Chapter 26 Hematologic Disorders
The hematologic system is a massive fluid organ that permeates the entire body, delivering nutrients and other vital elements throughout. Essential body functions carried out by blood include the transfer of respiratory gases, hemostasis, phagocytosis, and the provision of cellular and humoral agents to fight infection. Abnormalities of blood cells are seen in various disease states and alterations in nutrition, necessitating the use of diagnostic hematologic studies to differentiate common nutritional deficiencies with straightforward treatments from rare diseases with a genetic or chronic component for which extensive referral and a multidisciplinary approach are needed. Because of the effect of impaired cellular nutrition on normal growth and development of sensitive systems in pediatrics, early diagnosis of blood disorders is vital to ensure the best possible prognosis.
Anatomy and Physiology
Blood is made of cellular components, each with specialized functions, and a fluid component called plasma, which serves as the transport medium. The cells that comprise whole blood are categorized as erythrocytes (red blood cells [RBCs]); leukocytes (white blood cells [WBCs]); and thrombocytes (platelets). Leukocytes are further differentiated into subtypes (lymphocytes, granulocytes, and monocytes). Abnormally high or low counts of any of the cell categories may indicate the presence of a large variety and many forms of diseases. Due to its sensitivity in screening for a variety of disorders, the complete blood count (CBC) is among the most performed studies and is commonly used in routine health screening. Plasma is the clear yellow fluid in which proteins (primarily albumins, globulins, and fibrinogen) are the major solutes. These plasma proteins maintain intravascular volume, contribute to the coagulation of blood, and are important in acid-base balance. Figure 26-1 shows the breakdown of all components of whole blood.
Blood formation in the human embryo begins in the yolk sac during the first several weeks of gestation. During the second trimester blood is formed primarily in the fetus’s liver, spleen, and lymph nodes. In the last half of gestation, hematopoiesis shifts from the fetal liver and spleen to the bone marrow, where, by birth, most blood formation takes place. Most erythropoiesis occurs in the last month of gestation. The bone marrow produces erythrocytes, granulocytes, monocytes, and platelets and provides lymphocytes and lymphocytic precursors to the spleen, lymph nodes, and other lymphatic tissues.
Erythrocytes
Erythropoietin, produced primarily by renal glomerular epithelial cells, regulates erythrocyte (RBC) production. In response to a decrease in the number of circulating RBCs or a decrease in the oxygen pressure (Pao2 ) of arterial blood, erythropoietin stimulates the bone marrow to convert certain stem cells to proerythroblasts. Substances essential for RBC formation include iron, vitamin B12, folic acid, amino acids, and other nutrients.
The RBC matures through the following stages: proerythroblast, erythroblast, normoblast, reticulocyte, and erythrocyte. As cellular differentiation occurs, the nucleus present in the early forms of the cell is extruded and replaced by hemoglobin (Hgb). The RBC assumes its characteristic anucleated biconcave disk shape, which is easily distorted, thereby enabling it to pass through small capillaries and sinuses without being destroyed. The large surface-to-volume ratio of the semipermeable membrane facilitates rapid gas exchange.
The youngest RBCs are the reticulocytes. After release from the bone marrow, reticulocytes stay in circulation for about 1 day before becoming mature RBCs. The reticulocyte count is about 4% to 6% for the first 3 days of life, which reflects the relatively greater amount of erythropoiesis that occurs in the fetus. This increased reticulocyte count is followed by a sudden drop around 1 year of age to 0.5% to 1.5%, which remains the norm for the rest of life (Table 26-1). In cases of low RBC levels, such as anemia or sudden blood loss, the effectiveness of the body’s early response to treatment or progress of healing can be measured via the reticulocyte count. A mature RBC survives about 120 days before it is destroyed through phagocytosis in the spleen, liver, or bone marrow.
In the presence of anemia the reticulocyte count needs to be corrected to account for the decrease in circulating RBCs and the shift of immature reticulocytes prematurely from marrow into blood. This correction is the reticulocyte production index.
Table 26-2 presents an overview of the common clinical diagnostic blood tests including those used to assess red blood cell functioning.
