/hr for adult females (Gilbert-Barness & Barness, 2010; Grossman, 2014b).



b.    Elevated rates occur in many conditions, including acute and chronic inflammatory conditions, including cytokine release syndrome, hypersensitivity conditions, vasculitis, and systemic lupus erythematosus (Grossman, 2014b).



c.    Decreased rates occur in sickle cell anemia, polycythemia, spherocytosis, and congestive heart failure (Gilbert-Barness & Barness, 2010).



2.    C-reactive protein (CRP) is a nonspecific indicator of active inflammation.



a.    CRP, produced by the liver during periods of inflammation, enhances phagocytic activity of phagocytes, particularly of the neutrophil.



b.    CRP rises rapidly under an inflammatory stimulus, such as infection or injury. Levels are inappropriately low in systemic lupus erythematosus and scleroderma (Gilbert-Barness & Barness, 2010).



3.    Histocompatibility testing identifies the HLA antigens, the child’s genetic blueprint (Moriber, 2014).



a.    Histocompatibility testing is used for tissue typing for transplantation and forensics (Moriber, 2014).



b.    Two methods are used for histocompatibility testing: tissue typing and crossmatching.



i.    Tissue typing is the determination of an individual’s HLA class I and II specificities. This is routinely performed for organ and tissue transplantation using complement-dependent cytotoxic assay.



ii.    Crossmatching is performed before solid organ transplantation to prevent (or minimize) risk of rejection after surgery.



iii.    Crossmatching detects the presence of antibodies in the recipient’s serum that are directed against the HLA antigens of the potential donor. Various methods are used to complete HLA testing, with most patients awaiting transplantation undergoing initial crossmatching tests, including lymphocytes, T- or B-lymphocyte-enriched preparations, preformed antibodies, and auto-crossmatch.



c.    Molecular typing can be performed to define further DNA sequencing and assist in the selection of a more complete or precise match between the donor and recipient bone marrow cells.



4.    Complement assays evaluate the primary complement components of the classic pathway and some of the components of the alternate pathway (Mudge-Grout, 1992). Total hemolytic complement 50 (C5H50) is used to test the integrity of the entire complement system because the entire cascade must be intact to reflect a normal level. The individual complement components (both from a total and functional perspective) also are measured (Gilbert-Barness & Barness, 2010).



5.    Total immunoglobulin level and levels for the various classes and subclasses are measured. Normal immunoglobulin levels vary with age; therefore, it is imperative that age-adjusted values be used for all comparisons. Immunoglobulin levels can be diagnostic of congenital or primary immunodeficiencies (quantitative testing). If immunoglobulin levels are normal, in spite of suspected immunodeficiency, evaluation of the function and effectiveness of the immunoglobulin responding to an antigen may be indicated (qualitative testing).



6.    Coombs test, or direct antiglobulin test (DAT), is used to diagnose autoimmune hemolytic anemia (AIHA) through detection of immunoglobulin or complement on the RBC surface (Chou & Schreiber, 2015). Agglutination or clumping occurs if the RBCs are coated with antibodies or complement. The greater the quantity of antibodies against the RBCs, the more clumping will occur. Any clumping is read as a positive result using a scale of 1 to 4+. Coombs test differentiates types of hemolytic anemia and detects immune antibodies (Gilbert-Barness & Barness, 2010).



a.    Direct Coombs test is an antiglobulin test that determines that serum antibodies (IgG) have attached to RBCs. It is used to detect newborn hemolytic disease, autoimmune processes in newborns and children, or hemolytic transfusion reactions. After transfusion, a positive result may indicate an antibody-mediated hemolytic reaction, but a negative result does not rule out such a condition because the transfused RBCs may have been completely destroyed in the recipient’s bloodstream by the time the sample was drawn. A normal response is negative.



b.    Indirect Coombs test is a type of antibody screening that detects specific serum antibodies (IgG) to RBC antigens that are in the serum but not attached to the RBCs. It is used to detect IgG-positive antibodies in maternal blood and the 606newborn and is performed before RBC transfusions to detect any incompatibilities other than major ABO groups. A normal response is negative.



7.    Detection of antibody and antigens is accomplished through a variety of in vitro techniques such as immunodiffusion, agglutination, enzyme-linked immunosorbent assay (ELISA), monoclonal antibodies, radioimmunoassay (RIA), and others.



a.    ELISA. See “AIDS” section.



b.    Monoclonal antibodies are laboratory-produced antibodies for a single “destiny” antigen that are used for prevention, diagnosis, and treatment of graft rejection and graft versus host disease (GVHD).



i.    Monoclonal antibodies can also be used to monitor subsets of T lymphocytes at the site of organ graft to assist in the diagnosis or monitoring of graft rejection.



ii.    Monoclonal antibodies are used on serum, urine, sputum, and stool samples (among others) to diagnose infections with microorganisms such as herpes simplex virus, streptococci, Chlamydia, and Pneumocystis carinii.



iii.    Monoclonal antibodies assist in the identification of cells and tissues (e.g., B- and T-lymphocyte differentiation, or HLA or blood typing) and are used in the diagnosis of various diseases (e.g., cancer, autoimmune disease).



iv.    Monoclonal antibodies to various tumor antigens or tumor products can be used in vitro to confirm the diagnosis of certain types of cancers. A radioactive tracer can be attached to monoclonal antibodies so that after the monoclonal antibodies are administered, a body scan may reveal where the cancer is located.


C.    Coagulation



1.    Platelet Count



a.    Normal. 150,000 to 400,000/mm3



b.    For hemostasis, 50,000/mm3 is usually adequate.



2.    Prothrombin Time (PT). Assesses the extrinsic coagulation system by measuring factor VII and the common pathway or factors I (fibrinogen), II (prothrombin), V, and X.



a.    Normal. Control is usually 10 to 11 seconds (normal controls are established by the individual laboratory; Branchford & Di Paola, 2015).



b.    Abnormal values are the result of factors less than 40% (Browarsky, 2010).



c.    PT is prolonged with oral anticoagulants, DIC, liver disease, long-term use of antibiotics, vitamin K deficiency, and phenytoin use.



d.    Prolonged PT in the absence of other abnormalities may indicate factor VII deficiency (Branchford & Di Paola, 2015).



3.    International Normalization Ratio (INR). INR is the standardized method of expressing prolonged PT; this is helpful when monitoring Coumadin-type anticoagulants, as different thromboplastin preparations and different laboratories yielded diverse results (Branchford & Di Paola, 2015).



4.    Activated partial thromboplastin time (APTT) assesses the factor I (fibrinogen), II (prothrombin), V, VIII, IX, X, XI, and XII. APTT measures the time needed for a fibrin clot to form. The blood specimen is first mixed with a phospholipid source and surface-activating agent. The specimen is incubated for approximately 2 to 5 minutes and then an activating agent (calcium chloride) is added (Branchford & Di Paola, 2015).



a.    Normal APTT is usually 26 to 35 seconds (normal controls are established by the individual laboratory) in children, and 30 to 54 seconds in term infants (Branchford & Di Paola, 2015).



b.    APTT is prolonged with heparin therapy, DIC, severe vitamin K deficiency, liver disease, hemophilia, and some von Willebrand disease.



c.    Any sample with heparin contamination falsely elevates the PTT, thrombin time (TT), and FSPs. Contamination of central venous catheters with heparin may be a common cause of prolonged PT in hospitalized infants and children (Branchford & Di Paola, 2015). Venipuncture is a more reliable method for obtaining accurate values, although ensuring adequate “waste” prior to obtaining the specimen may assist with this limitation.



5.    TT reflects the time for thrombin to convert fibrinogen to fibrin.



a.    Normal. 10 to 15 seconds



b.    Results are normal in factor VIII deficiency.



c.    Results are prolonged when coagulation is inadequate due to decreased thrombin activity, DIC, antithrombin activity such as heparin therapy, insufficient or abnormal fibrinogen, or uremia.



6076.    Fibrinogen



a.    Although normal values of fibrinogen range from 200 to 400 mg/dL, only 70 to 100 mg/dL is required for hemostasis to occur.



b.    Decreased values reflect a risk of bleeding. Decreased values may be present in consumption disorders, such as DIC, and are also seen in hepatic dysfunction (Branchford & Di Paola, 2015).



c.    Increased values may reflect a hypercoagulable state or inflammatory conditions secondary to activation of plasma enzyme cascades.



7.    Ddimer. Measures the degradation of cross-linked fibrin; a specific test for DIC.



a.    Normal. A D-dimer level of 0.5 µg/mL is normal; any positive test is considered significant (Gilbert-Barness & Barness, 2010)



b.    Increased values are seen in DIC and inflammatory states.



8.    Specific factor assays measure amounts of each of the various plasma proteins such as II, V, VII, VIII, IX, XI, and XII.



9.    Thromboelastography (TEG) is a valuable study used to assess platelet function and the process of hemostasis, from clot formation to dissolution (Branchford & Di Paola, 2015).



10.  PFA-100 is a relatively new test, designed to simulate in vivo platelet adhesion and aggregation. This test may be useful in screening von Willebrand factor (vWF) levels, as it is inversely proportionate. Additional investigations are ongoing as PFA-100 accurately detects severe bleeding disorders that would likely have significant clinical symptoms adequate for diagnosis and is not currently sensitive or specific enough to screen for platelet disorders (Branchford & Di Paola, 2015).



11.  Platelet Function Tests. The most common is platelet aggregometry, which may be influenced by medications and may require a “wash out” period of approximately 10 days to provide an accurate result (Branchford & Di Paola, 2015).



12.  Global clotting assays, including TEG and thrombin generation assays (TGA) are gaining interest as a potential solution to the challenges of great phenotypic variability (Branchford & Di Paola, 2015).



a.    TEG. Monitors the entire process of coagulation from clot formation to its dissolution, providing a continuous profile of overall rheology changes (Branchford & Di Paola, 2015).



b.    TGA. Currently considered difficult to perform, although used extensively in research. Investigations of how to use TGA to monitor hemophilia treatment and anticoagulation therapy are underway (Branchford & Di Paola, 2015).



13.  Activated clotting time (ACT) is a bedside assessment that measures the level of heparin anticoagulation for patients on an extracorporeal life support circuit. A common target that balances the risk of bleeding and risk of clotting is between 180 and 200 seconds (Maclaren, Conrad, & Dalton, 2016).


D.    Blood Typing



1.    More than 300 different antigens have been identified against human blood cells, each of which can cause antigen–antibody reactions.



