	Patient Results	Reference Range
WBCs (×10⁹/L)	18.0	9-37
RBCs (×10¹²/L)	5.28	4.10-6.10
Hb (g/dL)	18.5	16.5-21.5
Hct (%)	55.5	48-68
WBC differential: 50% neutrophils and 50% lymphocytes
RBC morphology: Macrocytic with slight to moderate polychromasia. There were 7 NRBCs/100 WBCs.

1. Are the results for hemoglobin and hematocrit within the limits expected for a newborn?

2. What is the significance of the elevated MCV, NRBCs, and polychromasia?

3. Comment on the WBC and differential count.

Hematologic values are fairly stable throughout adult life, but significant differences exist in the pediatric and, to some extent, in the geriatric populations. This chapter focuses on the more significant differences.

Pediatric Hematology

Children are not merely “small adults.” The newborn infant, older child, and adult exhibit profound hematologic differences from one another. Because children mature at different rates, it is inappropriate to use adult reference ranges for the assessment of pediatric blood values. Historically, pediatric reference values were inferentially established from adult data because of the limitations in attaining analyzable data. Pediatric procedures required large blood draws and tedious methodologies and lacked standardization. The implementation of child-friendly phlebotomy techniques and micropediatric procedures has revolutionized laboratory testing. Pediatric hematology has emerged as a specialized science with age-specific reference ranges that correlate with the hematopoietic, immunologic, and chemical changes in a developing child.

Dramatic changes occur in the blood and bone marrow of the newborn infant during the first hours and days after birth, and there are rapid fluctuations in the quantities of all hematologic elements. Significant hematologic differences are seen between term and preterm infants and among newborns, infants, young children, and older children. This chapter reviews neonatal hematopoiesis, which is discussed in detail in Chapter 7, as a prerequisite to understanding the changes in pediatric hematologic reference ranges, morphologic features, and age-specific physiology.

Prenatal Hematopoiesis

Hematopoiesis, the formation and development of blood cells from stem cells, begins in the first weeks of embryonic development and proceeds systematically through three phases of development: mesoblastic (yolk sac), hepatic (liver), and myeloid (bone marrow). The first cells produced in the developing embryo are primitive erythroblasts formed in the yolk sac. These cells are particularly interesting because they do not develop into mature erythrocytes. They are erythropoietin insensitive and have the ability to differentiate into other cell lines upon exposure to appropriate growth factors.1–6

By the second month of gestation, hematopoiesis ceases in the yolk sac, and the liver becomes the center for hematopoiesis, reaching its peak activity during the third and fourth gestational months. Leukocytes of each cell type systematically make their appearance. In week 9 of gestation, lymphocytes can be detected in the region of the thymus. They are subsequently found in the spleen and lymph nodes. During the fourth and fifth gestational months, the bone marrow emerges as a major site of blood cell production, and it becomes the primary site by birth (see Chapter 7).^1–6

Hematopoiesis of the Newborn

Hematopoietically active bone marrow is referred to as red marrow, as opposed to inactive yellow (fatty) marrow. At the time of birth, the bone marrow is fully active and extremely cellular, with all hematopoietic cell lineages undergoing cellular differentiation and amplification. In addition to the mature cells in fetal blood, there are significant numbers of circulating progenitor cells in cord blood.7,8

In a full-term infant, hepatic hematopoiesis has ceased except in widely scattered small foci that become inactive soon after birth.1–6 Postembryonic extramedullary hematopoiesis is abnormal in a full-term infant. In a premature infant, foci of hematopoiesis are frequently seen in the liver and occasionally observed in the spleen, lymph nodes, or thymus.^1–10

Pediatric Developmental Stages

Pediatric hematologic values change markedly in the first weeks and months of life. As a result, many variables influence the interpretation of what might be considered normal values at the time of birth. It is important to provide age-appropriate pediatric hematology values that extend from neonatal life through adolescence. The pediatric population can be categorized with reference to three different developmental stages: (1) the neonatal period, which represents the first 4 weeks of life; (2) infancy, which incorporates the first year of life; and (3) childhood, which spans age 1 to puberty (age 8 to12 years).

Preterm, low-birth-weight infants are more apt to develop health problems than are other newborns. Since the 1990s, the rising quality of medical care in neonatal intensive care units has improved markedly the survival of smaller infants born at younger gestational ages with less mature hematopoietic systems.

Gestational Age and Birth Weight

Hematologic values obtained from full-term infants generally do not apply to preterm infants, and laboratory values for low-birth-weight preterm infants differ from ranges for extremely-low-birth-weight “micropreemies” (24 to 26 weeks’ gestation).¹¹ A full-term infant is defined as an infant who has completed 37 to 42 weeks of gestation. Infants born before 37 weeks’ gestation are referred to as premature or preterm, whereas infants delivered after 42 weeks are considered postterm.^11,12 Infants can be subcategorized further by birth weight as (1) appropriate size for gestational age; (2) small for gestational age, including low-birth-weight infants (2500 g or less); (3) very-low-birth-weight infants (1500 g or less); (4) extremely-low-birth-weight micropreemies (500 g or less); and (5) large for gestational age (more than 4000 g).¹¹

Red Blood Cell Values at Birth

Neonatal hematologic values are affected by the gestational age of the infant, the age in hours after delivery, the presence of illness, and the level of support required. Other important variables to be considered when evaluating laboratory data include site of sampling and technique (capillary versus venous puncture, warm or unwarmed extremity), timing of sampling, and conditions such as the course of labor and the treatment of the umbilical vessels.11,13,14 The presence of fetal hemoglobin (Hb F), bilirubin, and lipids in newborns can also interfere with hematology laboratory testing.^5–17 As with all laboratory testing, each laboratory should establish reference intervals based on its instrumentation, methods, and patient population (see Chapter 5).

Red Blood Cell Count

Refer to the inside front cover of this book for red blood cell (RBC) reference ranges. The RBC count increases during the first 24 hours of life, remains at this plateau for about 2 weeks, and then slowly declines. This “polycythemia of the newborn”¹⁸ may be explained by in utero hypoxia, which becomes more pronounced as the fetus grows. Hypoxia, the trigger for increased secretion of erythropoietin, stimulates erythropoiesis.¹⁹ At birth, the physiologic environment changes, and the fetus makes the transition from its placenta-dependent oxygenation to the increased tissue oxygenation of the lungs. This increased oxygen tension suppresses erythropoietin production, which is followed by a decrease in RBC and hemoglobin production. Studies show that erythropoietin levels before birth are equal to or greater than adult levels with a gradual drop to near zero a few weeks after birth.^20–23 This decline corresponds to the physiologic anemia seen at 5 to 8 weeks of life, with the RBCs reaching their lowest count at 7 weeks of age and hemoglobin reaching its lowest concentration at 9 weeks of age.¹⁹

Erythrocyte Morphology of the Neonate

Early normoblasts are megaloblastic, hypochromic, and irregularly shaped. During hepatic hematopoiesis, normoblasts are smaller than the megaloblasts of the yolk sac but are still macrocytic. Erythrocytes remains macrocytic from the first 11 weeks of gestation until day 5 of postnatal life (Figure 38-1).*

Figure 38-1 Peripheral blood film for a normal newborn demonstrating a normal lymphocyte, macrocytes, polychromasia, and one nucleated red blood cell (×1000).