TABLE 26-2 Clinical Diagnostic Interpretation
| Test | Description |
|---|---|
| Complete blood count (CBC) | Broad screening test for illnesses that cause alteration in red blood cell indices and white blood cell count |
| CBC with differential | Additionally assesses the amounts of the white cell subtypes present in a given sample of whole blood |
| CBC with peripheral smear | Additionally assesses the size and shapes of a sample of RBC |
| Red blood cell (RBC) | Increased with polycythemia vera and fluid loss—diarrhea, burns, dehydration. Decreased with anemia. |
| Hemoglobin (Hgb) | Iron-binding portion of RBC |
| Hematocrit (Hct) | Calculation of the percentage of RBC in a given volume of whole blood |
| Mean corpuscular volume (MCV) | Determines the volume of the average RBC in femtoliters; increased (macro) with B12, folic acid deficiency, hypothyroid; decreased (micro) with iron deficiency, thalassemia, lead poisoning, anemia of chronic disease |
| Mean corpuscular hemoglobin (MCH) | Average amount of Hgb in red cells. Used in determining type and severity of anemia. Mirrors MCV |
| Mentzer Index = MCV/RBC | Differentiates between iron deficiency and thalassemia.Ratio <13: ThalassemiaRatio >13: Iron deficiency, hemoglobinopathy |
| RBC distribution width (RDW) | Increased RDW indicates mixed population of RBCs; immature RBCs are larger than mature, so increase is associated with anemias |
| Reticulocyte count (Retic) | A percentage of the circulating erythrocytes; this reflects the bone marrow production of new RBCs, reticulocytes, and their subsequent release into the bloodstream. Important in assessing the body’s response to an anemic state. |
| Reticulocyte production index (RPI) | A calculation to more accurately reflect the reticulocyte production in the diagnosis of anemia because the absolute RBC count decreases in anemia; it indicates whether the bone marrow is responding and corrects for the degree of anemia
 RPI >3 associated with hemolysis or blood loss; <2 reflects decreased or ineffective production for the degree of anemia |
| Absolute neutrophil count (ANC) | Refers to the total number of neutrophil granulocytes present in the blood.Normal value: ≥1500 cells/mm3Mild neutropenia: ≥1000 to <1500 cells/mm3Moderate neutropenia: ≥500 to <1000 cells/mm3Severe neutropenia: ≤500 cells/mm3 |
| Poikilocytosis | Refers to an increase in abnormal RBCs of any shape where they make up 10% or more of the total population |
| White blood cell (WBC) | May be increased with infections, inflammation, cancer, leukemia; decreased with some medications, some severe infections; bone marrow failure |
Hemoglobin
Hgb is the oxygen-carrying protein molecule in the RBC. Production of Hgb requires circulating iron, the synthesis of a protoporphyrin ring, and the production of globin. Each Hgb molecule is comprised of two pairs of polypeptide chains. The globin portion contains protein in a precise sequence of amino acids that is coded by genes located on chromosome 16 and chromosome 11. Normal hemoglobin contains two alpha- and two beta-chains. These chains then attach to heme groups, large iron-containing disks, and porphyrin, a nitrogen-containing organic compound.
Each of the four iron atoms in the Hgb molecule combines reversibly with an atom of oxygen to form oxyhemoglobin. This reaction occurs when the oxygen concentration is relatively high, as in the lungs, where oxygen crosses the alveolo-capillary membrane and saturates about 96% of the Hgb. The percentage of oxyhemoglobin is the arterial oxygen saturation (Sao2), and it is measured through pulse oximetry or arterial blood gas determination. When the oxygen concentration is lower, as in the tissues, oxygen is released from Hgb to meet cellular demands.
Erythrocyte Development
Many dietary elements are essential to the developmental process of mature RBCs, including amino acids, carbohydrates, lipids, vitamin B12, folate, vitamin C, and iron. Free Hgb, which is released during red blood cell lysis, is transported to the reticuloendothelial system by haptoglobin. The reticuloendothelial system is located in the spleen, liver, and bone marrow and is where the lysis substrates, iron, amino acids, carbohydrate, and lipids are reclaimed. Transferrin transports iron to the bone marrow and into the maturing RBC, where it is incorporated into the new heme molecule. As this new cell matures, the nucleus eventually is extruded and the RBC is released into circulation as a reticulocyte. Within 1 to 2 days the reticulocyte becomes a mature RBC. The average life span of the RBC is 120 days.