2.    ABO is one system for typing the antigens for individuals.



a.    There are four blood groups (phenotypes). An individual inherits a specific type of blood; each type of blood has a specific antigen makeup with the antibodies described.



i.    Group A. Natural anti-B antibodies are present in the plasma.



ii.    Group B. Natural anti-A antibodies are present in the plasma.



iii.    Group AB. No natural anti-A or anti-B antibodies are present in the plasma.



iv.    Group O. Both natural anti-A and anti-B antibodies are present in the plasma.



b.    ABO compatibility is essential for blood transfusion.



3.    Rh system is a second important blood antigen grouping system involving several other antigens found on RBCs.



a.    The most potent and easy to detect is the Rh D antigen. Absence of the D antigen is termed Rh negative. If the Rh D antigen is detected, the blood is termed Rh positive.



b.    A person first must be exposed to Rh antigen before a significant reaction will occur. IgG antibodies can develop to the Rh antigens after sensitization by prior transfusion or pregnancy. A transfusion of Rh-positive blood to a sensitized Rh-negative person can provoke acute hemolysis.



c.    Coombs test, or DAT, is used to determine the presence of IgG antibodies (Rh factor antibodies in an Rh-negative person).



6084.    Cold-Reactive Autoantibodies. IgM antibodies present in the plasma of some persons can cause RBCs to clump when (a) complement fixation occurs and (b) blood plasma temperature is below normal body temperature. Antibodies react to RBCs regardless of the blood type of donor blood and may lead to circulatory impairment and RBC hemolysis. Screening is done by indirect agglutination tests and actual measurement by the antiglobulin test. The reaction is often not significant clinically because optimal activation of these antibodies is at 4°C. Reduce potential for reactions by administering blood through a warming system.



5.    Warm-Reactive Autoantibodies. IgG autoantibodies can cause a patient to react to his or her own RBCs as well as donor cells at 37°C. In cases of warm reactive AIHA, the DAT may reveal IgG plus complement, IgG only, or complement only. Although not fully understood, there seems to be an association between the IgG subtype (IgG1, IgG2, IgG3, IgG4) and the strength of the reaction and rate of RBC destruction (Chou & Schreiber, 2015).


E.    Radiologic Examination



1.    Chest x-ray examination is commonly valuable in detecting and tracking various inflammatory or malignant processes. However, just as other signs and symptoms of infection are masked during neutropenia, the chest x-ray examination may also be unreliable in revealing pneumonia in some immunocompromised children (Dinauer et al., 2015). Thoracic CT produces a much higher yield and is recommended in those neutropenic patients at risk for a complicated pulmonary infection. It has been observed in some neutropenic patients that once the neutrophil count begins to increase to a near-normal level, the chest x-ray results may worsen, revealing the existing pneumonia.



2.    Diagnostic imaging studies of other areas of the body are indicated by the child’s history and physical examination.


F.    Biopsies



1.    Bone Marrow. The bone marrow may be examined through a bone marrow aspirate (aspiration of fluid of the bone marrow) and biopsy (needle core biopsy) of the bone.



a.    Purpose. Biopsy provides a histologic and hematologic examination of cellular components of the blood.



b.    Technique. The patient is usually sedated, and the patient’s respiratory status is closely monitored. The preferred site is the posterior, superior iliac crest. In the case of difficult procedures or if unable to place the patient in a prone position, it is possible to obtain aspiration and biopsy from the anterior iliac crest. If the patient is younger than 1 month of age, the preferred site is the tibia.



c.    A contraindication is respiratory compromise such that positioning the patient for the procedure would exacerbate the compromise.



d.    Complications include bleeding, pain, and infection at the site.



e.    Transfusions given just before a biopsy is done will not affect bone marrow results.



2.    Lymph Node Biopsy or Excision



a.    Purpose. The purpose is to evaluate the architectural structure and histologic characteristics.



b.    Techniques. The patient is usually under general anesthesia. Areas other than the inguinal area are preferred for biopsy as they pose less risk for infection. Use the inguinal site only if other sites do not demonstrate enlargement.



c.    Contraindication. Bleeding and the inability to safely administer adequate analgesia are contraindications of biopsy.



d.    Complications include bleeding, pain, and infection at the site.


HEMATOLOGIC AND IMMUNOLOGIC PHARMACOLOGY



Numerous medications affect the hematologic and immunologic systems of the body. Mechanisms by which pharmacologic agents directly affect the hematologic and immunologic systems include those that increase production of cell lines (e.g., CSFs or growth factors) or that decrease production or increase destruction of cell lines or entire bone marrow production (e.g., chemotherapeutic agents). Side effects of pharmacologic agents on the hematologic and immunologic systems vary in intensity and range of cells affected (one cell line vs. the entire bone marrow function).


A.    Therapeutic Modalities That Enhance the Functions of the Hematologic and Immunologic Systems



1.    EPO



a.    Indications include anemia of prematurity, chronic kidney disease, zidovudine-induced 609anemia, or anemia from bone marrow suppression following chemotherapy, medication administration, and bone marrow transplant (BMT). EPO is useful in other conditions for which transfusions are to be avoided, such as those not consenting to transfusions for religious reasons.



b.    Mechanisms of action. EPO promotes RBC production by stimulating the division and differentiation of erythroid progenitor cells. EPO first releases reticulocytes into the bloodstream, which is followed by an increase in hemoglobin and hematocrit (Lexicomp, 2016).



c.    Side effects are generally well tolerated.



i.    Irritation at the injection site may occur.



ii.    Self-limiting side effects include nausea, vomiting, and flu-like syndrome.



iii.    In adult patients who have had long-term hemodialysis therapy, hypertension, thrombosis, and seizures have been reported to be associated with EPO.



iv.    Black box warnings have been issued for erythropoiesis-stimulating agents related to increased risk of cardiovascular events, including myocardial infarction, stroke, venous thromboembolism, and mortality when the target hemoglobin levels exceed 11 g/dL. Increased risk for similar adverse cardiovascular events was reported in chronic kidney disease patients as well. In addition, breast, cervical, head and neck, lymphoid, and non–small-cell lung cancer patients were found to have shortened overall survival and/or increase tumor progression/recurrence risk when erythropoiesis-stimulating agents (ESAs) were administered to maintain hemoglobin >12 g/dL. A recommendation of using the lowest effective dose has been issued as a result of these warnings (Lexicomp, 2016).



2.    Myeloid Growth Factors. Filgrastim (G-CSF), sargramostim (GM-CSF; see Table 8.4 and Figure 8.1)



a.    Indications. Myeloid growth factors are used to reduce the duration of neutropenia (and associated infection risk) associated with administration of chemotherapy, immunosuppressants, or bone marrow transplantation. These growth factors are also being used in patients with severe chronic neutropenia due to congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia, in the treatment of neonatal neutropenia, and in AIDS patients receiving zidovudine (Lexicomp, 2016).



b.    Mechanism of action. Growth factors stimulate maturation of myeloid precursors.



i.    G-CSF effects are more selective than those of GM-CSF because G-CSF stimulates the production, maturation, and activation of neutrophils without affecting monocytes or eosinophils. G-CSF increases neutrophil migration and cytotoxicity (Lexicomp, 2016).



ii.    GM-CSF is multipotent or has the potential to stimulate the proliferation, differentiation, and functional activity of several cell lineages, including neutrophils, monocytes, eosinophils, and macrophages (Lexicomp, 2016).



c.    The most common side effect is a flu-like syndrome, including low-grade fever, bone pain, chills and rigor, myalgias, and headache. The severity of symptoms is variable and is influenced by the dose, route of administration, and schedule. Symptoms are reversible once the agent is discontinued, and recovery time is variable, ranging from days to several weeks. “First-dose effect” can occur with symptoms that include hypotension, tachycardia, flushing, and syncope. This is rare and limited to the first dose.


B.    Therapeutic Modalities That Depress the Functions of the Hematologic and Immunologic Systems



1.    Marrow-suppressive agents that are administered for another purpose but suppress RBC, WBC, and platelet production and activity.



a.    Chemotherapeutic agents



i.    Indications include cancer and immunologically mediated diseases such as rheumatoid arthritis or lupus nephritis.



ii.    Mechanisms of action. Chemotherapeutic agents interfere with the normal cycle of cell replication; they especially affect cells with short life spans or those in a constant state of reproduction such as blood cells, hair cells, and cells lining the GI tract.



iii.    Hematologic side effects involve failure of the bone marrow to develop the cell line. Such aplasia is dose dependent and usually reversible.



(Nurses administering chemotherapy and other biologic agents on a regular basis should receive training and maintain competency through the Association of Pediatric Hematology/Oncology Nurses [APHON] Chemotherapy and Biotherapy Provider Course.)



610b.    Antibiotics, antivirals, and antiretrovirals



i.    Chloramphenicol (Chloromycetin). Classic example



1)  Indications include infection by susceptible organisms, such as Salmonella, rickettsia, H. influenzae, or pathogens commonly found in patients with cystic fibrosis. Chloramphenicol crosses the blood–brain barrier and is particularly effective in central nervous system (CNS) infections caused by susceptible organisms. Newer cephalosporins, however, have largely replaced chloramphenicol for H. influenzae meningitis and its use is limited to situations where less toxic medications are either contraindicated or ineffective (Lexicomp, 2016).



2)  Mechanism of action is through inhibition of bacterial protein synthesis. It is usually bacteriostatic but can be bacteriocidal against common meningeal pathogens (H. influenzae, N. meningitidis, S. pneumoniae).



3)  Hematologic side effects are both dose related and idiosyncratic (e.g., aplastic anemia). Reversible bone marrow suppression, which is primarily characterized by anemia (with or without thrombocytopenia and leukopenia), is believed to be dose related. It is more likely to occur in patients receiving large doses, prolonged therapy, or serum concentrations greater than or equal to 25 mcg/mL. It is more common than aplastic anemia and is reversible within 1 to 3 weeks after the drug is discontinued. Hemolysis has occurred in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency who receive chloramphenicol. Bone marrow aplasia is rare, idiosyncratic, and frequently fatal. It is not dose related and occurs weeks to months after the drug is discontinued. The mechanism of action is unknown.



ii.    Trimethoprim–sulfamethoxazole (TMP–SMX, Bactrim)



1)  Indications include pneumocystis pneumonia (PCP; caused by Pneumocystis jirovecii pneumonia [PJP]) prophylaxis and treatment.



2)  Mechanisms of action. TMP–SMZ interrupts bacterial folic acid synthesis and growth as it inhibits dihydrofolic acid formation (Lexicomp, 2016). Most bacteria are more susceptible to the combination of agents than to either agent used alone. Individual agents at therapeutic levels are bacteriostatic, but the combination is usually bacteriocidal.