The macrocytic RBC morphology gradually changes to the characteristic normocytic, normochromic morphology. Orthochromic normoblasts frequently are observed in the full-term infant on the first day of life but disappear within postnatal days 3 to 5. These nucleated RBCs (NRBCs) may persist longer than a week in immature infants. The average number of NRBCs ranges from 3 to 10 per 100 white blood cells (WBCs) in a normal full-term infant to 25 NRBCs per 100 WBCs in a premature infant. The presence of NRBCs for more than 5 days suggests hemolysis, hypoxic stress, or acute infection.*

The erythrocytes of newborns show additional morphologic differences. The number of biconcave discs relative to stomatocytes is reduced in neonates (43% discs, 40% stomatocytes) compared with adults (78% discs, 18% stomatocytes).²⁷ In addition, increased numbers of pitted cells, echinocytes, spherocytes, and other abnormally shaped erythrocytes are seen in neonates. The number of these “dysmorphic” cells is even higher in premature infants. Zipursky et al found 40% discs, 30% stomatocytes, and 27% additional poikilocytes in premature infants.²⁷

Reticulocyte Count

An apparent reticulocytosis exists during gestation, decreasing from 90% reticulocytes at 12 weeks’ gestation, to 15% at 6 months’ gestation, and ultimately to 4% to 6% at birth. Reticulocytosis persists for about 3 days after birth, then declines abruptly to 0.8% reticulocytes on postnatal day 4 to 7. At 2 months, the number of reticulocytes increases slightly, followed by a slight decline from 3 months to 2 years, when adult levels of 0.5% to 1.5% are attained.^† The reticulocyte count of premature infants is typically higher than that of term infants; however, the count can vary dramatically depending upon how ill the newborn is. Significant polychromasia seen on a Wright-stained blood film is indicative of postnatal reticulocytosis (Figure 38-2).

Figure 38-2 Peripheral blood film for a premature infant showing a normal lymphocyte, four nucleated red blood cells, and increased polychromasia (×500).

Hemoglobin

Full-Term Infants

Hemoglobin synthesis results from an orderly evolution of a series of embryonic, fetal, and adult hemoglobins. At birth Hb F constitutes 70% to 80% of the total hemoglobin.²⁸ Hb F declines from 90% to 95% at 30 weeks’ gestation to approximately 7% at 12 weeks after birth and stabilizes at 3.2 ± 2.1% at 16 to 20 weeks after birth.²⁹ The switch from Hb F to Hb A is genetically controlled and determined by gestational age; it does not appear to be influenced by the age at which birth occurs.³⁰ Chapter 10 provides an in-depth discussion of the ontogeny, structure, and types of hemoglobin.

The concentration of hemoglobin fluctuates dramatically in the weeks and months after birth as a result of physiologic changes, and various factors must be considered when analyzing pediatric hematologic values. The site of sampling, gestational age, and time interval between delivery and clamping of the umbilical cord can influence the hemoglobin level in newborn infants.* In addition, there are significant differences between capillary and venous blood hemoglobin levels. Capillary samples in newborns generally have a higher hemoglobin concentration than venous samples, which can be attributed to circulatory factors.^† Racial differences must also be considered when evaluating hemoglobin levels in children. African American children have hemoglobin levels averaging 0.5 g/dL lower than those in white children.³¹

The average hemoglobin for a full-term infant at birth is 16.5 to 21.5 g/dL; levels less than 14 g/dL are considered abnormal.20,21 The average hemoglobin value for a preterm infant who is small for gestational age is 17.1 g/dL, lower than that for a full-term infant; hemoglobin values less than 13.7 g/dL are considered abnormal in preterm infants.²¹

Physiologic Anemia of the Neonate

The hemoglobin concentration of term infants decreases during the first 5 to 8 weeks of life, a condition known as physiologic anemia of infancy. Infants born prematurely also experience a decrease in hemoglobin concentration, which is termed physiologic anemia of prematurity.1,32–34 Along with a decrease in hemoglobin, there is a reduction in the number of RBCs, a decrease in the reticulocyte percentages (Table 38-1), and undetectable levels of erythropoietin associated with the transition from the placenta to the lungs as a source of oxygen. When the hemoglobin concentration decreases to approximately 11 g/dL, erythropoietic activity increases until it reaches its adult levels by 14 years of age.^{11,18,35–40} Also contributing to the physiologic anemia is the shortened life span of the fetal RBC. Studies of chromium-labeled newborn RBCs estimate a survival time of 60 to 70 days with correction for the elution rate of chromium from newborn cells.¹ The life span of RBCs in premature infants is about 35 to 50 days.¹ The more immature the infant, the greater the degree of reduction.^{1,21–23,26,41} The reasons for the shortened life span of the erythrocytes are unclear. This physiologic anemia is not known to be associated with any abnormalities in the infant. Hemodilution related to the increased blood volume that accompanies the rapid weight gain seen in the first few months of life is not thought to play a key role in the anemia.¹

TABLE 38-1

Hematologic Values for Very-Low-Birth-Weight Infants During the First 6 Weeks of Life

	AGE OF INFANT (DAYS)
Hematologic Value	3	12-14	24-26	40-42
Hemoglobin (g/dL)	15.6	14.4	12.4	10.6
Hematocrit (%)	47	44	39	33
Red blood cells (×10¹²/L)	4.2	4.1	3.8	3.4
Reticulocytes (%)	7.1	1.7	1.5	1.8
Platelets (×10⁹/L)	203.5	318	338	357
White blood cells (×10⁹/L)	9.5	12.3	10.4	9.1

Modified from Obladen M, Diepold K, Maier RF, et al: Venous and arterial hematologic profiles of very low birth weight infants, Pediatrics 106:707-711, 2000.

The hemoglobin levels of premature infants are typically 1 g/dL or more below the values of full-term infants. Thereafter, a gradual recovery occurs, which results in values approximating those of normal full-term infants by about 1 year of age.* Very-low-birth-weight infants (less than 1500 g) show a progressive decline in hemoglobin, RBC count, mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC), and have a slower recovery than other preterm and term infants.

Hematocrit

The average hematocrit (Hct) at birth for full-term infants is 53% (range, 48% to 68%).⁴² Frequently, newborns with increased hematocrits, especially values greater than 65%, experience hyperviscosity of the blood. This can cause problems in producing a high-quality peripheral blood film.

The hematocrit usually increases approximately 5% during the first 48 postnatal hours; this is followed by a slow linear decline to 46% to 62% at 2 weeks and 32% to 51% between the second and fourth months. Normal adult values of 47% for males and 42% for females are achieved during adolescence.