Structural Variations
Hgb molecules normally represent the majority of the body’s Hgb and, in adult Hgb, are composed of two fundamental subunit chains, alpha (α) and beta (β). Equal numbers of each chain are essential for normal cell function. An imbalance of the chains damages and destroys RBCs thereby producing anemia.
Various forms of Hgb are found in the embryo, fetus, and adult, depending on changes in globin chain synthesis. At birth, approximately 70% of Hgb is made up of fetal hemoglobin (Hgb F), which is composed of two α-chains and two gamma-chains (γ). By 12 months of age, 95% of a person’s Hgb typically consists of adult Hgb molecules (Hgb A), which are composed of two α- and two β-polypeptide chains attached to four heme groups. In the majority of individuals, Hgb F remains present at levels of less than 2%. Hgb A2 is another type of adult Hgb but consists of two α- and two delta (δ)-chains. Hbg A2 normally makes up about 2.5% of the total Hgb and may be increased in beta-thalassemia. Mutations occur whenever there are gene defects in either of the subunit chains resulting in Hgb variants. Any alteration of the amino acid sequencing on the chromosomes (11, 16) that code production of the beta globin chain results in one of over 600 identified variants of Hgb. Some abnormal hemoglobins are the result of amino acid substitutions. While many mutations are innocuous, with indiscernible physiological impact, other structural defects are devastating.
Among the most commonly occurring Hgb variants are Hgb S (sickle), Hgb C, Hgb E, persistence of Hgb F, and Hgb H. The incidence of these hemoglobins tends to peak within certain regional or racial populations. Atypical combinations of Hgb variants can occur, each with its own resulting condition or problems. Hemoglobin electrophoresis, which separates each hemoglobin out on a gel medium, is used to differentiate the Hgb variants from Hgb A thus aiding in the diagnosis of specific hemoglobinopathies (Ohls and Christensen, 2007; Wu, 2006).
Diminished production of one of the two subunit chains results in disorders referred to as “thalassemias.” Thalassemias are categorized into two types: alpha and beta, and are named based on the affected chain. In the carrier state for alpha-thalassemia, there is one α-chain present enabling the production of adequate amounts of hemoglobin with no symptoms in the carrier. In alpha-thalassemia the beta-globulin subunits cluster into groups of four in the absence of any α-chains with which to partner. These beta-tetramers are incapable of carrying oxygen, and the affected fetuses die in utero (hydrops fetalis). In beta-thalassemia major, the α-chains do not bind with each other but rather degrade in the absence of β-chains. Conversely, in beta-thalassemia minor, there are sufficient β-chains present to bind with the abundant α-chains to create functional Hgb molecules and a resultant asymptomatic mild microcytic anemia.
There are also altered states of Hgb, such as occurs with methemoglobin. In this condition, the ferrous form of iron oxidizes to the ferric state causing the heme moiety to be incapable of carrying oxygen. If reduced Hgb levels exceed 5 g/dL serious tissue hypoxia and cyanosis can occur. Methemoglobinemia can be congenital or caused by exposure to certain drugs and chemicals.
Normal Values
Hgb levels in a newborn range from 12.5 to 20.5 g/dL and then drop to its lowest point around 2 to 4 months of age (Wu, 2006). This drop represents a physiologic anemia caused by the shortened survival of fetal RBCs and the rapid expansion of blood volume during this period. A decrease in Hgb can also develop secondary to a decrease in RBC production, blood loss, or increased RBC destruction. Due to the effect of these processes, oxygen transport to the tissues is adversely affected and the individual can become clinically anemic. Table 26-1 summarizes the RBC indices.