3)  Side effects. Most common are rash (secondary to a hypersensitivity to the sulfonamide component), fever, nausea and vomiting, and neutropenia. Less common are thrombocytopenia, hepatitis, azotemia, bone marrow aplasia, and hemolytic anemia (secondary to hypersensitivity and G6PD deficiency). Discontinuation of medication is associated with complete resolution of neutropenia.



iii.    Linezolid (Zyvox)



1)  Indications include community- and hospital-acquired pneumonia, skin and soft-tissue infections, endocarditis, and infection by other drug-resistant organisms such as vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus(MRSA; Lexicomp, 2016).



2)  Mechanisms of action. Bacterial protein synthesis is inhibited by preventing the formation of 70 S initiation complex, which is necessary for bacterial translation. Linezolid is bacteriostatic against enterococci and staphylococci and bacteriocidal against most streptococci (Lexicomp, 2016).



3)  Hematologic side effects include anemia, leukopenia, eosinophilia, neutropenia, and thrombocytopenia.



iv.    Zidovudine (previously known as azidothymidine, AZT; see “AIDS” section) was the first licensed antiretroviral drug for HIV infection.



1)  Mechanisms of action. Zidovudine, a thymidine analog, inhibits viral replication, interfering with viral RNA-dependent polymerase. Other dideoxynucleosides are commonly used in children (e.g., didanosine (or ddI), stavudine, lamivudine) and have less hematologic toxicity than zidovudine.



2)  Hematologic side effects involve anemia, neutropenia, and thrombocytopenia.



611v.    Ganciclovir



1)  Indications include prophylaxis and treatment of CMV in the immunocompromised patient; ganciclovir also provides antiviral activity against herpes simplex virus 1 and 2 (Lexicomp, 2016).



2)  Mechanisms of action. Ganciclovir is a derivative of acyclovir that belongs to a class of agents called purine nucleosides. This purine analog acts by incorporation into nucleic acids of DNA. This leads to abnormal transcription and translation and the loss of viral infectivity.



3)  Hematologic side effects. May cause anemia, neutropenia (ANC <500/mm3), and thrombocytopenia.



vi.    Foscarnet (Foscavir)



1)  An alternative to ganciclovir; indications include prophylaxis and treatment of CMV in the immunocompromised patient. Foscarnet also provides antiviral activity against herpes simplex virus infections and acyclovir-resistant herpes zoster infections (Lexicomp, 2016).



2)  Mechanisms of action. Foscarnet acts as a noncompetitive inhibitor of viral RNA and DNA polymerases. Foscarnet is a virostatic agent (Lexicomp, 2016).



3)  Hematologic side effects. May cause abnormal WBC differential, abnormal platelet function, bone marrow suppression leading to anemia, granulocytopenia, leukopenia, neutropenia, and thrombocytopenia (Lexicomp, 2016)



2.    Marrow-suppressive agents given to suppress one or more type of WBCs (therapeutic immunosuppression) that have dose-related effects leading to an increased risk of infection.



a.    Corticosteroids



i.    Indications include certain malignancies, treatment of acute or chronic GVHD, prevention and treatment of rejection of transplanted tissue, hypersensitivity reactions, and other inflammatory diseases. Corticosteroids do not reduce hemolysis in transfusion reactions, but they ameliorate drug-induced hemolysis. In ITP, corticosteroids are thought to act by inhibiting the phagocytosis of antibody-associated coated platelets, thus increasing the platelet life span.



ii.    Mechanisms of action. Corticosteroids alleviate temporary lymphocytopenia and reduce the migration of neutrophils and monocytes to sites of inflammation. Other actions include decreasing the number of cells available to participate in the inflammatory response; stabilizing the vascular beds by decreasing capillary permeability, thus inhibiting the movement of cells from the vascular space to the tissues; and reducing the functional capabilities of immunologically active cells. Corticosteroids increase the neutrophil count secondary to mature neutrophil release from the bone marrow and decrease movement of the neutrophils from the blood to the tissues.



iii.    Side effects are significant, especially with long-term use, and include hyperglycemia, hypertension, sodium and water retention, depression and sleep disturbances, increased risk of infection (especially viral and opportunistic infection), acne, delayed wound healing, and osteopenia.



b.    Cyclosporine A



i.    Indications include the prevention and treatment of GVHD; prevention of rejection of transplanted tissue, stem cells, or bone marrow; and treatment of other conditions such as severe aplastic anemia, nephrotic syndrome with focal glomerulosclerosis, and rheumatoid arthritis (Lexicomp, 2016).



ii.    Mechanisms of action. Cyclosporine A (CSA) depresses the body’s natural response to “nonself,” antigenic tissue. CSA binds to cyclophilin intracellularly, forming an active, protein–drug complex. CSA inhibits the production and activation of the cytotoxic T lymphocytes secondary to calcineurin inhibition. Once T cells are activated, however, CSA cannot suppress T-cell proliferation. Thus, CSA works well at preventing but not treating rejection of transplanted tissues. CSA inhibits macrophage release but has little effect on function of B lymphocytes or T suppressor cells and antibody production.



iii.    Administration. CSA is given intravenously or orally. Utilization of cyclosporine microemulsion (Neoral) has greatly reduced the absorptive variability previously associated with Sandimmune (Nevins, 2000). Continuous IV infusion is less toxic than bolus infusions and is often given in combination with steroids.



612iv.    Side effects include nephrotoxicity, hypertension, hepatotoxicity, neurologic disturbances (seizures and posterior reversible leukoencephalopathy syndrome [PRES]), hyperglycemia, gynecomastia, hirsutism, and gingival hypertrophy.



c.    Tacrolimus



i.    Indications. Tacrolimus (Prograf) is a potent immunosuppressant used for the prevention and treatment of organ rejection in kidney, heart, and liver transplants. The frequency of use in the prevention and treatment of GVHD is increasing, although this remains an off-label indication (Lexicomp, 2016).



ii.    Mechanism of action. Tacrolimus is a calcineurin inhibitor that suppresses the first phase of T-cell activation by blocking the production of calcineurin and IL-2 production.



iii.    Side effects include nephrotoxicity, neurotoxicity (tremor, seizure, PRES), GI disturbances, hypertension, hyperglycemia, hypomagnesemia, nephrotoxicity, and infectious complications. Posttransplant lymphoproliferative disorder (PTLD) is the most severe complication associated with tacrolimus. It is believed that PTLD occurs as the result of active Epstein–Barr virus replication.



d.    Sirolimus (Rapamune)



i.    Indications. Used in combination with corticosteroids or a calcineurin inhibitor to prevent or treat transplanted organ rejection, to prevent acute GVHD in allogeneic stem cell transplantation, to treat refractory acute or chronic GVHD, and is therapeutic in vascular anomalies (Lexicomp, 2016).



ii.    Mechanism of action. The mechanism of action for sirolimus differs from that of tacrolimus and cyclosporine. A mechanistic target or rapamycin (mTOR) inhibitor, sirolimus suppresses the second phase of T-cell activation.



iii.    Side effects are often dose related, and include increased serum creatinine, hypertension, hypertriglyceridemia, increased lactate dehydrogenase (LDH), infection, and impaired wound healing (Lexicomp, 2016).



e.    Mycophenolate mofetil (MMF, Cellcept)



i.    Indications include prevention of rejection of transplanted tissues, treatment of chronic GVHD, uveitis, and refractory immune thrombocytopenia (Lexicomp, 2016). MMF is almost always used in conjunction with other immunosuppressive therapies such as corticosteroids and calcineurin inhibitors.



ii.    Mechanism of action. MMF is hydrolyzed to form mycophenolic acid (MPA). MPA causes a depletion of certain amino acids within the purine biosynthesis pathway, resulting in a cytostatic effect on T and B lymphocytes (Lexicomp, 2016).



iii.    Side effects occur as the result of GI dysfunction (diarrhea, dyspepsia, anorexia, ulcers, pancreatitis), bone marrow suppression (leukopenia, neutropenia, anemia, thrombocytopenia), nephrotoxicity, and increased risk of infection.



f.    Azathioprine (Azasan, Imuran)



i.    Indications include prevention of kidney transplant rejection in adults and in the treatment of autoimmune diseases, including systemic lupus erythematosus, juvenile idiopathic arthritis, and inflammatory bowel disease (Lexicomp, 2016).



ii.    Mechanisms of action. Azathioprine is a purine synthesis inhibitor. It blocks RNA and DNA synthesis, thus preventing cytotoxic T-cell proliferation and antibody production. It inhibits promyelocyte proliferation within the bone marrow.



iii.    Side effects include bone marrow suppression, GI tract disturbances (nausea, vomiting, diarrhea), malaise, hepatotoxicity, increased risk of other cancers, and thrombocytopenia.



iv.    Special considerations. Serious drug interactions can occur with allopurinol (Zyloprim), which inhibits the metabolism of azathioprine, causing increased serum levels of these active metabolites (mercaptopurinol), leading to increased toxicity. Therefore, a reduced dose of azathioprine is required if a patient is receiving both of these medications.



g.    Lymphocyte immune globulin preparations



i.    Production. Purified polyclonal immune globulins are derived from animal sources (commonly equine or rabbit), which are injected with human thymus or lymphoid cells. Antibodies are formed against these cells and accumulate in the animal’s serum. The antibodies are extracted from the animal’s serum, followed by purification to yield the immune globulin.



613ii.    Indications include prevention or treatment of acute rejection of transplanted tissue, prevention and treatment of GVHD following bone marrow transplantation, and aplastic anemia.



iii.    Mechanisms of action. A purified, concentrated, and sterile gamma-globulin (IgG) reduces the number of circulating lymphocytes, making them susceptible to phagocytosis by macrophages.



iv.    Preparations.



1)  Antithymocyte globulin (ATGAM), also known as lymphocyte immune globulin, is produced from the serum of horses immunized with human thymus lymphocytes. It reduces the number of circulating, thymus-dependent lymphocytes.



2)  Antithymocyte globulin (Thymoglobulin) is derived from the serum of rabbits.



v.    Side effects of ATGAM and Thymoglobulin are similar and include fever, chills, anemia, thrombocytopenia, skin reactions (rash, pruritus, urticaria), and serum sickness-like symptoms (dyspnea; arthralgia; chest, back, and flank pain; diarrhea; nausea and vomiting).



vi.    Infusions should be administered over a period of time determined to be safe by the pharmacy. If the patient experiences fever, chills, or other mild symptoms during the infusion, the rate may be slowed to improve tolerance (Lexicomp, 2016).



vii.    Anaphylaxis is uncommon but may occur anytime during therapy. Observe the child continuously for possible allergic reactions throughout the infusion. Preinfusion treatment with an antipyretic, antihistamine, or steroid is highly recommended. Perform an intradermal skin test before administration to rule out serious allergic reactions before the administration of ATGAM. The patient may require ATGAM desensitization if the patient has positive results from a skin test. A test dose is not administered before the initiation of thymoglobulin; however, it is necessary to premedicate with an antipyretic, antihistamine, and steroid. Given the risk for serious reaction, immediate access to epinephrine and other emergency equipment is recommended (Lexicomp, 2016).



viii.    Other effects may include reactivation of CMV, herpes simplex virus, or EBV or antigen- or antibody-induced glomerulonephritis.