Very-low-birth-weight preterm infants are frequently anemic at birth (see Table 38-1). Many require transfusions or erythropoietin injections or both.

Anemia in Infants and Children

Nutritional deficiencies in infants and children can result in iron deficiency anemia and, rarely, in megaloblastic anemia (see Chapter 20), particularly in low-birth-weight and premature infants. These anemias are associated with abnormal psychomotor development; however, they can easily be treated with dietary fortification.^44–48

Iron Deficiency Anemia

Iron deficiency anemia is the most common pediatric hematologic disorder and the most frequent cause of anemia in childood.⁴⁹ The occurrence of iron deficiency anemia in infants has decreased in the United States due to iron fortification of infant formula and increased rates of breastfeeding.⁵⁰ However, the prevalence is still 2% in toddlers 1 to 2 years of age and 3% in children 3 to 5 years of age⁵¹ and is related to early introduction and excessive intake of whole cow’s milk.^44,52 Refer to Chapter 19 for an in-depth discussion of iron deficiency anemia.

Ancillary Tests for Anemia in Infants and Children

The differential diagnosis of anemia in infants and children relies on a variety of ancillary tests. The reference ranges for a number of these tests differ from those for adults. Haptoglobin levels are so low as to be undetectable in neonates, which makes it unreliable as a marker of infant hemolysis.⁵³ Transferrin levels are also lower in neonates, increasing rapidly after birth and reaching adult values at 6 months.⁵³ Both serum ferritin and serum iron are high at birth, rise during the first month, drop to their lowest level between 6 months and 4 years of age, and remain low throughout childhood.^54–56 Consideration of these differences is important when interpreting hematology laboratory results for infants and children.

White Blood Cell Values in the Newborn

Fluctuations in the number of WBCs are common at all ages but are greatest in infants (Table 38-2). Leukocytosis is typical at birth for full-term and preterm infants, with a wide range of normal.⁵⁷ There is an excess of segmented neutrophils and bands, and an occasional metamyelocyte, with no evidence of disease. The neutrophilic leukocyte count rises within the first 12 hours following birth, decreases between 1 month and 1 year, then gradually increases to stabilize at 4.4 × 10⁹/L at about 4 years of age.⁵⁷

TABLE 38-2

Normal Leukocyte Counts *

	TOTAL LEUKOCYTES		NEUTROPHILS^†			LYMPHOCYTES			MONOCYTES		EOSINOPHILS
Age	Mean	Range	Mean	Range	%	Mean	Range	%	Mean	%	Mean	%
Birth	—^‡	—	4.0	2.0-6.0	—	4.2	2.0-7.3	—	0.6	—	0.1	—
12 hr	—	—	11.0	7.8-14.5	—	4.2	2.0-7.3	—	0.6	—	0.1	—
24 hr	—	—	9.0	7.0-12.0	—	4.2	2.0-7.3	—	0.6	—	0.1	—
1-4 wk	—	—	3.6	1.8-5.4	—	5.6	2.9-9.1	—	0.7	—	0.2	—
6 mo	11.9	6.0-17.5	3.8	1.0-8.5	32	7.3	4.0-13.5	61	0.6	5	0.3	3
1 yr	11.4	6.0-17.5	3.5	1.5-8.5	31	7.0	4.0-10.5	61	0.6	5	0.3	3
2 yr	10.6	6.0-17.0	3.5	1.5-8.5	33	6.3	3.0-9.5	59	0.5	5	0.3	3
4 yr	9.1	5.5-15.5	3.8	1.5-8.5	42	4.5	2.0-8.0	50	0.5	5	0.3	3
6 yr	8.5	5.0-14.5	4.3	1.5-8.0	51	3.5	1.5-7.0	42	0.4	5	0.2	3
8 yr	8.3	4.5-13.5	4.4	1.5-8.0	53	3.3	1.5-6.8	39	0.4	4	0.2	2
10 yr	8.1	4.5-13.5	4.4	1.8-8.0	54	3.1	1.5-6.5	38	0.4	4	0.2	2
16 yr	7.8	4.5-13.0	4.4	1.8-8.0	57	2.8	1.2-5.2	35	0.4	5	0.2	3
21 yr	7.4	4.5-11.0	4.4	1.8-7.7	59	2.5	1.0-4.8	34	0.3	4	0.2	3

^*Numbers of leukocytes are × 10⁹/L (or thousands per microliter), ranges are estimates of 95% confidence limits, and percentages refer to differential counts.

^†Neutrophils include band cells at all ages and a small number of metamyelocytes and myelocytes in the first few days of life.

^‡Dashes indicate insufficient data for a reliable estimate.

From Cairo MS, Bracho F: White blood cells. In Rudolph CD, Rudolph AM, Hostetter MK, et al, editors: Rudolph’s pediatrics, ed 21, New York, 2003, McGraw-Hill, p 1548.

Neutrophilic Leukocytes

Refer to Table 38-2 and the inside front cover for the leukocyte reference ranges for full-term infants. Term and premature infants show a greater absolute neutrophil count than that found in older children, who characteristically maintain a predominance of lymphocytes. Band forms are also higher for the first 3 to 4 days after birth (Table 38-3). Newborn females have neutrophil counts averaging 2000 cells/mcL higher than those of males; neonates whose mothers have undergone labor have higher counts than neonates delivered by cesarean section with no preceding maternal labor.^58,59 There is some evidence that absolute neutrophil counts are lower in healthy black children than in white children.⁶⁰

TABLE 38-3

Neutrophil and Band Counts for Newborns during the First 2 Days of Life *

Age	Absolute Neutrophil Count (× 10⁹/L)	Absolute Band Count (× 10⁹/L)
Birth	3.5-6.0	1.3
12 hr	8.0-15.0	1.3
24 hr	7.0-13.0	1.3
36 hr	5.0-9.0	0.7
48 hr	3.5-5.2	0.7

^*Normal values were obtained from the assessment of 3100 separate white blood cell counts obtained from 965 infants; 513 counts were from infants considered to be completely normal at the time the count was obtained and for the preceding and subsequent 48 hours. There was no difference in the normal ranges when values were stratified by infant birth weight or gestational age.

Modified from Luchtman-Jones L, Schwartz AL, Wilson DB: Hematologic problems in the fetus and neonate. In Martin RJ, Fanaroff AA, Walsh MC, editors: Fanaroff and Martin’s neonatal-perinatal medicine, ed 8, Philadelphia, 2006, Mosby Elsevier, p 1310.