Antigenic Properties of Red Blood Cells
Red cells are classified into different types according to the presence of antigens on the cell membrane. The antigenicity is genetically determined and represents contributions from both parents. The most common antigens are designated A, B, and Rh. A person inherits either A or B antigen (type A or B blood), both antigens (type AB blood, which is the universal recipient), or neither antigen (type O blood, which is the universal donor) (Fig. 26-2). In the U.S., 85% of Caucasians and 95% of African-Americans are Rh-positive (Guyton and Hall, 2010). Clinically these distinctions become important when blood transfusions are necessary or in the assessment for maternal-fetal blood incompatibilities. The International Society for Blood Transfusion recognizes more than 20 blood group systems (including Rh and ABO).
Leukocytes
Leukocytes, or WBCs, are larger and fewer in number than erythrocytes. Normally about 5000 to 10,000 leukocytes are contained in a microliter of blood. The primary function of WBCs is protection of the body from invasion by foreign organisms and distribution of antibodies and other immune response components. When levels reach critical low and high values for leukocytes there are great risks to the child. A WBC count of less than 500/mm3 places the patient at risk for a fatal infection. However, a WBC count greater than 30,000/mm3 indicates massive infection or a serious disease such as leukemia.
Five distinct types of WBCs can be grouped into two broad classifications: granulocytes (also known as polymorphonuclear leukocytes [PMNs], or “polys”) and agranulocytes. Granulocytes contain large granules and horseshoe-shaped nuclei that become segmented and are connected by thin strands (Table 26-3). With Wright stain the cytoplasm stains blue or pink. Granulocytes are further divided into neutrophils; eosinophils, which absorb the acid dye eosin; and basophils, which absorb a basic dye. The agranulocytes include lymphocytes (also known as immunocytes) and monocytes.
TABLE 26-3 Overview of Leukocytes
| Cell Type | Characteristics | Diagram |
|---|---|---|
| Granulocytes (Polymorphonuclear Leukocytes, Polys) | ||
| Neutrophils | Have small, fine, light pink or lilac acidophilic granules when stained and a segmented, irregularly lobed, purple nucleus |  |
| Eosinophils | Have large round granules that contain red-staining basic mucopolysaccharides and multilobed purple-blue nuclei |  |
| Basophils | Coarse blue granules conceal the segmented nucleus. Granules contain histamine, heparin, and acid mucopolysaccharides. |  |
| Agranulocytes | ||
| Lymphocytes | Small cells with a large, round, deep-staining, single-lobed nucleus and very little cytoplasm. The cytoplasm is slightly basophilic and stains pale blue. |  |
| Monocytes | Large cells with a prominent, multishaped nucleus that sometimes is kidney shaped. Chromatin in the nucleus looks like lace, with small particles linked together like strands. The gray-blue cytoplasm is filled with many fine lysozymes that stain pink with Wright stain. |  |
Data from Bullock B, Henze R: Hematology: adaptations and alterations in function. In Bullock B, editor: Focus on pathophysiology, Philadelphia, 2000, Lippincott Williams & Wilkins, p 359; McCance K, Huether S: Pathophysiology: the biologic basis for disease in adults and children, ed 5, St Louis, 2006, Mosby.
Granular Leukocytes (Polymorphonuclear Leukocytes, Polys)
Neutrophils, Basophils, Eosinophils
In children, granulocytes comprise 40% to 70% of all WBCs. They mature in the bone marrow through the following stages: stem cells, myeloblasts, promyelocytes, myelocytes, metamyelocytes, band forms, and, finally, mature segmented neutrophils. This maturational process takes approximately 6 to 11 days. Once a neutrophil is released into the bloodstream it circulates for about 6 to 9 hours before entering the tissues, where the major function of PMNs is phagocytosis of harmful particles and cells, particularly bacterial organisms. Thus neutrophils are the primary WBC involved in fighting bacterial infections.
A frequency distribution of the types of WBCs is obtained by the differential count, and quantitative alterations within the categories are important diagnostically (Table 26-4). A relative increase in the number of circulating immature neutrophils (band forms, metamyelocytes, and myelocytes) is referred to as a “shift to the left,” a term derived from how the differential count used to be tabulated on written forms. This phenomenon is indicative of an inflammatory process or the body’s immunologic response to an acute bacterial infection. The phrase “shift to the right” indicates an increase in the total lymphocyte count.