3.    Monoclonal Antibodies. Several types of monoclonal antibody are available for the treatment of hematologic, oncologic, and immunologic disorders. These include rituximab, infliximab, alemtuzumab, and eculizumab (Solaris, complement inhibitor).



a.    Rituximab (Rituxan, anti-CD20)



i.    Indications. Used to treat CD20-positive diseases, such as non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia, and systemic autoimmune diseases such as AIHA. In addition, Rituxan has been used in chronic GVHD, PTLD, and chronic ITP (Garzon & Mitchell, 2015; Lexicomp, 2016).



ii.    Mechanism of action. CD20 regulates cell cycle initiation; rituximab binds to the antigen on the surface of CD20 cells and activates complement-dependent B-cell cytotoxicity (Lexicomp, 2016).



iii.    Side effects. Fever, fatigue, chills, gastric disturbances, anemia, lymphopenia, leukopenia, neutropenia, thrombocytopenia, increased risk of infection, and infusion-related reactions such as angioedema, bronchospasm, fever, headache, changes in blood pressure, pruritus, rash, and urticaria (Lexicomp, 2016).



b.    Infliximab (Remicade, tumor necrosis factor blocking agent)



i.    Indications. Used to treat Crohn’s disease, ulcerative colitis, and severe rheumatoid arthritis (Food and Drug Administration [FDA] approved for adults at this time); Lexicomp, 2016).



ii.    Mechanism of action. Binds to tumor necrosis factor alpha and interferes with its activity, including induction of proinflammatory cytokines, enhancement of leukocyte migration, activation of neutrophils and eosinophils, and induction of acute-phase reactants (Lexicomp, 2016).



iii.    Side effects. May cause fatigue, chills, gastric disturbances, anemia, leukopenia, thrombocytopenia, increased risk of infection, and infusion-related reactions. Premedication for infusion-related reactions with acetaminophen and diphenhydramine 614may be considered. Patients with a history of severe reaction may also require corticosteroid premedication (Lexicomp, 2016).



c.    Alemtuzumab (Campath, anti-CD52)



i.    Indications. Current labeled indications include treatment of B-cell chronic lymphocytic leukemia and relapsing multiple sclerosis; however, off-label uses include administration as part of a stem cell transplant conditioning regimen, induction therapy for renal transplant, and treatment of steroid refractory acute GVHD.



ii.    Mechanism of action. CD52 is a nonmodulating antigen on the surface of B and T lymphocytes, that also affects monocytes, macrophages, NK cells, and certain granulocytes. Antigen-dependent lysis of malignant cells occurs after binding with CD52 (Lexicomp, 2016).



iii.    Side effects. May cause headache, fatigue, insomnia, skin rash, urticaria, gastric disturbances, anemia, lymphocytopenia, and increased risk of infection. Due to the increased risk of infection, prophylactic antimicrobials should be administered. In addition, antiemetics may prevent or reduce symptoms such as nausea and vomiting (Lexicomp, 2016).



d.    Eculizumab (Solaris, complement inhibitor)



i.    Indications. Current labeled indications include treatment of atypical hemolytic–uremic syndrome (a.0) and paroxysmal nocturnal hemoglobinuria (PNH; Lexicomp, 2016).



ii.    Mechanism of action. The MAC is blocked, which results in stabilization of hemoglobin and reduced need for transfusions of packed red blood cells (PRBCs). Eculizumab binds to complement protein C5, preventing cleavage to C5a and C5b fragments, thus inhibiting formation of terminal complexes (Lexicomp, 2016).



iii.    Side effects. May cause hypertension, peripheral edema, headache, skin rash, pruritus, gastric disturbances, renal insufficiency, fever, increased risk for infection, and infusion-related reactions. Due to the increased risk of infection, patients must receive the meningococcal vaccine at least 2 weeks prior to the initiation of treatment and education about serious signs/symptoms of infection should be provided. In addition, due to the risk of infusion-related reactions, patients should be monitored for 1 hour after completion of the infusion (Lexicomp, 2016).



4.    Platelet-Suppressive Agents. Given for another purpose that results in the suppression of platelet activity.



a.    Aspirin (ASA)



i.    Indications include the need for antipyretic, anti-inflammatory, analgesic, or antiplatelet effects.



ii.    Mechanisms of action. ASA inhibits platelet aggregation by inhibiting thromboxane A2 for the life of an exposed platelet (7–10 days). Effects do not disappear with drug clearance. ASA also inhibits prostacyclin.



iii.    Hematologic side effects include the prolongation of bleeding time to one to three times normal. If aspirin is given to those with liver disease or to those receiving anticoagulant therapy, the effects are amplified.



b.    NSAIDs (e.g., Ibuprofen, Naproxen)



i.    Indications include the need for anti-inflammatory, analgesic, and antipyretic actions.



ii.    Mechanism of action involves a decrease in function of platelets, which is reversible on the affected platelet when the NSAID is eliminated from the blood.



iii.    Hematologic side effects include prolonged bleeding time.



5.    Agents Affecting Plasma Clotting Factors



a.    Heparin is an anticoagulant made from porcine intestinal mucosa or bovine lung.



i.    Indications include prophylaxis and treatment of deep-vein thrombosis, pulmonary embolism, and other thromboembolic disorders. Also, heparin is used as an anticoagulant during extracorporeal procedures, hemodialysis or hemofiltration, cardiac catheterization, or for hemodynamic monitoring. Heparin may also be used for selected causes of DIC, such as acute promyelocytic leukemia (APL), and to maintain patency of vascular access devices.



ii.    Mechanisms of action. Heparin inhibits clot formation but has no effect on formed clots. It dramatically accelerates the body’s own anticoagulant mechanism, particularly that provided by antithrombin III (enhances the inactivation of thrombin II, inhibits X). Heparin promotes the destruction of factor X and has a direct inhibitory effect on factors IX, X, and thrombin. It also prevents conversion of fibrinogen to fibrin (Lexicomp, 2016).



615iii.    Administration. For acute thrombosis, continuous IV infusion is preferred. Titrate to maintain the PTT or APTT one and a half to two times normal (Lexicomp, 2016). After acute anticoagulation is achieved, initiate concomitant oral therapy with warfarin (Coumadin) or an alternative oral anticoagulant.



iv.    Side effects are reversed with protamine sulfate, which binds heparin to a complex that lacks anticoagulant activity. Bleeding occurs, especially with children who have deficiencies of coagulation factors, such as hemophilia, or those with liver disease, platelet dysfunction syndromes (such as with aspirin therapy), peptic ulcer disease, and severe hypertension. HIT is a potential side effect. See “Heparin-Induced Thrombocytopenia” section for more information.



b.    Warfarin (Coumadin) is an anticoagulant.



i.    Indications include prophylaxis thromboembolic disorders, chronic anticoagulant therapy, such as long-term oral treatment of deep venous thrombosis and prevention of intracardiac clot formations associated with decreased wall motion, such as chronic atrial fibrillation.



ii.    Mechanisms of action. Warfarin inhibits the liver’s activation of factor VII, followed by depression of factors II, IX, and X. It also increases plasma antithrombin III levels. Effectiveness is dependent on absorption from the GI tract, vitamin K status of the patient, and rate of hepatic metabolism of warfarin.



iii.    Administration. The oral route is used and dose is titrated to achieve an INR that is increased two to 3.5 times. Frequent, routine monitoring is required.



iv.    Side effects. Minor to life-threatening GI tract bleeding may occur. Side effects are reversed with vitamin K. Many drug interactions are possible, resulting in excessive anticoagulation; therefore, the nurse should consult with the pharmacist about any possible drug interactions before administration of warfarin.



c.    Apixaban (Eliquis) is an anticoagulant. At this time, safety and efficacy have not been established in patients younger than 18 years of age.



i.    Indications include reduction in risk of stroke and embolism in atrial fibrillation, thromboprophylaxis in acute medical illness, and treatment or secondary prevention of deep venous thrombosis and/or pulmonary embolism (Lexicomp, 2016).



ii.    Mechanisms of action. Apixaban is a direct activated factor Xa inhibitor.



iii.    Administration. The oral route is administered twice daily without regard to food. Apixaban may be preferable in some cases, as routine monitoring is not required while on this medication (Lexicomp, 2016).



iv.    Side effects. Sensitivity reactions, bleeding, risk of thrombosis if discontinued prematurely (Lexicomp, 2016).



d.    Fibrinolytic agents are drugs that dissolve clots (thrombus).



i.    Indications include great vein, atrial, arterial, and renal vein thromboses; occlusion of grafts; superior vena cava syndrome; and obstruction of vascular access devices such as central lines.



ii.    Mechanisms of action. Fibrinolytic agents promote conversion of plasminogen into plasmin and induce systemic fibrinolysis. Plasmin is a proteolytic enzyme that degrades proteins.



iii.    Specific agents



1)  Streptokinase, a biologic product of certain strains of streptococci, is antigenic in nature. Repeat exposures to this drug increase the risk of anaphylaxis and are not recommended.



2)  Urokinase, initially isolated from urine and fetal kidney cells, is produced using recombinant DNA technology and is not antigenic. This enzyme directly activates plasminogen. It has a lower incidence of allergic reactions than streptokinase, but availability varies.



3)  Alteplase (tPA) activates plasminogen in the presence of fibrin. It binds to fibrin in the clot and converts entrapped plasminogen to plasmin. Concurrent heparin or antiplatelet therapy is sometimes given. It has the advantage of relatively selectively activating only the plasminogen bound to fibrin.



iv.    Monitor fibrinogen levels, fibrinogen degradation products, PT, PTT, CBC; look for evidence of bleeding such as hematuria and gingival bleeding.



616v.    Side effects. There is an increased risk of bleeding in children who have had major surgery within the preceding 10 days, a biopsy, or a history of active bleeding, especially from the GI tract. As with heparin, risks of bleeding must be weighed against the risks of the thrombosis. Effects can be reversed with the administration of fresh frozen plasma (FFP).


BLOOD COMPONENT THERAPY



A.    Blood Products


Blood products commonly used for critically ill pediatric patients, indications, dosages, and nursing implications are outlined in Table 8.8.