Premature Infants

At birth, preterm infants exhibit a left shift, with promyelocytes and myelocytes frequently observed. The trend to lymphocyte predominance occurs later than in full-term infants. The neutrophil counts in premature infants are similar to or slightly lower than the neutrophil counts in full-term infants during the first 5 days of life; however, the count gradually declines to 2.5 × 10⁹/L (1.1 to 6.0 × 10⁹/L) at 4 weeks.⁶¹ There is no significant difference in the neutrophil count of infants by birth weight or gestational age; however, very-low-birth-weight infants have a significantly lower limit (1 × 10⁹/L) compared with larger infants.^61–63

Neutropenia

Neutropenia is defined as a reduction in the number of circulating neutrophils to less than 1.5 × 10⁹/L. Neutropenia accompanied by bands and metamyelocytes is often associated with infection, particularly in preterm neonates. Neutropenia represents a decrease in neutrophil production or an increase in consumption.⁶⁴

Neutrophilia

Neutrophilia refers to an increase in the number of neutrophils to greater than 8 × 10⁹/L. Morphologic changes associated with infection include Döhle bodies, vacuoles, and toxic granulation.⁶⁵

Eosinophils and Basophils

The percentages of eosinophils and basophils remain consistent throughout infancy and childhood. Refer to the inside front cover of this book for reference ranges.

Lymphocytes

Lymphocytes constitute about 30% of the leukocytes at birth and increase to 60% at 4 to 6 months. They decrease to 50% by 4 years, to 40% by 6 years, and to 30% by 8 years.13,14,20,24 Benign immature B cells (hematogones), although predominantly found in the bone marrow, can sometimes be seen in the peripheral blood of newborns. These lymphocytes are primarily mid-stage B cells^66,67 and are frequently referred to as “baby” or “kiddie” lymphocytes. They vary in size from 10 to 20 µm, have scant cytoplasm and condensed but homogeneous nuclear chromatin, and may have small, indistinct nucleoli (Figures 38-3 and 38-4).^68–70 Although these lymphocytes may be similar in appearance to the malignant cells seen in childhood acute lymphoblastic leukemia (ALL), these benign cells lack the asynchronous or aberrant antigen expression seen in ALL and thus can be differentiated from the lymphocytes of infant ALL by immunophenotyping (see Chapter 33).^71,72

Figure 38-3 Peripheral blood film for a normal newborn showing a benign lymphocyte (×1000).

Figure 38-4 Peripheral blood film for a normal newborn showing a benign lymphocyte with visible nucleoli (×1000).

Monocytes

The mean monocyte count of neonates is higher than adult values. At birth the average proportion of monocytes is 6%. During infancy and childhood, an average of 5% is maintained except in the second and third weeks, when the proportion increases to around 9%. The count reaches adult levels at 3 to 5 months.

Neonatal Hematologic Response to Infection

Sepsis in neonates is a common cause of morbidity, particularly in premature and low-birth-weight infants.73–77 Defective B-cell response against polysaccharide agents as well as abnormal cytokine release by neutrophils and monocytes has been implicated.^78–81 Because of the transient neutrophilia that occurs during the first 24 hours after birth, followed by a rapid decline, the neutrophil count is not a satisfactory index of infection in the newborn.⁸² Newborns with bacterial infections frequently have normal or below normal neutrophil counts with a shift to the left. Thus, many practitioners depend upon the band count and its derived immature-to-total neutrophil ratio as an indicator of sepsis in neonates,⁸³ although CD64, C-reactive protein, and procalcitonin levels have been suggested as more sensitive markers of sepsis in infants and children.^83,84

Platelet Values in the Newborn

The platelet count usually ranges from 150 to 400 × 10⁹/L for full-term and preterm infants, comparable to adult values (Table 38-4).^85,86 Platelet counts generally increase in both term and preterm infants in the first few months of life, as evidenced by increased mean platelet volume the first month of life. Thrombocytopenia of fewer than 100 × 10⁹ platelets/L may be seen in high-risk infants with sepsis or respiratory distress and neonates with trisomy syndromes, and investigation should be undertaken for underlying pathology.^87,88 Platelets of a newborn infant show great variation in size and shape. Neonatal thrombocytopenia is discussed in Chapter 43.

TABLE 38-4

Normal Platelet Counts for Full-Term and Preterm Infants

Age	Platelet Count (× 10⁹/L; mean ± 1 SD)
Preterm infants, 27-31 wk	275.0 ± 60.0
Preterm infants, 32-36 wk	290.0 ± 70.0
Term infants	310.0 ± 68.0
Normal child/adult	300.0 ± 50.0

SD, Standard deviation.

Adapted from Oski FA, Naiman JL: Normal blood values in the newborn period. In Hematologic problems in the newborn, Philadelphia, 1982, WB Saunders.

Neonatal Hemostasis

The physiology of the hemostatic system in infants and children is different from that in adults (see Chapter 40). The vitamin K–dependent coagulation factors (factors II, VII, IX, and X) are at about 30% of adult values at birth; they reach adult values after 2 to 6 months, although the mean values remain lower in children than in adults. Levels of factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen are between 35% and 55% of adult values at birth, reaching adult values after 4 to 6 months. In contrast, the levels of fibrinogen, factor VIII, and von Willebrand factor are similar to adult values throughout childhood.^89,90 Factor V decreases during childhood, with lower levels during the teen years as compared with adults. The physiologic anticoagulants and inhibitors of coagulation—protein C, protein S, antithrombin, and a disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs 13 (ADAMTS 13)—are reduced to about 30% to 40% at birth. Antithrombin reaches adult values by 3 months, whereas protein C does not normalize until after 6 months.⁸⁹ In the fibrinolytic system, levels of plasminogen and α₂-antiplasmin are similar to adult levels at birth, whereas levels of tissue plasminogen activator are low and levels of plasminogen activator inhibitor (PAI) are increased (Table 38-5).⁹⁰ The hemostatic components are not only changing in concentration over the first few weeks to months of life, but their values are also dependent upon the gestational age of the child, and premature infants have different values at birth than term infants (Table 38-6).

TABLE 38-5

Reference Intervals for Coagulation Tests in the Healthy Full-Term Infant during the First 6 Months of Life

