8
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.
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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.
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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.
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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.
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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.
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).
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.
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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.