B.    Special Donor Designation and Crossmatching Issues



1.    Knowledge regarding special donor requirements of individual patients is vital. Document the number of products available for immediate transfusion and when to send blood for type and cross.



2.    Donor-directed (designated) blood is the donation of blood by family or friends for a specific patient.



a.    This is not possible for emergent needs.



b.    This has not offered a safety advantage over volunteer donors. There is a potential for clerical errors resulting from the additional steps in the donation process as well as from inaccurate history disclosure.



c.    Directed donation from parents to neonates is not recommended due to maternal alloantibodies and maternal antibodies in the infant’s circulation.



d.    Directed donation from family members is not recommended for any patient who is a candidate for bone marrow transplantation.



3.    HLA-matched platelets are needed when a patient has developed antibodies to antigens on platelets (e.g., multiple transfusions). This minimizes the chance of reaction to donor platelets so that the patient achieves an adequate rise in platelet count.



4.    Patients who require lifelong transfusions (e.g., sickle cell disease patients) may develop multiple alloantibodies to donor blood antigens, which make crossmatching difficult.



5.    O-negative unmatched blood may be given to patients with an urgent, life-threatening need for RBCs.


C.    Modification of Blood Products


The goal of modification before transfusion is to minimize the risks of transfusions for patients with special needs.



1.    Leukodepletion is used for patients who have experienced febrile transfusion reactions to decrease frequency of recurrent febrile nonhemolytic transfusion reactions, reduce incidence of HLA alloimmunication, and reduce risk of transfusion-transmitted CMV (American Association of Blood Banks [AABB], 2017).



a.    Leukodepletion does not prevent transfusion-associated graft versus host disease (TA-GVHD; AABB, 2013).



b.    Apheresis granulocytes should not be administered through a leukocyte reduction filter (AABB, 2017).



2.    Irradiation



a.    This process destroys the leukocytes’ ability to engraft in the immunosuppressed patient at risk for TA-GVHD (AABB, 2013).



b.    Irradiation is indicated for patients who are susceptible to TA-GVHD, including recipients of products from a blood relative, patients who are receiving hematopoietic stem cell transplantation, select immunocompromised patients, and transplant candidates whose donor has been selected for HLA compatibility (AABB, 2013).



c.    Irradiated blood products pose no danger to healthcare personnel (AABB, 2013).



3.    Filtration at the Bedside



a.    To remove clots and aggregates, 150 to 260 micron filters are used.



b.    Each filtered set can be used for up to 4 units and should hang no longer than 4 hours.



c.    WBC filters may be used if indicated and if leukofiltration is not accomplished before storage at the blood bank.


D.    Administration of Blood Products


Recent literature has suggested a general hemoglobin threshold of 7 g/dL for PRBC transfusion in acute a critically ill children, with some exceptions based on cardiac pathophysiology and other specific conditions (Chegondi, Sasaki, Raszynski, & Totapally, 2016; Lacroix, Tucci, & Du Pont-Thibodeau, 2015).



1.    A blood warmer is indicated for transfusions of more than 1 unit of blood every 10 minutes, exchange transfusions in neonates, hypothermic patients, and those who have cold agglutinin disease.


617image


618image


619image



620a.    Warming prevents severe hypothermia, dysrhythmias, and cardiac arrest.



b.    Devices should be temperature controlled and heated through an inline system only.



c.    RBCs heated above 37°C may hemolyze.



2.    Mechanical pumps (e.g., volumetric or syringe pumps) may be used to administer RBCs at a specific rate with minimal hemolysis. Pumps should be tested and validated for use with blood components (AABB, 2013).



3.    Reduced-volume blood products (i.e., platelets) may be available from the blood bank and used for infants and children who need small-volume infusions or those who require a longer duration of infusion (AABB, 2013).



a.    RBC volumes may be ordered in small aliquots. Several aliquots may be prepared from a single donor unit, thus limiting donor exposure and risks.



b.    Small aliquots in specific amounts may be provided by the blood bank, occasionally in a syringe.


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621image


E.    Complications


Primary prevention includes meticulous verification of the patient’s identification and specific unit crossmatching. Table 8.9 summarizes reactions, signs and symptoms, and treatments for transfusion reactions. Early detection of reactions includes staying with the patient and administering the initial part of the transfusion slowly prior to increasing it to a more rapid rate (AABB, 2013).



1.    Hemolytic Reaction



a.    Most serious reaction occurs when the patient has antibodies to an antigen on the transfused RBCs (e.g., ABO incompatibility from mismatched blood).



b.    Reactions may be immediate (fever, hematuria, chills, dyspnea, chest/back pain), or delayed (2–14 days) after transfusion with anemia, unexplained fever, and decreased hemoglobin/hematocrit.



c.    Hemolytic reactions often result in a positive DAT (AABB, 2013).



d.    Acute reactions require supportive care, including correction of coagulopathy when present, maintenance of blood pressure, and careful attention to ensure adequate urine output. Delayed reactions usually require no treatment (AABB, 2013).



2.    Febrile Nonhemolytic Reaction



a.    In a febrile nonhemolytic reaction, the temperature increases by greater than or equal to 1oC as a result of an immune response to infused WBCs or the action of cytokines.



b.    Discontinue transfusion if patient’s temperature rises 1°C or more above baseline.



c.    The incidence of febrile nonhemolytic reactions decreases with the use of leukocyte-reduced blood products (AABB, 2013).



d.    Antipyretics may be administered for symptom relief (AABB, 2013).



3.    Allergic Reaction



a.    If the reaction is mild (local erythema, pruritis), transfusion is temporarily stopped, antihistamine is given, and infusion may be 622restarted if symptoms are resolving. Patient is pretreated with antihistamine before subsequent transfusions.



b.    Anaphylactic reactions with more severe symptoms of bronchospasm and hypotension are rare. Reaction typically occurs after a few milliliters of blood product is transfused, often in patients who are IgA or haptoglobin deficient. Interventions include discontinuing the product as well as administering epinephrine, fluids, and corticosteroids (AABB, 2013).



c.    Washed cellular products may be helpful in preventing or reducing the severity of such reactions (AABB, 2013).



4.    Alloimmunization



a.    Risk is related to the immunizing substances that exist in blood components, forming antibodies against antigens on the surface of donor cells. Primary immunization presents days to weeks after the immunization takes place and is often without symptoms. However, these antibodies will destroy future transfused cells that possess targeted antigens upon their subsequent transfusion.



b.    Alloimmunized patients who receive platelet transfusions receive no therapeutic effect. Single-donor or HLA-matched platelets may offset this problem.



c.    Patients who are alloimmunized against red cell antigens may hemolyze donor cells.



d.    Leukocyte-depleted blood components reduce risk of alloimmunization.



5.    Transfusion-associated circulatory overload (TACO) occurs when transfusion volume exceeds circulatory system capacity.



a.    Blood bank can divide red cells (aliquots) and provide “volume-reduced” platelets for volume-sensitive patients.



b.    Volumes and rates of transfusion should be based on patient’s size, fluid status, and clinical state.



c.    Treatment of pulmonary edema should be treated immediately, often with diuretics and supportive care, and administration of colloid products should be reduced (AABB, 2013).



6.    Transfusion-related acute lung injury (TRALI) is a serious immunologic complication posttransfusion, characterized by acute onset of hypoxemia and noncardiogenic pulmonary edema without other identifiable causes (AABB, 2013).



a.    Onset is within 6 hours of a blood component transfusion, and recognition of symptoms and potential correlation to a previous transfusion should prompt immediate notification of blood-bank services to complete necessary evaluations (AABB, 2013).



b.    The cause may be WBC antibodies from sensitized donors, prior transfusion or transplantation, or stores of proinflammatory molecules in the blood product (AABB, 2013).



c.    Treatment includes aggressive interventions to support the respiratory system, often including mechanical ventilation.



d.    One of the leading causes of transfusion-related mortality (El Kenz & Van der Linden, 2014)



7.    Citrate Toxicity



a.    CPDA (citrate–phosphate–dextrose–adenine) is still used in some blood centers to preserve blood. Citrate anticoagulant causes depression of ionized calcium (AABB, 2013).



b.    Patients who receive very rapid transfusions or multiple transfusions over a short period and patients with existing hepatic or renal dysfunction and those with circulatory collapse preventing adequate hepatic blood flow are at risk (AABB, 2013).



c.    Complications of citrate toxicity include the metabolic derangement of hypocalcemia (ionized). Ventricular arrhythmias may occur if large volumes of citrated blood products are delivered rapidly through a central venous catheter (AABB, 2013).



d.    Monitoring should include ionized calcium and electrocardiograms, as serum calcium is not necessarily reflective of ionized versus complexed hypocalcemia (AABB, 2013).



8.    Transmission of infectious diseases is greatest with paid donors, multiple transfusions, and pooled plasma fractions. Mandatory screening of donor blood for hepatitis (B and C), HIV, human T-cell lymphotrophic virus (anti-HTLV-I/II), West Nile Virus, and CMV before it is transfused decreases the risk.



9.    Bacterial transmission remains a risk of blood component transfusions. It is more likely for products that require thawing in a water bath or those stored at room temperature, such as platelets.



a.    Contamination is confirmed by prompt Gram staining of the residual blood in the blood 623bag. Also, culturing the blood bag and filter may provide further evidence of the specific organism.



b.    Clinical symptoms are noted in Table 8.9. Management includes immediate discontinuation of the transfusion, obtaining blood cultures, and initiation of broad-spectrum antibiotics plus supportive treatment.



c.    Bacterial sepsis may result from infected blood products, and will often present as high fever, chills, hypotension, and hemodynamic instability during or shortly after a blood product transfusion. Such reactions may require vasopressors and other interventions to maintain vital organ function in the pediatric intensive care unit (PICU; AABB, 2013).



10.  Coagulopathy can occur during massive transfusion (replacement of more than one blood volume).



a.    The patient’s body cannot replace more than a small fraction of coagulation factors and platelets, and stored blood has lost activity for platelet and coagulation factors.



b.    It is recommended that for every 3 units of RBCs administered, the child also receives 1 unit of FFP and 1 unit of platelets. Coagulation studies may be done to determine specific component requirements.



11.  TA-GVHD occurs when T lymphocytes present in donated blood react against recipient’s tissues. It occurs most often in severely immunocompromised patients or after bone marrow transplantation. TA-GVHD has also been reported in patients who were being treated with purine analogues such as fludarabine. Although leukocyte reduction is not adequate in the removal of T lymphocytes, this can be prevented by irradiation of donor blood (AABB, 2013).



12.  Metabolic complications are associated with massive transfusion or when a patient has severe liver or kidney disease. Hypothermia and hypocalcemia can occur and are addressed in Chapter 5. An additional metabolic abnormality may be hyper- or hypokalemia.