	Day 1	Day 5	Day 30	Day 90	Day 180	Adult
Screening Tests
PT (Sec)	10.1-15.9	10.0-15.3	10.0-14.3	10.0-14.2	10.7-13.9	10.8-13.9
PT (INR)	0.53-1.62	0.53-1.48	0.53-1.26	0.53-1.26	0.61-1.17	0.64-1.17
PTT (Sec)	31.3-54.3	25.4-59.8	32.0-55.2	29.0-50.1	28.1-42.9	26.6-40.3
TCT (Sec)	19.0-28.3	18.0-29.2	19.4-29.2	20.5-29.7	19.8-31.2	19.7-30.3
Factor Assays
Fibrinogen (mg/dL)	167-399	162-462	162-378	150-379	150-387	156-400
II (%)	26-70	33-93	34-102	45-105	60-116	70-146
V (%)	34-108	45-145	62-134	48-132	55-127	62-150
VII (%)	28-104	35-143	42-138	39-143	47-127	67-143
VIII (%)	50-178	50-154	50-157	50-125	50-109	50-149
VWF (%)	50-287	50-254	50-246	50-206	50-197	50-158
IX (%)	15-91	15-91	21-81	21-113	36-136	55-163
X (%)	12-68	19-79	31-87	35-107	38-118	70-152
XI (%)	10-66	23-87	27-79	41-97	49-134	67-127
XII (%)	13-93	11-83	17-81	25-109	39-115	52-164
PK (Fletcher, %)	18-69	20-76	23-91	41-105	56-116	62-162
HMWK (Fitzgerald, %)	6-102	16-132	33-121	30-146	36-128	50-136
XIIIa (%)	27-131	44-144	39-147	36-172	46-162	55-155
XIIIb (%)	30-122	32-180	39-173	48-184	20-170	57-137
Control Proteins
Antithrombin (%)	39-87	41-93	48-108	73-121	84-124	79-131
α₂-Macroglobulin (%)	95-183	98-198	106-194	126-226	149-233	52-120
C₁ lnhibitor (%)	36-108	60-120	47-131	71-159	89-193	71-131
α₁-Antitrypsin (%)	49-137	49-129	36-88	42-102	47-107	55-131
Heparin Cofactor II (%)	10-93	0-96	10-87	10-146	50-190	66-126
Protein C (%)	17-53	20-64	21-65	28-80	37-81	64-128
Protein S (%)	12-60	22-78	33-93	54-118	55-119	60-124
Fibrinolytic Proteins
Plasminogen (%)	125-265	141-293	126-270	174-322	221-381	248-424
Tissue Plasminogen Activator (ng/mL)	5.0-18.9	4.0-10.0	1.0-6.0	1.0-5.0	1.0-6.0	1.4-8.4
α₂-Antiplasmin (%)	55-115	70-130	76-124	76-140	83-139	68-136
Plasminogen Activator Inhibitor 1 (%)	20-151	0-81	0-88	10-153	60-130	0-110

HMWK, High-molecular-weight kininogen; INR, international normalized ratio; PK, prekallikrein; PT, prothrombin time; PTT, partial thromboplastin time; TCT, thrombin clotting time; VWF, von Willebrand factor.

From Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant, Am J Pediatr Hematol Oncol 12(1):95-104, 1990.

TABLE 38-6

Reference Intervals for Coagulation Tests in the Healthy Premature Infant of 30 to 36 Weeks’ Gestation During the First 6 Months of Life

	Day 1	Day 5	Day 30	Day 90	Day 180	Adult
Screening Tests
PT (Sec)	10.6-16.2	10.0-15.3	10.0-13.6	10.0-14.6	10.0-15.0	10.8-13.9
PT (INR)	0.61-1.70	0.53-1.48	0.53-1.11	0.53-1.32	0.05-1.48	0.64-1.17
PTT (Sec)	27.5-79.4	26.9-74.1	26.9-62.5	28.3-50.7	27.2-53.3	26.6-40.3
TCT (Sec)	19.2-30.4	18.8-29.4	18.8-29.9	19.4-30.8	18.9-31.5	19.7-30.3
Factor Assays
Fibrinogen (mg/dL)	150-373	160-418	150-414	150-352	150-360	156-400
II (%)	20-77	29-85	36-95	30-106	51-123	70-146
V (%)	41-144	46-154	48-156	59-139	58-146	62-150
VII (%)	21-113	30-138	21-145	31-143	47-151	67-143
VIII (%)	50-213	53-205	50-199	58-188	50-187	50-149
VWF (%)	78-210	72-219	66-216	75-184	54-158	50-158
IX (%)	19-65	14-74	13-80	25-93	50-120	55-163
X (%)	11-71	19-83	20-92	35-99	35-119	70-152
XI (%)	8-52	13-69	15-71	25-93	46-110	67-127
XII (%)	10-66	9-69	11-75	15-107	22-142	52-164
PK (Fletcher, %)	9-57	25-75	31-87	37-121	40-116	62-162
HMWK (Fitzgerald, %)	9-89	24-100	16-112	32-124	41-125	50-136
XIIIa (%)	32-108	57-145	39-147	71-155	65-161	55-155
XIIIb (%)	35-127	68-158	57-157	75-167	67-163	57-137

From Andrew M, Paes B, Milner R, et al: Development of the human coagulation system in the healthy premature infant, Blood 72(5):1651-1657, 1988.

Bleeding and Thrombosis

The reference ranges for the prothrombin time and partial thromboplastin time for neonates extend higher than those for adults; however, these values normalize by 6 months (see Table 38-5). The risk of bleeding is not increased in a healthy newborn despite the decreased levels of the vitamin K–dependent coagulation factors, which is primarily related to the reduced levels of the physiologic anticoagulants protein C and protein S.⁹¹

The risk of thrombosis is considerably less in neonates and children than in adults. However, two age-related peaks in frequency occur—the first in the neonatal period and the second in postpuberty adolescence.⁹² The presence of central venous catheters, cancer, and chemotherapy are the most common risk factors in both of these groups.^93–96 Hemorrhagic and thrombotic disorders are discussed in Chapters 41 and 42, respectively.

Geriatric Hematology

The life expectancy and quality of life of the elderly have improved dramatically in recent decades. Americans are living longer than ever before. Life expectancies at both age 65 and age 85 have increased. Under current conditions, people who survive to age 65 can expect to live an average of 18.6 more years—almost 7 years longer than people aged 65 in 1900. The life expectancy of people who survive to age 85 today is 7.2 years for women and 6.1 years for men.⁹⁷ The U.S. Census Bureau projects that in 2020 about 1 in 6 Americans will be elderly (age 65 and over) and 6.5 million persons will be age 85 and older.⁹⁸ Global aging is also occurring at a record-breaking rate. The World Health Organization (WHO) reports that by 2050, one fifth of the global population will be adults aged 65 years and older, and the number of centenarians will reach 1.1 million.⁹⁷

Disease and disabilities are not a function of age, although age is a risk factor for many diseases. However, with the increase in the aging population, the incidence of age-related health conditions also is likely to increase. Thus, the care of the elderly has become a growing concern as the life expectancy of the population continues to increase.

The elderly can be roughly divided into three age categories: (1) the “young-old,” aged 65 to 74; (2) the “old-old,” aged 74 to 84; and (3) the “very old,” aged 85 and older.⁹⁹ The 85 and older age group is the fastest growing segment of the elderly population.

Geriatric medicine is a rapidly growing branch of medicine. The use of inappropriate reference values may lead to unnecessary testing and investigations or, more importantly, result in failure to detect a critical underlying disease. The growing concern about the interpretation of hematologic data in reference to age is due partly to the tremendous heterogeneity in the aging process and partly to the difficulty in separating the effects of age from the effects of occult diseases that accompany aging.¹⁰⁰ This section focuses on hematologic changes in the elderly and discusses hematologic reference ranges for various geriatric age groups as well as hematopathologic conditions seen in the geriatric population.