TABLE 26-4 White Blood Cell Differential and Key Characteristics
| Major Division of WBCs | Differential | Description |
|---|---|---|
| Granulocytes (50%-75%) | Neutrophils | Primary defense against bacterial infection and mediating stress. Elevated with bacterial or inflammatory disorders |
| Bands (<1%) | Immature neutrophils put out by the bone marrow | |
| Eosinophils (2%-4%) | Associated with antigen-antibody response; elevated with exposure to allergens or inflammation of skin, parasites | |
| Basophils (1%-2%) | Phagocytes: contain heparin, histamines, and serotonin. Increased in leukemia, chronic inflammation, hypersensitivity to food, radiation therapy. Mast cells | |
| Nongranulocytes (30%-40%) | Lymphocytes (25%-35%) | Primary components of the immune system. Elevated with viral infections, leukemia, radiation exposure; decreased with diseases affecting the immune system |
| Monocytes (<2%) | Elevated in infections and inflammation, leukemia; decreased with some bone marrow injury, leukemias |
WBCs, White blood cells.
Data from Wu AHB: Tietz clinical guide to laboratory tests, ed 4, Philadelphia, 2006, Saunders; and Gilbert-Barness E, Barness LA: Clinical use of pediatric diagnostic tests, Philadelphia, 2006, Lippincott Williams & Wilkins.
Basophils, which account for less than 1% of circulating leukocytes, are closely related to tissue mast cells. Both cells react immediately in the face of a hypersensitivity reaction by granules releasing heparin and histamine into the bloodstream during systemic allergic reactions. Renal disease, rare carcinomas, and medications such as estrogen and antithyroid agents are among the reasons for increased basophils.
Eosinophils (1% to 2% WBCs) have two main functions: to immediately release histamine in hypersensitivity reactions and to destroy parasites. Other causes of eosinophilia include connective tissue and collagen vascular diseases, immunodeficiencies, and neoplasms, such as carcinoma, lymphoma, and Hodgkin disease. Eosinophils contain receptor sites for immunoglobulin E (IgE), levels of which are elevated in people with allergies; they also prevent clot formation in the microcirculation. Eosinophils are found in the mucosa of the gastrointestinal (GI) tract and in the lungs and are weakly phagocytic.
Agranulocytes-Leukocytes
Lymphocytes
Lymphocytes (or immunocytes) comprise 25% to 35% of WBCs. Although not phagocytic, they protect the body against specific antigens. They originate in the bone marrow, but differentiate in lymphoid tissues, such as the spleen, liver, thymus, lymph nodes, and intestines. Thymus-dependent lymphocytes, or T cells, are part of the cell-mediated immune response in which cytotoxic agents and macrophages are synthesized. B-cell lymphocytes are precursors of the humoral immune response whereby the cells are transformed into plasma cells that release immunoglobulins or antibodies into the bloodstream. Lymphocytes are an important defense component.
Monocytes
Monocytes, which contain a large lobulated nucleus, are relatively immature cells that circulate for about 8 hours before migrating to tissues where they assume their mature form as macrophages. They constitute 4% to 6% of WBCs with the absolute monocyte count of 0.1 to 0.9 × 109/L. After briefly circulating in the peripheral vascular system, monocytes migrate to the tissue to mature and become part of the monocyte/histiocyte/immune cell system. Fixed and mobile macrophages are located primarily in the liver, spleen, lymph nodes, and GI tract and make up the mononuclear phagocyte system. Like granulocytes, which are the first line of defense against microbe invasion, their primary function is phagocytosis of bacteria and cellular debris. Monocyte elevation occurs in collagen vascular disease, Hodgkin disease, non-Hodgkin lymphoma, and chronic infections such as tuberculosis, and syphilis.
Platelet Cells and Coagulation Factors
The smallest cellular components in blood are the platelets, or thrombocytes, which are essential to hemostasis and clot formation. Circulating platelets are fragments of megakaryocytes, which are precursor cells that form in the bone marrow. The normal platelet count ranges from 150,000 to 300,000 cells/mm3.