13.  Iron overload occurs with chronic infusions over an extended period (years) in patients with severe chronic anemia (e.g., sickle cell anemia). It is due to the quantity of iron administered by transfusion being greater than that which is excreted. Overload results in deposits of iron in the cells of the myocardial, endocrine, and liver cells, leading to organ damage. It is managed by giving an iron-chelating agent or phlebotomy.


SYSTEM DYSFUNCTIONS



Anemia


A.    Definition and Etiology


Anemia is defined as a reduction in red cell mass or blood hemoglobin concentration or a combination of the two.


B.    Pathophysiology


Pediatric anemia most frequently occurs as the result of a decrease in RBC production, an increase in RBC destruction, a combination of the two, or blood loss. Decreased production may be due to ineffective erythropoiesis or absolute failure of erythropoiesis. Aplastic anemia is associated with pancytopenia (decreased RBCs, platelets, and WBCs) and hypocellular bone marrow without dysplasia or fibrosis (Hartung, Olson, & Bessler, 2013).


C.    Clinical Presentation


The most significant problems seen in PICU patients with anemia include decreased oxygen carrying capacity, altered tissue perfusion, and altered fluid volume. Nursing assessment and management are targeted at these three key problems.



1.    History. Signs and symptoms of anemia vary with the rapidity of its onset and with the underlying cause. If anemia develops rapidly, signs and symptoms may be more pronounced. If anemia develops more slowly, compensatory mechanisms such as expanding plasma volume decrease the cardiovascular symptoms. The patient may have only slight dyspnea on exertion despite significant anemia. Young children will self-regulate dyspnea by decreasing their activity level. Patients may report a history of fatigue, cold intolerance, dizziness, dyspnea, and decreased physical activity tolerance (Brugnara et al., 2015).



2.    Physical Examination



a.    Clinical signs and symptoms include tachycardia, tachypnea, diminished level of consciousness, lightheadedness, postural hypotension, and pallor of skin and mucous membranes.



b.    Jaundiced skin and icteric sclera may be indicative of a hemolytic process.



6243. Diagnostic Tests



a.    Laboratory data. Hemoglobin less than two standard deviations below the mean for the normal population is considered consistent with anemia (Brugnara et al., 2015).



b.    Additional tests, including a complete blood cell count, reticulocyte count, and evaluation of a peripheral blood smear, will aid in the evaluation of anemia, potentially identifying other cell lines involved (Brugnara et al., 2015).



c.    Evaluation for G6PD, hemoglobin electrophoresis, and iron studies should also be performed (Brugnara et al., 2015).



d.    Studies to evaluate for intravascular hemolysis, such as LDH, will also assist in evaluation for hemolytic anemia (Brugnara et al., 2015).


D.    Patient Care Management



1.    Preventive Care



a.    Prevent iatrogenic anemia caused by large quantities of blood required for diagnostic procedures.



b.    Use smaller blood collection tubes; modern blood chemistry analyzers can perform a number of tests on a few drops of serum.



c.    Monitor and document cumulative total volume of blood drawn.



d.    Use diagnostic techniques to obtain capillary blood for testing whenever practical.



2.    Direct Care



a.    Administer blood products as ordered.



b.    Improve oxygenation. Reduce fear and anxiety to minimize oxygen demand. Assist in activities to reduce physiologic oxygen demand. Administer supplemental oxygen as ordered (only effective if adequate hemoglobin is present to carry the oxygen). Use semi-Fowler’s position for optimal ventilation–perfusion match.



c.    Administer EPO in selected situations to promote endogenous RBC production.



3.    Supportive Care



a.    Decreased gas exchange occurs related to decreased red cell mass or decreased hemoglobin production.


WBC Hypoactivity


A.    Definition and Etiology


WBC hypoactivity may be the result of decreased numbers of WBCs or subtypes of WBCs, or a consequence of dysfunction within WBCs.


B.    Pathophysiology


Various conditions may cause WBC hypoactivity, including deficiencies, pharmacologic therapies, and the presence of malignancy.


C.    Clinical Presentation



1.    History



a.    In some cases, WBC deficiency will be diagnosed at birth on a newborn screening evaluation.



b.    In others, patients may present with a history of multiple or atypical infections.



2.    Physical Examination



a.    Local signs and symptoms of inflammation include erythema, edema, warmth, pain, and decreased function of an affected area. Also note the presence and characteristics of exudate (serous vs. suppurative).



b.    Systemic clinical signs and symptoms of infection include body temperature below 36°C or above 38°C, tachycardia, tachypnea, altered mental status (e.g., confusion, irritability), diaphoresis, rigors or chills, and generalized symptoms such as change in activity level, fatigue, or malaise.



3.    Diagnostic Tests



a.    Alterations in WBC count. Leukocytosis, leukopenia, increased number of bands



b.    Positive blood or body fluid cultures



c.    Significant findings in site-specific diagnostic tests (e.g., pneumonia demonstrated on a chest radiograph)


D.    Patient Care Management



1.    Preventive Care



a.    Institute good handwashing and universal precautions for all individuals who may have contact with the patient. Use proper technique for initiating and maintaining all intravascular 625lines and during all invasive procedures. Promote optimal fluid and nutritional intake.



b.    Ensure a clean environment and restrict the patient’s contact with individuals who may have infectious processes. Use a health screening tool for siblings wishing to visit the patient. Prevent the spread of infectious processes through the use of appropriate isolation procedures.



c.    Critically ill children have a higher risk of developing impaired skin integrity secondary to inadequate nutrition, decreased oxygenation/perfusion, immobility, immunosuppression, and use of medical technology and invasive procedures. The goal of nursing care is to promote skin integrity.



d.    Assess and monitor skin integrity, body orifices, IV sites, and pressure areas for evidence of inflammation, infection, or skin breakdown.



2.    Direct Care



a.    Nurses caring for hematology/oncology patients on a regular basis should familiarize themselves with the clinical practice guidelines from the professional organization dedicated to the nursing care of these patients, the APHON.



b.    Assess for and differentiate between inflammation and infection, which are not synonymous terms. Although all infections occur in the presence of inflammation, not all inflammation indicates infection. Infection is the pathologic process caused by the invasion of normally sterile tissue, fluid, or body cavity by pathogenic or potentially pathogenic microorganisms (Levy et al., 2003). Special attention must be paid to patients in whom the cardinal signs of the local inflammatory response may be diminished or absent (e.g., immunocompromised patients, patients receiving medications suppressing the inflammatory response, newborns with a delayed or limited ability to localize infection). In these patients, the most reliable signs of the local inflammatory response are often pain, fever, and other subtle changes in the vital signs.



c.    Assess and monitor specific sites for infectious processes.



i.    Pulmonary or lower respiratory tract infection. Note tachypnea, any change in level of consciousness, feeding, behavior or activity level, presence of cough, signs of respiratory distress, and abnormal breath sounds.



ii.    Bacteremia, both primary and catheter related. Note systemic signs and symptoms of infection.



d.    Assess for and differentiate between systemic infection and a systemic inflammatory response syndrome. SIRS is the acute development of two or more of the following (American College of Chest Physicians/Society of Critical Care Medicine, 1992):



i.    Fever (>38°C) or hypothermia (<36°C)



ii.    Tachycardia (outside age-appropriate range)



iii.    Tachypnea (outside age-appropriate range)



iv.    Alteration in WBC count, either leukocytosis (WBC >12,000/mm3; use age-appropriate range [see Table 8.6]), leukopenia (WBC < 4,000/mm3), or greater than 10% bands



v.    It is important to note that there has been debate about the sensitivity and specificity of SIRS criteria. Adult criteria is evolving and the pediatric nurse is encouraged to stay informed as these guidelines and recommendations evolve.



e.    Administer prescribed antimicrobial agents and monitor response. Dilute medication per formulary guidelines to diminish venous irritation and ensure complete administration by following antibiotic with an adequate flush. Establish a schedule to maximize pharmacologic effects and minimize late administration. Assess for superinfections that may occur with long-term antibiotic use. Accurately obtain labs to assess kinetic levels of antimicrobials as ordered.



f.    Administer granulocytes or biologic response modifiers as ordered.



g.    Institute measures to decrease the patient’s risk of infection with endogenous organisms. Assist in personal hygiene measures (oral care, etc.) as indicated. In collaboration with the physician, explore the possibility of using the patient’s GI tract for feeding to minimize the risk of bacterial translocation.



3.    Supportive Care



a.    Administer supportive care per PICU guidelines paying careful attention to organ function and frequent assessment to identify dysfunction promptly.



626b.    Support the family of a critically ill child with explanations of care, education, and opportunities for involvement in family-centered care as appropriate.



4.    Collaborative Diagnoses and Comorbidities



a.    Patients are at risk for infection resulting from unintentional stressors (e.g., immunodeficiency, malnutrition, iatrogenic interventions such as placement of multiple invasive devices, immobility, or environmental pathogens) or intentional stressors (e.g., bone marrow suppression in preparation for transplantation or therapeutic regimens, including chemotherapy or radiation).



i.    Differentiate between hyperthermia and fever:



1)  Hyperthermia occurs when body temperature exceeds the set point secondary to cytokine activity. This response is often secondary to microorganisms and substances called pyrogens. Noninfectious processes can also cause fever, such as malignancy and pulmonary emboli (Porth, 2015).



2)  Hyperpyrexia, or fever, is an elevation in set point such that the body temperature is regulated at a higher level and typically occurs as the result of an infectious process.



ii.    Clinical signs and symptoms of fever include elevated temperature of 38° to 41°C. Young infants and immunocompromised patients may respond with hypothermia in the presence of infection. Other symptoms include tachycardia; tachypnea; altered mentation, confusion, or irritability; warm, dry skin with flushed cheeks; and diaphoresis.



iii.    Positive implications of increased temperature include enhanced activity of cells of the immune system and a nonconducive environment for the growth and activity of invading microorganisms (antigens). Negative implications of increased temperature include increased metabolic demand, increased insensible water loss and potential dehydration, discomfort, and fatigue.



iv.    Interventions



1)  Monitor and document fever pattern. In collaboration with the physician or advanced practice provider, determine the cause of fever. Fever may be the only sign of infection in the immunocompromised patient, and the patient is presumed to have an infection until proven otherwise.



2)  Monitor for dehydration. Estimate insensible water losses. In collaboration with the physician or advanced practice provider, evaluate the need for adjustment of fluid requirements.



3)  Identification of the source of infection is a primary concern in a febrile patient. Indwelling catheters should be sampled for culture. If possible, two peripheral blood samples should be obtained from separate venipuncture sites. Other cultures that may be obtained include sputum, tracheal, routine urinalysis and culture, and a stool examination and culture (especially if diarrhea is present).