Aging and Hematopoiesis

The aging process is associated with the functional decline of several organ systems, such as cardiovascular, renal, musculoskeletal, pulmonary, and bone marrow reserve. Certain cells lose their ability to divide (e.g., nervous tissue, muscles), whereas others, such as bone marrow and the gastrointestinal mucosa, remain mitotic. Marrow cellularity begins at 80% to 100% in infancy and decreases to about 50% after 30 years, followed by a decline to 30% after age 65.101–103 These changes may be due to a reduction in the volume of cancellous (spongy) bone along with an increase in fat, rather than to a decrease in hematopoietic tissue.¹⁰³ Telomere shortening, which determines the number of divisions a cell undergoes, has not been definitively related to age-related bone marrow stem cell exhaustion in humans¹⁰⁴; however, it is speculated to be associated with hematopoietic stem cell differentiation.¹⁰⁵

Assessment of Hematologic Parameters in Healthy Elderly Adults

In 1930, Wintrobe published hematologic normal ranges that are still in use today. These were derived from healthy young adults, mostly medical students and nurses. What constitutes “normal” for elderly patients is a matter of considerable debate. There is controversy concerning the assignment of geriatric age-specific reference ranges, especially because aging is often accompanied by physiologic changes, and the prevalence of disease increases markedly. The baseline values for the elderly are the same reference values used for healthy adults. Proper interpretation of hematologic data, however, requires a complete understanding of the association between disease and older age. The next section highlights hematologic reference ranges for healthy elderly individuals with and without evidence of underlying disease.

Red Blood Cells

Most RBC parameters (e.g., RBC count and indices and RDW) for normal healthy elderly do not show significant deviations from those for younger adults. There is a gradual decline in hemoglobin starting at middle age, with the mean level decreasing by about 1 g/dL during the sixth through eighth decades.¹⁰⁶ Men older than 60 years have average hemoglobin levels of 12.4 to 15.3 g/dL, whereas men aged 96 to 106 years have a mean hemoglobin level of 12.4 g/dL.^107,108 The hemoglobin levels in women may increase slightly with age or remain unchanged. Elderly women have hemoglobin concentrations ranging from 11.7 to 13.8 g/dL. Males characteristically have higher hemoglobin levels than females, owing to the stimulating effect of androgens on erythropoiesis; however, the difference narrows as androgen levels decrease in elderly men and estrogen levels decrease in older women.^109,110 Characteristically, the lowest hemoglobin levels are found in the oldest patients (Table 38-7).

TABLE 38-7

Hematologic Values in Ambulatory Healthy Adults *

	84-98 yr	30-50 yr
Red blood cells (× 10¹²/L)
Males	4.8 ± 0.4	5.1 ± 0.2
Females	4.5 ± 0.3	4.6 ± 0.3
Hemoglobin (g/dL)
Males	14.8 ± 1.1	15.6 ± 0.7
Females	13.6 ± 1.0	14.0 ± 0.8
Hematocrit (%)
Males	43.8 ± 3.3	45.3 ± 2.2
Females	40.7 ± 2.9	41.6 ± 2.3
Mean cell volume (fL)
Males	91.3 ± 5.4	87.8 ± 2.8
Females	90.5 ± 4.1	90.5 ± 5.0
Mean cell hemoglobin (pg)
Males	31.0 ± 2.0	30.1 ± 1.6
Females	30.2 ± 1.2	30.3 ± 2.1
Mean cell hemoglobin concentration (g/dL)
Males	33.7 ± 1.5	34.2 ± 1.5
Females	33.4 ± 1.2	33.5 ± 1.5
White blood cells (×10⁹/L)	7.6 ± 0.5	8.8 ± 0.4
Platelets (×10⁹/L)	277 ± 2.1	361.0 ± 38.0
Neutrophils (×10⁹/L)	4.5 ± 0.3	5.9 ± 0.3
Lymphocytes (×10⁹/L)	1.9 ± 0.3	1.9 ± 0.8

^*Mean values ± 1 standard deviation.

Adapted from Zauber NP, Zauber AG: Hematologic data of healthy very old people, JAMA 357:2181-2184, 1987; and Chatta GS, Lipschitz DA: Aging of the hematopoietic system. In Hazzard WR, Blass JP, Ettinger WH, et al: Principles of geriatric medicine and gerontology, ed 4, New York, 1999, McGraw-Hill, p 894.

Leukocytes

In the absence of any underlying pathologic condition, there are no statistically significant differences between the total leukocyte count and WBC differential for the young-old and old-old and those for middle-aged adults.¹⁰⁸ Some investigators, however, have reported a lower leukocyte count, 3.1 to 8.5 × 10⁹/L, in individuals older than age 65, owing primarily to a decrease in the lymphocyte count. Others have reported a decrease in the lymphocyte and the neutrophil counts in women, but not in men, older than age 50.¹⁰⁹

Immune Response in the Elderly

Infectious diseases are an important cause of morbidity and mortality in the elderly. Aged adults are more susceptible to infection, take longer to recover from infection, and are often less responsive to vaccination.¹¹¹ The adverse changes that occur in the function of the immune system with age are called immunosenescence.¹¹² Although all components of immunity are affected, T cells appear to be the most susceptible.¹¹³ The thymus disappears by early middle age, and adults must then depend on their T-lymphocyte pool in the secondary tissues to mediate T cell–dependent immune responses.^114,115 The number of naive T cells decreases in the elderly, which increases the dependence on memory T cells. T cells of the elderly have impaired responsiveness to mitogens and antigens as a result of decreased expression of costimulator CD28. There is also an alteration of T-cell signaling with aging.^116–118 B-lymphocyte function depends on T-cell interaction. Thus, the decreased ability to generate antibody responses, especially to primary antigens, may be the result of T-cell changes rather than intrinsic defects in B lymphocytes.^{114,115,119,120}

Many neutrophil functions are decreased in the elderly, including chemotaxis, phagocytosis of microorganisms, and generation of superoxide. Studies indicate that these defects may be associated with changes to the cell membrane and/or to receptor signalling.¹¹¹

Monocytes and Macrophages

The aging process does not significantly affect the number of monocytes. Information on the effects of aging on monocyte and macrophage function is limited and often conflicting.¹¹¹ Recent studies provide evidence for defects in the toll-like receptor (TLR) function in monocytes and macrophages in older individuals.¹¹¹ The TLRs play a crucial role in the immune response.¹²¹

Platelets

The platelet count is not significantly changed with age. There have been reports of increased levels of β-thromboglobulin and platelet factor 4 in the α-granules and increased platelet phospholipid content.122,123 Thrombocytopenia may be drug induced or secondary to marrow infiltration of metastatic cancer, lymphoma, or leukemia. Thrombocytosis can be categorized into primary and secondary. Essential thrombocytosis is a myeloproliferative neoplasm characterized by sustained proliferation of megakaryocytes resulting in platelet counts of 450 × 10⁹/L or greater (see Chapter 34).¹²⁴ Primary thrombocytosis can also be seen in chronic myelogenous leukemia. Secondary thrombocytosis, or reactive thrombocytosis, is associated with infections, rheumatoid arthritis, chronic inflammatory bowel disease, iron deficiency anemia, sickle cell anemia, and splenectomy.^125–127

Anemia and the Elderly

Anemia is common in the elderly and its prevalence increases with age; however, anemia should not be viewed as an inevitable consequence of aging.128,129 Although anemia in the elderly is typically mild, it has been associated with substantial morbidity and mortality.^130,131 WHO defines anemia as hemoglobin less than 13 g/dL in males and less than 12 g/dL in females. Using the WHO definition of anemia, the Third National Health and Nutrition Examination Survey (NHANES III), a national study that samples clinical specimens, found the prevalence of anemia in the United States in individuals over the age of 65 to be 11.0% in men and 10.2% in women.¹³² However, studies of the prevalence of anemia in the elderly show great variability in the definitions of anemia used as well as differences in sample sizes, patient populations studied, countries in which the study was conducted, and study design. Thus, estimates of the prevalence of anemia vary from 2.9% to 61% in elderly men and from 3.3% to 41% in elderly women.¹³³

The factors contributing to anemia include a decrease in bone marrow function, a decline in physical activity, nutritional deficiencies, cardiovascular disease, and chronic inflammatory disorders. Anemia of chronic inflammation, iron deficiency anemia, and unexplained anemia are the most common anemias in the elderly.