When a blood vessel is injured (or in the presence of intrinsic damage to the blood), platelets adhere to the inner surface of the vessel and form a hemostatic plug. As platelets degrade, a series of at least 13 clotting factors or proteolytic enzymes are released that bring about the clotting process in a cascading sequence of successive reactions. These clotting factors are listed in Table 26-5.
TABLE 26-5 Blood Coagulation Factors
| Factor (International Nomenclature) | Common Synonyms |
|---|---|
| I | Fibrinogen |
| II | Prothrombin* |
| III | Tissue thromboplastin, thrombokinase |
| V | Proaccelerin, labile factor, accelerator globulin |
| VII | Proconvertin,* stable factor |
| VIII | Antihemophilic globulin (AHG), antihemophilic factor (AHF),antihemophilic factor A |
| IX | Plasma thromboplastin component (PTC), Christmas factor,* antihemophilic factor B |
| X | Stuart-Prower factor, Stuart factor* |
| XI | Plasma thromboplastin antecedent (PTA), antihemophilic factor C |
| XII | Hageman factor, contact factor, antihemophilic factor |
| XIII | Fibrin-stabilizing factor (FSF), plasma transglutaminase |
| Kininogen | Fitzgerald factor |
| Prekallikrein | Fletcher factor |
The basic reactions that occur in the sequential process of blood coagulation are as follows: factor X activates and prothrombin (factor II) converts to thrombin, which then catalyzes the conversion of fibrinogen (factor I) to fibrin. Fibrin provides the matrix in which blood cells aggregate to form a clot. A deficiency of any of the proteins in the pathway leads to a clotting disorder. In particular, if factor VIII is deficient (as in classic hemophilia A) or the number of platelets is inadequate (thrombocytopenia), activation of factor X is impaired. Figure 26-3 illustrates the entire coagulation cascade. Age-specific coagulation values exist for each aspect of the coagulation process and should be referenced for proper assessment and treatment management.
FIGURE 26-3 The classical coagulation cascade. Note the common link between the intrinsic and extrinsic pathways at the level of factor IX activation. Factors in white boxes represent inactive molecules; activated factors are indicated with a lowercase a and a black box. HMWK, High-molecular-weight kininogen. Not shown are the inhibitory anticoagulant pathways.
(From Kumar V, Abbas A, Fausto N, et al: Robbins basic pathology, ed 8, Philadelphia, 2007, Elsevier.)
Pathophysiology
Hematologic problems are generally classified as disorders of RBC function, WBC function, and platelet and coagulation function. These three broad categories are further divided into disorders of blood cell production, maturation, or destruction. Although most RBC disorders result in a decrease quantity of cells or cell abnormalities, it is important not to forget the congenital, though rare, proliferative disorder, primary polycythemia (polycythemia rubra vera). This entity is a panmyeloproliferative disorder. Children usually have hepatosplenomegaly, neurologic and cardiovascular symptoms caused by erythrocytosis, diarrhea and pruritus due to histamine release related to granulocytosis, and thrombosis or hemorrhage from thrombocytosis (Burns and Camitta, 2007). Knowledge of these pathophysiologic classifications gives the pediatric provider a rationale for routine screening and useful algorithms to guide further clinical investigation.
Assessment of Disorders of Erythrocytes
History
A comprehensive history and physical examination are essential to unravel the mystery behind suspected hematologic disorders. Many hematologic processes have genetic bases. In order to discern inheritable disorders, it is necessary to identify the child’s ethnicity and race(s), plus obtain a detailed family medical history. Certain disorders occur with greater frequency in individuals of certain races or ancestrally from specific geographic regions. One example of this phenomenon is sickle cell anemia (SCA) which primarily affects those of African ancestry. Recording all family health data in a genogram provides visual clues to patterns of heritability and assists with narrowing the diagnostic possibilities.
The provider should obtain information about family members with a history of any of following:
• Genetically based disorders (include, but are not exclusive to, sickle cell or thalassemia disease or trait)
Maternal history is significant in young children and should include:
A comprehensive review of a child’s medical history and a review of systems are fundamental. Particular attention should focus on the following:
• Prematurity (especially if anemia detected in infancy)
• Environmental exposures (lead, cadmium, pesticides, toxic waste, etc.)