4)  In collaboration with the physician or advanced practice provider, consider the administration of antipyretics (only after the fever is evaluated) and broad-spectrum antibiotic therapy (until the specific cause of the infection is determined). Keep in mind that some antipyretics, such as ibuprofen, may affect the platelets in such a way that they are contraindicated in the thrombocytopenic patient.



5)  Institute measures to decrease the temperature when the patient is febrile. Remove excess clothing or bed linens. Apply cool moist compresses, especially to the forehead and axilla. Use a cooling blanket but discontinue use if shivering ensues. Prevent chills or shivering because the associated peripheral vasoconstriction may actually further increase body temperature and decrease heat loss (Porth, 2015).



6)  Institute measures to increase comfort when the patient is febrile. Change wet bed linens in the presence of diaphoresis or with the use of a cooling blanket. Cool the patient’s room if possible. Provide rest periods.



7)  If possible, discontinue medications that may cause fever as an adverse reaction.



627b.    Patients are at risk for altered integrity of mucous membranes resulting from oral infection or the side effects of chemotherapy or radiation.



i.    Assessment



1)  This is a common, dose-limiting toxicity caused by chemotherapy, radiation, and neutropenia.



2)  Clinical signs and symptoms are variable and range from reddened areas to deep ulcerations. Other manifestations include pain; dysphagia; thick oral secretions; the presence of white patches; cracked, dry lips; scalloping of the tongue edges; and drooling. The risk of infection increases greatly with impaired tissue integrity within the oral cavity. The fungal infection candidiasis (moniliasis or thrush) is identified by microscopic examination of scrapings (Porth, 2015). Appropriate antifungals, such as nystatin mouth rinse, may be indicated.



ii.    Implications of altered oral mucous membranes include impaired integrity and increased risk of infection, inadequate nutritional intake or absorption, pain, and difficulty swallowing or speaking (if not intubated).



iii.    Interventions. Assess and monitor the condition of the oral mucosa. Institute measures to prevent inflammation (mucositis) or to prevent further injury to existing inflammation. Avoid exposure to chemical or physical irritants, and provide adequate fluid intake. Provide oral hygiene measures at least three times a day. Provide treatment based on assessment findings, and institute measures to increase comfort. If the patient is able to tolerate PO intake, encourage bland, soft foods that are not especially dry for pain control and effective swallowing.


WBC Hyperactivity


Hypersensitivity Reactions


A.    Definition and Etiology


Hypersensitivity reactions are classified according to the source of the antigen that stimulates the immune response (Table 8.10). Type I immediate hypersensitivity reaction or anaphylaxis results in hyperactivity of the surveillance function of the immune system.


B.    Pathophysiology


The pathophysiology of the four types of hypersensitivity reactions are described in Table 8.10.


C.    Clinical Presentation



1.    History. Clinical signs and symptoms typically occur within minutes of exposure to the antigen and are the result of the action of inflammatory mediators on surrounding tissues and blood vessels (Porth, 2015).



2.    Physical Examination



a.    Increased capillary permeability can lead to profound hypotension, circulatory collapse, and facial edema.



b.    Constriction of smooth muscle can result in wheezing, crackles, and progressive difficulty in breathing and stridor.



c.    An influx of eosinophils can produce erythema and pruritus.



3.    Diagnostic Tests. Although a hypersensitivity reaction may prompt testing for allergies and sensitivities, diagnostic confirmation is not required at the time of an actual reaction and should not be performed as it may delay critical interventions.


D.    Patient Care Management



1.    Diagnosis and management of anaphylaxis are based on clinical manifestations.



2.    Maintain oxygenation and ventilation. Administer supplemental oxygen as needed. Intubation and mechanical ventilation may be necessary. In the presence of tracheal or laryngeal edema, intubation may be difficult and there is a possibility that the patient may require an emergency tracheotomy. Epinephrine 1:1,000 is administered for treatment of bronchoconstriction, per pediatric advanced life support (PALS) protocol.



3.    Support circulation with fluid administration and epinephrine administration to counteract vasodilation. Other vasoactive medications (e.g., dopamine, norepinephrine) may be required.



4.    Administer Prescribed Medications. Antihistamines serve as antagonists to most of the effects of histamine. Bronchodilators relax bronchial smooth muscle. Corticosteroids are anti-inflammatory agents that serve to enhance the effects of bronchodilators.



5.    Identify the antigen and avoid future exposures.


628TABLE 8.10    Hypersensitivity Reactions
























Type


Description


Example


Type I (anaphylactic reaction)


Triggered in response to an exposure to an environmental antigen


Mediated by IgE antibodies that bind to specific receptors on the surface of mast cells and basophils


Results in the release of a host of mediators to produce a classic anaphylactic response


Anaphylaxis


Asthma


Allergic rhinitis, hay fever


Type II (tissue-specific hypersensitivity)


Triggered by the presence of an antigen found only on a cell or tissue


Mediated by antibody (usually IgM, but also IgG) through two different mechanisms (complement and Fc receptors on phagocytes)


Results in the destruction of the antibody-coated cell with consequences dependent on the cell that is destroyed (e.g., RBC, WBC, or platelet)


ABO incompatibility


Rh incompatibility


Drug-induced thrombocytopenia


Type III (immune complex reaction)


Triggered by the formation of antigen–antibody complexes that activate the complement cascade


Immune complexes are formed in the circulation and are later deposited in blood vessels or healthy tissue; multiple forms of the response exist depending on the type and location of the antigen


Results in local edema and neutrophil attraction and thus degradative lysosomal enzymes resulting in tissue injury


Serum sickness


Glomerulonephritis


Type IV (delayed hypersensitivity)


Triggered by the recognition of an antigen


Mediated by activated T lymphocytes and release of lymphokines, which then stimulate the macrophage to phagocytize foreign invaders and some normal tissue


Results in a delayed onset; does not have an antibody component; this response is strictly a cellular reaction


Contact sensitivities such as poison ivy and dermatitis


Tuberculin reactions


Graft rejection


Ig, immunoglobulin; RBC, red blood cell; WBC, white blood cell.


Autoimmune Disease


A.    Definition and Etiology


Autoimmune disease is the hyperactivity of the homeostasis function of the immune system.


B.    Pathophysiology



1.    The homeostasis function of the immune system removes old and damaged “self” components from the body.



2.    The immune system mistakenly identifies itself as “nonself” and begins to form antibodies (autoantibodies) against its own healthy cells (autoantigens). This results in the development of immune complexes that are deposited in tissues (e.g., skin, joints, kidneys) and in tissue damage.


C.    Examples of autoimmune diseases of childhood include systemic lupus erythematosis and juvenile-onset diabetes mellitus.


PLATELETS AND PLASMA FACTORS



Bleeding Disorders


A.    Definition and Etiology


Bleeding disorders may be the result of inadequate platelet production, excess platelet destruction, abnormal function, impairment of the coagulation stage of hemostasis, or disordered vessel integrity (Grossman, 2014c).


B.    Pathophysiology



1.    Bone marrow dysfunction, as in the case of severe aplastic anemia, causes inadequate platelet production.



2.    Platelet destruction is the result of an immune process, such as the platelet antibodies responsible for ITP, or a nonimmune process such as mechanical destruction by prosthetic valves or excess consumption in processes such as acute DIC or TTP.



3.    Defects in von Willebrand factor or other inherited diseases, such as hemophilia A and B, are responsible for disordered bleeding.



6294.    Bleeding may be the result of medications that predispose a patient to bleeding, such as heparin, NSAIDs, and aspirin (Grossman, 2014c).


C.    Clinical Presentation



1.    History



Patients and caregivers may report a history of excessive bruising or bleeding. Reports of blood in the stool, emesis, urine, or during routine activities, such as flossing or brushing teeth, should alert the healthcare provider to a potential bleeding disorder. In addition, the history may reveal prolonged bleeding after minor injuries.



2.    Physical Examination



a.    Assessment should include vital signs (tachycardia and hypotension), fluid and electrolyte status (decreased urine output, emesis, diarrhea), characteristics of fluid losses (assess for gross or occult blood), perfusion status, capillary refill, mental status, and urine output.



b.    Use urine and stool tests to detect the presence of blood.



3.    Diagnostic Tests



a.    Coagulation studies, including the PT, PTT, and fibrinogen, should be assessed.



b.    Additional studies to evaluate factors VIII and V may also be indicated, as well as an evaluation of natural anticoagulants, including protein C, protein S, and antithrombin III.



c.    TEG and TGA, as described previously in this chapter, may also be useful as a global clotting assays (Branchford & Di Paola, 2015).


D.    Patient Care Management



1.    Preventive Care



a.    Identify which patients are at increased risk for bleeding.



b.    Avoid intramuscular and subcutaneous injections; if necessary, apply pressure for 10 minutes. If intravascular access is needed, peripheral IV access rather than central access poses less risk for trauma and bleeding to the patient.



c.    Provide a safe environment, such as padding the side rails and other firm surfaces, especially if the child is combative or at risk for seizure activity.



d.    Do not administer aspirin or NSAIDs because of their effects on platelets. Parents should be taught to read nonprescription medication labels to avoid giving the child aspirin.



e.    Prevent intracranial bleeding related to increased intracranial pressure. Teach the patient to avoid the Valsalva maneuver and to cough, sneeze, and blow nose gently.



f.    Administer stool softeners.



g.    Provide mouth care with foam swabs and a mild saline or bicarbonate and peroxide solution. Do not floss if thrombocytopenia is present.



h.    Administer vitamin K (normally obtained from diet and enteric bacterial synthesis) when indicated. Vitamin K is needed for factors II, VII, IX, and X to be effective. Deficiencies are seen with malnutrition, obstructive biliary disease, liver disease, and with use of certain broad-spectrum antibiotics. Vitamin K can be administered orally if absorption is not impaired, subcutaneously, intramuscularly, and intravenously. Anaphylactoid reactions are rare but are seen more often with the IV route (Pipe & Goldenberg, 2015).



2.    Direct Care



a.    Volume replacement. Administer crystalloids or colloids or both, blood products, and vasoactive infusions as ordered.



b.    Control of bleeding. Apply direct pressure or cold compresses, and elevate the extremity. Application of topical hemostatic agents may also be necessary.



3.    Collaborative Diagnoses and Comorbidities. Hypovolemia related to bleeding


RBC DISORDERS



Sickle Cell Disease


A.    Definition and Etiology



1.    Sickle cell disease (SCD) is the general term used to describe a group of genetic disorders that are characterized by mutations in the hemoglobin gene. These mutations lead to sickling of the RBCs in response to deoxygenation.