Ineffective erythropoiesis and hypoproliferation may also be seen in the elderly. Ineffective erythropoiesis is associated with vitamin B₁₂ or folate deficiency, sideroblastic anemia, and thalassemia in the elderly. Hypoproliferative anemia often occurs secondary to iron deficiency, vitamin B₁₂ or folate deficiency, renal failure, hypothyroidism, chronic inflammation, or endocrine disease.¹³⁴ To a lesser extent, the elderly are prone to anemias such as aplastic anemia, hemolytic anemia, myelophthisic anemia, and anemia due to protein-calorie malnutrition.

The initial laboratory evaluation of anemia should include a complete blood count (CBC), a reticulocyte count, peripheral blood film review, and chemistry panel, along with other diagnostic tools including iron studies (with ferritin), vitamin B₁₂ and folate levels, and free erythrocyte protoporphyrin (Table 38-8). In addition, assessment for signs of gastrointestinal blood loss, hemolysis, nutritional deficiencies, malignancy, chronic infection, renal or hepatic disease, or other chronic disease can provide important information for the evaluation of anemia in the elderly.

TABLE 38-8

Classification of Geriatric Anemia Based on Mean Cell Volume (MCV) and Red Cell Distribution Width (RDW)

MCV	RDW	Anemia
Normal	Normal	Anemia of chronic inflammation (some) Hemorrhagic anemia Leukemia-associated anemia
Normal	High	Early iron deficiency anemia Mixed deficiency anemia (e.g., vitamin B₁₂ and iron) Sideroblastic anemia
Low	Normal	Anemia of chronic inflammation (some)
Low	High	Iron deficiency anemia
High	Normal	Anemia associated with myelodysplastic syndrome
High	High	Vitamin B₁₂ deficiency anemia Folate deficiency anemia Hemolytic anemia

Anemia of Chronic Inflammation

Anemia of chronic inflammation, also known as anemia of chronic disease, frequently occurs with inflammatory disorders (e.g., rheumatoid arthritis, renal failure, liver disease), chronic infections, bedsores, collagen vascular disease, protein malnutrition, endocrine disorders, vitamin C deficiency, and neoplastic disorders.134–142 This hypoproliferative anemia is the most common form of anemia in the hospitalized geriatric population.¹⁴³ The severity of the anemia generally correlates with the severity of the underlying disease.¹⁴⁴ An impaired erythropoietin-dependent erythropoiesis triggered by proinflammatory cytokines, impaired iron mobilization, and shortened RBC survival is involved in the pathogenesis of anemia of chronic inflammation.¹⁴⁵ Chapter 19 discusses anemia of chronic inflammation.

Iron Deficiency Anemia

Iron deficiency anemia is common in the elderly. Iron deficiency affects not only erythrocytes, but also the metabolic pathways of iron-dependent tissue enzymes.¹³⁹ Hemoglobin synthesis is reduced, and even a minimal decrease can cause profound functional disabilities in an elderly patient. The serum iron level decreases progressively with each decade of life, particularly in females. Nevertheless, healthy elderly adults usually have normal serum iron levels.

Iron deficiency anemia in the elderly is rarely due to dietary deficiency in industrialized nations because of the prevalence of iron fortification of grains as well as a diet that includes meats containing heme iron. Iron deficiency in the elderly most frequently results from conditions leading to chronic gastrointestinal blood loss, including long-term use of nonsteroidal antiinflammatory medications, gastritis, peptic ulcer disease, gastroesophageal reflux disease with esophagitis, colon cancer, and angiodysplasia.146–148 It also may be due to poor diet in an elderly individual who has lost the taste or desire for food or is unable to prepare nutritious meals. Chapter 19 discusses iron disorders in detail.

Ineffective Erythropoiesis

Ineffective erythropoiesis has been attributed not only to maturation disorders such as vitamin B₁₂ and folic acid deficiency, but also to sideroblastic anemia and thalassemia. Sideroblastic anemias are characterized by impaired heme synthesis, and abnormal globin synthesis occurs in the thalassemias (see Chapter 27). Megaloblastic anemia results from defective synthesis of deoxyribonucleic acid (DNA) (see Chapter 20) with compromised cell division, but normal cytoplasmic development (i.e., asynchrony).^149–151 These megaloblastic cells are more prone to destruction in the bone marrow, which results in “ineffective” erythropoiesis. Two causes of megaloblastic anemia are deficiency of vitamin B₁₂ and folate deficiency.

Vitamin B₁₂ Deficiency

Vitamin B₁₂ (cobalamin) deficiency causes a megaloblastic disorder in 5% to 10% of the elderly.¹³⁴ It may be difficult to detect, because anemia is present in only about 60% of patients.¹⁵² Neurologic complications are found in 75% to 90% of individuals with clinically apparent vitamin B₁₂ deficiency.^153,154 In the absence of anemia, neurologic symptoms may be the only indication. Even when anemia is present, it does not always manifest with the classic macrocytic and megaloblastic picture but may be normocytic or microcytic.

Vitamin B₁₂ deficiency in the elderly has been attributed to inadequate intestinal absorption of food-bound vitamin B₁₂ and pernicious anemia rather than inadequate intake.¹⁵⁵ Many elderly individuals have atrophic gastritis resulting in decreased gastric production of acid. In this condition there is low vitamin B₁₂ absorption because protein-bound vitamin B₁₂ is not dissociated and cannot bind to intrinsic factor. In addition, the loss of gastric acid can result in bacterial overgrowth, particularly with Helicobacter pylori, which also interferes with vitamin B₁₂ absorption.^156,157 Inadequate vitamin B₁₂ absorption in the elderly has also been reported in other infrequent conditions such as small bowel disorder, gastric resection, pancreatic insufficiency, resection of the terminal ileum, blind loop syndrome, and tropical sprue.¹⁵⁸ Pernicious anemia develops slowly and insidiously in patients when autoimmune antibodies to intrinsic factor or to parietal cells destroy their parietal cells so that they are left without intrinsic factor.¹⁵⁹ Given the high risk of vitamin B₁₂ deficiency in the aged and the risks of the condition, some authors have proposed that all elderly adults be screened periodically for vitamin B₁₂ deficiency.^160–162 Chapter 20 discusses megaloblastic anemias.