• Growth changes or weight loss, unexplained
• Jaundice episodes (including in the newborn period)
• Extremity pain, with or without swelling
• Prolonged or usual blood loss (particularly from mucous membranes)
• Unexplained petechiae, easy bruising
• Behavioral changes: Irritable, quiet, restless, subdued
• GI disorders: Liver disease, abdominal pain, changes in stool patterns
• Changes in stool characteristics indicating GI bleeding
• Recent acute infections or drug exposure
The nutritional history of the child (and of the breastfeeding mother) should include the following:
• Dietary intake of iron sources, quantities and types of milk, and meat
• Type and dosing of vitamin supplements, include possibility of excessive ingestion
• Any history of pica, protracted mouthing behaviors (particularly when iron deficiency or plumbism is suspected)
Newborn screening panel results need to be reviewed. In most states routine screening of newborn cord blood is done to detect genetic and metabolic disorders, such as sickle cell disease, sickle cell trait, and other hemoglobinopathies. The primary care provider needs to verify and document the infant’s results in the medical record.
Physical Examination
The physical examination of the child should be comprehensive and include vital signs and growth documentation. The following positive signs are particularly important to identify due to their association with specific problems:
• Pallor (especially of the conjunctivae, buccal mucosa, and palmar creases)
• Jaundice (indicates a hemolytic process)
• Petechiae (indicates multiple cell involvement)
• Retinal hemorrhages (hemolytic disorders)
• Excessive bruising, multiple stages (coagulopathy)
• Bleeding from mucous membranes (coagulopathy)
• Lymphadenopathy (infection, malignancy)
• Frontal bossing and/or prominent maxilla (secondary to bone marrow expansion in thalassemia major)
• Joint or extremity pain (sickle cell, leukemia)
• Heart murmurs (may be heard with anemias), signs of congestive heart failure, or tachycardia (acute process with poor compensation)
• Hepatomegaly or splenomegaly (splenomegaly—associated with hemolytic processes, malignancy, acute infection; hypersplenism due to portal hypertension)
• Congenital anomalies that are associated with hematologic disorders
Pancytopenia
Pancytopenia is marked by a decrease in all three formed elements of the blood—erythrocytes, leukocytes, and platelets. A child usually presents with clinical findings of infection or bleeding rather than anemia because of the longer life span of RBCs compared with platelets and WBCs. As such it is not a single disease, but results from a combination of disease processes. Pancytopenia is caused by one of three processes:
• Production failure (intrinsic bone marrow disease as occurs in aplastic anemia)
• Sequestration (as occurs with hypersplenism)
• Increased peripheral destruction of mature cells (Panepinto and Scott, 2011; Zitelli and Davis, 2007)
The child should be referred to a pediatric hematologist for treatment focused at correcting the underlying mechanism, such as hematopoietic stem cell transplantation (failure of production), splenectomy, or other treatments aimed at reducing peripheral destruction of cells or sequestration.
Erythrocyte Disorders
Anemia
Classification of the Anemias
Anemia is a reduction in circulating red blood cells and results from a reduction in RBC production, abnormalities of the RBC itself, shortened RBC life span or RBC destruction, or an acute or chronic loss of circulating RBCs. Various anemias are more common in specific races and geographic populations, such as SCA and glucose-6-phosphate dehydrogenase (G6PD) deficiency in people of African and Mediterranean decent. Nutritional deficiencies and toxic ingestions play integral roles in the incidence of anemias (i.e., folic acid deficiency, B12 deficiency, iron deficiency anemia [IDA], lead poisoning). Anemia affects many systems because it causes stress on the cardiovascular and respiratory systems. This may manifest as decreased exercise tolerance, fatigue, shortness of breath, or congestive heart failure. However, the majority of children and adolescents with anemia are asymptomatic.