2.    SCD is a serious, chronic, autosomal-recessive, hemolytic disease. The most common forms are hemoglobin SS disease (HbSS), hemoglobin SC disease (HbSC), hemoglobin S-beta thalassemia (HbSβthal), and other rare variants. Clinical manifestations will vary in type and severity among each of these phenotypes.



6303.    SCD occurs almost exclusively in individuals of African descent and typically manifests at approximately 1 year of age when most of the fetal hemoglobin (HbF) has been replaced with HbSS or HbSC (Heeney & Ware, 2015)


B.    Pathophysiology



1.    When the oxygen saturations fall, RBCs with HbSS (an abnormal form of hemoglobin associated with SCD) become crescent or sickle shaped. These sickled RBCs become trapped in small vessels, leading to erythrostasis and occlusion of the microvasculature. Hypoxemia, acidosis, hypothermia or hyperthermia, and dehydration lead to further sickling and increased viscosity of the blood.



2.    Masses of sickled RBCs occlude blood vessels, leading to thrombosis, ischemia, and infarction. Specific organs involved will present with signs of hypoperfusion, vascular occlusion, and tissue ischemia. The body recognizes and hemolyzes the abnormal RBC structure. Sickled RBCs may return to normal shape when the blood is more oxygenated (such as in the pulmonary vein). However, after repeated occasions, a portion of RBCs released into free circulation will be more sensitive to mechanical trauma, even normal trauma experienced during circulation, or they will not return to their nonsickled shape even when the blood is well oxygenated.


C.    Clinical Presentation



1.    History



a.    Nearly all states (44 per the 2015 publication by the National Institutes of Health [NIH]) provide screening for SCD as part of the newborn screen, which will assist in diagnosis prior to requirement of a blood transfusion or development of clinical manifestations.



b.    High-risk infants, identified as those of African, Mediterranean, Middle Eastern, Indian, Caribbean, and South and Central American ancestry, should be screened if they are born in states that have not standardized a hemoglobinopathy initial screening test (NIH National Heart, Lung, and Blood Institute, 2015).



2.    Physical Examination



a.    Clinical manifestations occur secondary to the anemia and organ dysfunction caused by vascular occlusion. Specific symptoms include painful episodes, including aching bones, especially hands and feet in infants; sudden severe abdominal pain; chest pain; and splenomegaly in young children. Older children and adolescents with SCD may report pain in the lumbosacral spine, knee, shoulder, elbow, and femur.



b.    The spleen is nonfunctional in children with HbSS disease, even if the spleen is enlarged.



c.    SCD is not associated with bleeding.



d.    Impaired growth and development, failure to thrive, and increased tendency to develop serious infections are results of decreased splenic function (Table 8.11).



3.    Diagnostic Tests



a.    Peripheral blood smear will show sickled erythrocytes. If only the sickle cell trait is present, the smear will be normal.



b.    Hemoglobin electrophoresis indicates the precise type of hemoglobinopathy as it differentiates between types of hemoglobin and reports the percentage of blood composition of each.



c.    CBC reflects hemolytic anemia with reduced hemoglobin, hematocrit, and RBC count because the spleen has destroyed sickled cells. Platelets and reticulocyte count may be elevated as a compensatory response to anemia.



d.    Bilirubin may be elevated because of the hemolysis of the sickled cells.



e.    Radiologic findings



i.    Bone x-rays may show no abnormality in the face of severe bone pain.



ii.    Chest x-rays may show cardiomegaly and pulmonary infiltrate with acute chest syndrome (ACS).



iii.    Transcranial Doppler screen (TCD) measures the blood velocity in the circle of Willis. Identification of intracranial arterial vasculopathy and thus, higher risk of stroke, is possible via this method. Interventions for primary and secondary stroke prevention based on this assessment have proven effective (Heeney & Ware, 2015).



iv.    CT scan and MRI/magnetic resonance angiography (MRA) should be performed after stabilization if a cerebrovascular accident (CVA) is suspected.


D.    Patient Care Management



1.    Pain Management: Supportive Interventions



a.    Prevent pain by rapid recognition and management of dehydration, hypoxemia, and acidosis to prevent sickling.


631TABLE 8.11    Clinical Manifestation of Sickle Cell Anemia*
































































Manifestation


Comments


Anemia


Chronic, onset 3–4 months of age; may require folate therapy; hematocrit usually 18%–26%


Aplastic crisis


Parvovirus infection, reticulocytopenia; acute and reversible; may need transfusion


Sequestration crisis


Massive splenomegaly (may involve liver), shock; treat with transfusion


Hemolytic crisis


May be associated with G6PD deficiency


Dactylitis


Hand–foot swelling in early infancy


Painful crisis


Microvascular painful vaso-occlusive infarcts of muscle, bone, bone marrow, lung, intestines


Cerebrovascular accidents


Large- and small-vessel occlusion → thrombosis/bleeding (stroke); requires chronic transfusion


Acute chest syndrome


Infection, atelectasis, infarction, fat emboli, severe hypoxemia, infiltrate, dyspnea, absent breath sounds


Chronic lung disease


Pulmonary fibrosis, restrictive lung disease, cor pulmonale


Priapism


Causes eventual impotence; treated with transfusion, oxygen, or corpora cavernosa-to-spongiosa shunt


Ocular


Retinopathy


Gallbladder disease


Bilirubin stones; cholecystitis


Renal


Hematuria, papillary necrosis, renal-concentrating defect; nephropathy


Cardiomyopathy


Heart failure (fibrosis)


Skeletal


Osteonecrosis (avascular) of femoral or humeral head


Leg ulceration


Seen in older patients


Infections


Functional asplenia, defects in properdin system; pneumococcal bacteremia, meningitis, and arthritis; deafness from meningitis in 35%; Salmonella and Staphylococcus aureus osteomyelitis; severe Mycoplasma pneumonia


Growth failure, delayed puberty


May respond to nutritional supplements


Psychologic problems


Narcotic addiction (rare), dependence unusual; chronic illness, chronic pain


G6PD, glucose-6-phosphate dehydrogenase.


*Clinical manifestations with sickle cell trait are unusual but include renal papillary necrosis (hematuria), sudden death on intraocular hyphema extension, and sickling in unpressurized airplanes.


Source: From Scott, J. P. (2000). Hematology. In R. E. Behrman & R. M. Kliegman (Eds.), Nelson’s essentials of pediatrics (4th ed.). Philadelphia, PA: W. B. Saunders.



b.    Obtain a history of past and present pain management.



c.    Conduct frequent, ongoing pain assessments using the appropriate pain scale for age, developmental level, and clinical condition.



d.    Use analgesics and anti-inflammatory agents as indicated and ordered. Monitor effectiveness in decreasing pain. Patient-controlled analgesia is an effective method to use to achieve adequate pain control.



e.    Use nonpharmacologic pain management techniques as indicated (e.g., heat, massage, distraction, guided imagery).



f.    In selected clinical situations (e.g., severe ACS) RBC transfusion or exchange transfusion is given to decrease the percentage of 632HbSS-containing RBCs. Goal is usually a hematocrit of 25% to 30% with less than 30% HbS. Avoid raising the hematocrit to more than 35% because this will increase the viscosity of the blood and promote increased sickling.



2.    Bed rest minimizes oxygen demand and consumption.



3.    Hydroxyurea. Hydroxyurea enhances the production of HbF, thereby decreasing the ability of the RBCs with HbSS to sickle. Indications for hydroxyurea therapy are limited to severe complications such as frequent pain episodes, acute chest, severe symptomatic anemia, or other severe vaso-occlusive events. Frequency monitoring for toxicities is required for patients receiving hydroxyurea therapy. In addition, guidance regarding contraception methods is necessary for males and females, as hydroxyurea is a teratogen (NIH, 2015).



4.    Bone marrow or stem cell transplant is the only current therapy that may provide a cure for SCD. Results of matched sibling donor (MSD) bone marrow transplantation are promising, with reports of greater than 90% survival and approximately 85% survival without SCD. Research regarding the use of alternative donors, such as umbilical cord blood (UCB), matched unrelated donors (MUDs), and haploidentical donors, is ongoing (NIH, 2015).



5.    Gene therapy may offer a future cure for SCD. Gene transfer to correct the molecular defect in the hemoglobin is under investigation as a future treatment.



6.    Transfusion therapy may include episodic or chronic transfusions of RBCs (Heeney & Ware, 2015).



a.    Simple transfusions are useful in the treatment of symptomatic anemia, severe or progressive ACS, splenic sequestration, stroke, and priapism.



b.    Exchange transfusions withdraw blood (manually or through erythrocytapheresis) and then transfuse nonsickle cell blood. The goal of this therapy is to reduce the HbS concentration to less than 30%.



c.    Episodic transfusions may be simple or exchange transfusions; these are useful in the treatment of an acute event. Goal hemoglobin will not exceed 10 to 11 g/dL.



d.    Chronic transfusions are indicated for severe cases in which the risk of morbidity from sickle cell outweighs the risk of chronic transfusion therapy (allosensitization, infection, iron overload). Chronic transfusions are usually performed every 4 weeks and may involve simple or exchange transfusions to maintain HbS less than 30%.



e.    Transfusions may also be indicated to achieve a preoperative Hgb greater than 10 g/dL prior to surgical procedures (Heeney & Ware, 2015).



7.    Collaborative Diagnoses and Comorbidities. Patients are at risk for impaired gas exchange, activity intolerance, and pain.



8.    Goals and Desired Patient Outcomes: Prevention of Complications



a.    Promote early diagnosis through newborn screening.



b.    Encourage follow-up in a comprehensive sickle cell clinic.



i.    Educate the family regarding the importance of mandatory prophylactic penicillin starting at 2 months of age. Discontinuation of penicillin prophylaxis is controversial.



ii.    Teach parents that fever (temperature >38.5°C) or other signs of infection, such as lethargy, irritability, poor oral intake, chills, or vomiting, must be promptly evaluated to determine the source of the fever and the need for treatment (NIH, 2015).



iii.    Teach parents to palpate the spleen for possible enlargement.



c.    Prevent crises through prevention of dehydration, hypoxemia, and acidosis.



d.    Prevent infection with all recommended childhood vaccines. Children with SCD require additional immunizations, including four doses of the seven-valent pneumococcal-conjugated vaccine (Prevnar) followed by two additional doses of the 23-valent pneumococcal polysaccharide vaccine (Pneumovax) starting at 24 months old. Children with SCD can begin to receive annual influenza vaccines after 6 months of age (NIH, 2015).

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Feb 19, 2020 | Posted by in NURSING | Comments Off on Hematology and Immunology Systems
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