Folate Deficiency

A second megaloblastic anemia that may be seen in the elderly results from folate deficiency. In contrast to vitamin B₁₂ deficiency, folic acid deficiency usually develops from inadequate dietary intake, because the body stores little folate.110,163 However, the incidence of low serum and RBC folate levels has declined in all age groups, including the elderly, since countries began to fortify their grains with folic acid in the 1990s.¹⁶⁴ Alcoholic elderly patients are particularly prone to folic acid deficiency, because alcohol interferes with folate absorption, enterohepatic recycling, metabolism, breakdown, and excretion (see Chapter 20).^165,166

Hemolytic Anemia

Hemolytic anemias are characterized by a shortened RBC survival time. There are three major types of hemolytic anemias: (1) those caused by immunologic mechanisms; (2) those due to intrinsic defects, such as an RBC membrane defect, abnormal hemoglobins, or RBC enzyme defects; and (3) those resulting from extrinsic factors, such as mechanical or lytic processes.135,167 The elderly are at risk for drug-induced anemia because they may take multiple medications. Drug-induced hemolytic anemia has been associated with high doses of antibiotics (penicillin, chloramphenicol, cephalosporins), several nonsteroidal antiinflammatory drugs, quinidine, phenacetin, and others. Hemolytic anemias in the elderly also can result from collagen vascular diseases, infections, and chronic lymphocytic leukemia. The hemolytic anemias are discussed in Chapters 24 and 25.

Hematologic Neoplasia in Older Individuals

Although hematologic malignancies may occur at any age, certain disorders are common in those older than 50 years. A brief overview of these is included in this chapter, with references to more detailed discussions.

Chronic Myeloid Neoplasms

The 2008 WHO classification of adult chronic myeloid neoplasms includes four broad categories: myelodysplastic syndrome, myeloproliferative neoplasms, myelodysplastic syndrome/myeloproliferative neoplasm overlap, and myeloid neoplasms associated with eosinophilia and abnormalities of platelet-derived growth factor receptor α, platelet-derived growth factor receptor β, or fibroblast growth factor receptor 1. The chronic myeloid neoplasms show increased incidence in the elderly.

Myelodysplastic Syndrome

Myelodysplastic syndrome represents a heterogeneous group of clonal bone marrow disorders that may affect multiple cell lineages. Myelodysplasia is the most common hematologic malignancy in the elderly.¹⁶⁸ The incidence of myelodysplastic syndrome increases from 8.9 cases per 100,000 for individuals aged 60 to 69 to 26.2 per 100,000 for those aged 70 to 79, and is 47.6 per 100,000 for those aged 80 and older.¹⁶⁹ See Chapter 35 for a complete discussion of myelodysplastic syndrome.

Myeloproliferative Neoplasms

Myeloproliferative neoplasms are monoclonal proliferations of hematopoietic stem cells with overaccumulation of RBCs, WBCs, or platelets in various combinations. Myeloproliferative disorders include chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, myeloid neoplasms with eosinophilia and tyrosine kinase mutations, chronic eosinophilic leukemia not otherwise classified, mast cell disease, chronic neutrophilic leukemia, and unclassifiable myeloproliferative neoplasms. The incidence of myeloproliferative neoplasms increases from 6.3 per 100,000 for individuals aged 60 to 69, to 11.6 per 100,000 for those aged 70 to 79, and to 13.8 per 100,000 for those 80 years of age and older.¹⁶⁹ Chapter 34 discusses the myeloproliferative neoplasms.

Leukemia

Leukemia is a neoplastic disease characterized by a malignant proliferation of hematopoietic stem cells in the bone marrow, peripheral blood, and often other organs. Leukemia is broadly classified on the basis of the cell type involved (lymphoid or myeloid) and the stage of maturity of the leukemic cells (acute or chronic). Although the overall incidence of leukemia has decreased in the past 5 decades, there has been a disproportionately greater incidence in leukemia in the elderly (Table 38-9). The peaks in leukemia incidence seem to occur in the very young (age 1 to 4 years) and the very old (age 70 or older, especially men). Chronic myelogenous leukemia (see Chapter 34) and chronic lymphocytic leukemia (see Chapter 37) show the most dramatic age-related increase in incidence.

TABLE 38-9

SEER Incidence of Leukemia in the Elderly in the United States per 100,000 (2002-2007)*

Age at Diagnosis	All Leukemias	ALL	CLL	AML	CML
65-69 yr	34.9	1.4	16.0	9.5	4.1
70-74 yr	47.3	1.5	20.9	14.0	5.6
75-79 yr	62.7	1.6	27.5	18.7	7.5
80-84 yr	74.4	1.5	30.7	23.0	9.2
≥85 yr	79.8	1.7	33.2	21.2	9.2

ALL, Acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia.

^*Surveillance, Epidemiology, and End Results (SEER) rates are age adjusted to the 2000 U.S. standard population census.

Adapted from Altekruse SF, Kosary CL, Krapcho M, et al, editors: SEER cancer statistics review, 1975-2007, Bethesda, Md, 2010, National Cancer Institute. Based on November 2009 SEER data submission, posted to the SEER website in 2010. Available at: http://seer.cancer.gov/csr/1975_2007/. Accessed July 10, 2010.

Approximately 13% of patients with acute leukemia have had previous hematologic disorders, such as myelodysplastic syndrome, hypoplastic bone marrow, polycythemia, or myelofibrosis. Geriatric patients are more likely than younger patients to die due to the toxicity of, or resistance to, chemotherapy.169–171

Geriatric Hemostasis

Fibrinogen, factor V, factor VII, factor VIII, factor IX, factor XIII, high-molecular-weight kininogen, and prekallikrein increase in healthy individuals as they age.¹⁷³ Fibrinogen, which has been implicated as a primary risk factor for thrombotic disorders, increases approximately 10 mg/dL per decade in the elderly (65 to 79 years),¹⁷⁴ from 280 mg/dL to over 300 mg/dL. Elevated levels of factor VIII also have been associated with increased risk of venous thrombosis.¹⁷⁵ Studies of the association between factor VII and venous thrombosis have yielded conflicting findings.¹⁷³

PAI-1, the major inhibitor of fibrinolysis, increases with aging. PAI-1 has been shown to promote age-dependent thrombosis in animal models and could play an important role in causing hypercoagulability in the elderly.176–178

Platelets increase in activity with age, as evidenced by a decrease in bleeding time as males age from 11 to 70 years ¹⁷⁹ and an increase in markers of platelet activation, platelet β-thromboglobulin and platelet factor 4.¹⁸⁰ Increased platelet activity with aging is also associated with increased platelet phospholipids, which suggests an age-related increase in platelet transmembrane signalling.¹⁸¹