RBCs may be described by the cell size, shape, or color (e.g., hypochromic, microcytic; macrocytic; normochromic, normocytic). The use of this standardized nomenclature facilitates the diagnostic process by distinguishing the various anemias (Table 26-6). For instance, IDA is microcytic (small cell) and hypochromic (pale), whereas aplastic anemia is macrocytic (large), and anemia from malignancies and chronic illness tends to be normocytic (Fig. 26-4).
FIGURE 26-4 Use of the complete blood count, reticulocyte count, and blood smear in the diagnosis of anemia. DIC, Disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; HIV, human immunodeficiency virus; HUS, hemolytic-uremic syndrome; R/O, rule out; RPI, reticulocyte production index; TTP, thrombotic thrombocytopenic purpura.
(From Scott J: Hematology. In Kliegman R, Marcdante K, Jenson H, Behrman R, editors: Nelson essentials of pediatrics, ed 5, Philadelphia, 2006, Saunders.)
In toddlers and young children, approximately 90% of anemias are caused by either IDA, lead poisoning (also called plumbism), infection, or hemoglobinopathy. The first two of these problems result from a reduction in available Hgb for nutrient transport within the RBC. This reduction of circulating Hgb results in small, pale RBCs (microcytic, hypochromic) with decreased oxygen-carrying potential. Inadequate RBC production can be either acquired or constitutional resulting is such anemias as aplastic anemia, red cell aplasia, and transient erythroblastosis of childhood (TEC). Table 26-7 outlines the history, physical findings, and laboratory diagnosis and treatment of the common RBC anemias in infants and children.
Another classification system defines anemias by the type of problem with RBC production (Fig. 26-5). Hypoproliferative anemias result from a failure in erythrocyte marrow production. These anemias tend to be normocytic-normochromic with a reticulocyte count less than 2, giving the semblance of the body not responding to the anemia. Among the causes for the hypoproliferative anemias are iron deficiency, marrow damage, decreased stimulation of the marrow (as in renal disease), inflammation, and metabolic disorders. Maturational anemias, in which there is a defect in nuclear maturation, are caused by nutritional disturbances, such as deficiencies in folic acid and vitamin B12 and exposure to chemotherapeutic agents. In chronic illnesses there may be a decrease in red cell survival time, the bone marrow response or impaired iron transport. Such an effect is often seen in chronic inflammatory illnesses, chronic infections, renal and liver disease, endocrine disorders, and malignant neoplastic diseases. In the last category increased cell destruction produces hemolytic anemias. The hemolysis may be caused by defects in the red cell membrane, hereditary hemoglobinopathies (as in SCA), or congenital enzyme defects. Among these syndromes are hereditary spherocytosis (HS) and G6PD deficiency.
Epidemiology
Despite steady declines in the U.S., anemia continues to be a major health problem here and to an even greater extent internationally. Iron deficiency is the most common cause of anemia, even as cases steadily decline when nutritional practices improve.
The thalassemias are a group of inherited disorders that cause a significant number of pediatric anemias. One of the most common single gene disorders in the world is alpha-thalassemia. This genetic disorder affects more than half of the population in the southwest Pacific, one fourth in western Africa, and 5% to 10% in the Mediterranean region. Historically the disease was rare in the U.S., although approximately 30% of African-Americans are genetic carriers for this disease. However, the incidence is increasing with the recent surge in Asian immigration. Beta-thalassemia manifests with greater numbers in Mediterranean, northern African, and Indian peoples, whereas SCA is highest among African populations, and all are rare in persons of northern European ancestry.
Workup for Anemia
Anemia may be suspected on the basis of clinical judgment, but is often detected though hematocrit (Hct) and Hgb screening. Understanding which tests to order and how to interpret laboratory data are integral to analyzing the information communicated by the hematopoietic system (see Tables 26-1 and 26-2). Laboratory norms vary slightly with the individual lab so evaluate the child’s results in accordance with local lab norms. The initial laboratory evaluation of suspected anemia includes the following:
A standardized vocabulary is used to describe the characteristics of erythrocytes that enable the provider to differentiate and categorize the disorders. The language of morphology is summarized in Box 26-1 with examples of associated disorders.
BOX 26-1 Erythrocyte Morphology
Macrocytic Erythrocyte/Megalocyte (Abnormally Large Red Blood Cells)
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