Rodak's Hematology: Clinical Principles and Applications, 5th Ed.

CHAPTER 45. Pediatric and geriatric hematology and hemostasis

Linda H. Goossen

OUTLINE

Pediatric Hematology and Hemostasis

Prenatal Hematopoiesis

Hematopoiesis of the Newborn

Pediatric Developmental Stages

Gestational Age and Birth Weight

Red Blood Cell Values at Birth

White Blood Cell Values in the Newborn

Platelet Values in the Newborn

Neonatal Hemostasis

Geriatric Hematology and Hemostasis

Aging and Hematopoiesis

Assessment of Hematologic Parameters in Healthy Elderly Adults

Anemia and the Elderly

Hematologic Neoplasia in Older Individuals

Geriatric Hemostasis

Objectives

After completion of this chapter, the reader will be able to:

1. Describe the major differences in reference intervals for the complete blood count, reticulocyte count, and nucleated red blood cells (NRBCs) in preterm newborns, full-term newborns, infants, children, adults, and elderly adults.

2. Explain the cause of physiologic anemia of infancy and the time frame in which it is expected.

3. Describe normal RBC morphology in neonates.

4. Compare the RBC survival in preterm and full-term infants with that in adults.

5. Recognize and list factors affecting sample collection that can have an impact on the interpretation of hematology values in newborns.

6. Compare and contrast the morphology of lymphocytes in children and in adults, and indicate reasons for differences.

7. Describe the general association between age and hemoglobin levels in the elderly.

8. Explain the clinical significance of anemia in the elderly.

9. Name the two most common anemias seen in the elderly and their common causes in this age group.

10. List other anemias affecting elderly individuals.

11. Compare the frequency of acute lymphoblastic leukemias and chronic lymphocytic leukemias in children and the elderly.

12. Compare the hemostatic systems of newborns, children, adults, and the elderly, including the risk of bleeding and thrombosis.

13. Name hematologic malignancies that are more common in the elderly than in other age groups.

CASE STUDY

After studying this chapter, the reader should be able to respond to the following case study:

A full-term newborn infant in no apparent distress had a complete blood count (CBC) performed as part of a panel of testing for infants born to mothers who received no prenatal care.

Results were as follows:

 

Patient Results

Reference Intervals

WBCs (×109/L)

18.0

9.0–37.0

RBCs (×1012/L)

5.28

4.10–6.10

HGB (g/dL)

18.5

16.5–21.5

HCT (%)

55.5

48–68

MCV (fL)

105.1

95–125

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 reference intervals 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 and hemostasis

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 intervals for the assessment of pediatric blood values. Historically, pediatric reference intervals 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 intervals 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 intervals, morphologic features, and age-specific physiology.

Prenatal hematopoiesis

Hematopoiesis, the formation and development of blood cells from hematopoietic 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 appear megaloblastic and circulate as large nucleated cells, synthesizing embryonic hemoglobins. A second wave of yolk-sac derived erythroid progenitor cells, termed burst forming units–erythroid (BFU-E), appear around four weeks and are thought to seed the fetal liver.

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 (Chapter 7).

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 almost completely 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.78

In a full-term infant, hepatic hematopoiesis has ceased except in widely scattered small foci that become inactive soon after birth. 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.

Pediatric developmental stages

Pediatric hematologic values change markedly in the first weeks and months of life, and many variables influence the interpretation of what might be considered healthy at the time of birth. Thus it is important to provide age-appropriate pediatric hematology reference intervals that extend from neonatal life through adolescence. The pediatric population can be categorized with reference to three different developmental stages: the neonatal period, which represents the first 4 weeks of life; infancy, which incorporates the first year of life; and childhood, which spans age 1 to puberty (age 8 to 12 years).

Preterm, low-birth-weight infants are more apt to develop health problems than are other newborns. Since the 1970s, the rising quality of medical care in neonatal intensive care units in the United States and other industrialized countries 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 values for extremely low-birth-weight infants. 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.1112 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 (1000 g or less); and (5) large for gestational age (more than 4000 g).1112

Red blood cell values at birth

Neonatal hematologic values are affected by the gestational age of the infant, birth weight, 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, and maternal drug use.1213 The presence of fetal hemoglobin (Hb F), bilirubin, and lipids in newborns can also interfere with hematology laboratory testing. As with all laboratory testing, each laboratory should establish reference intervals based on its instrumentation, methods, and patient population (Chapter 5).

Red blood cell count

Refer to the inside front cover of this book for red blood cell (RBC) reference intervals. 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 newborn18 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 by 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. 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 remain macrocytic from the first 11 weeks of gestation until day 5 of postnatal life ().Figure 45-1121320212425

Image 

FIGURE 45-1 Peripheral blood from a healthy 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 healthy 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.1261320-24

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).26 In addition, increased numbers of pitted cells, burr cells, spherocytes, and other abnormally shaped erythrocytes are seen in neonates. The number of these “dysmorphic” cells is even higher in premature infants. Zipursky and colleagues found 40% discs, 30% stomatocytes, and 27% additional poikilocytes in premature infants.126

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 and then declines abruptly to 0.8% reticulocytes on postnatal days 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 2.5% are attained.1261320-24 The reticulocyte count of premature infants is typically higher than that of term infants; however, the count can vary dramatically, depending on the extent of illness in the newborn. Significant polychromasia seen on a Wright-stained blood film is indicative of postnatal reticulocytosis (Figure 45-2).

Image 

FIGURE 45-2 Peripheral blood film from a premature infant showing a normal lymphocyte (arrow), 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 60% to 90% of the total hemoglobin.27 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.28 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.2429 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.126In 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.14, , 2425 Racial differences must also be considered when evaluating hemoglobin levels in children. Black children have hemoglobin levels averaging 0.5 g/dL lower than those in white children.30

The reference interval for 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.22021 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.2021

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.232-34 Along with a decrease in hemoglobin, there is a reduction in the number of RBCs, a decrease in the reticulocyte percentages (Table 45-1), 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.1835-40 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.12124 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.

TABLE 45-1

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 healthy full-term infants by about 1 year of age.151823353640 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 capillary hematocrit (HCT) at birth for healthy full-term infants is 61% (reference interval, 48% to 68%).1224 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 40% between the second and fourth months.12,25 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 (Table 45-1). Many require transfusions or erythropoietin injections or both.

Red blood cell indices

The RBC indices and RBC distribution width (RDW) provide one means for assessing the type of anemia (Chapter 19).

Mean cell volume. 

The erythrocytes of newborn infants are markedly macrocytic at birth. The average MCV for full-term infants is 119 ± 9.4 fL; however, a sharp decrease occurs during the first 24 hours of life.12 The MCV continues to decrease to 90 ± 12 fL in 3 to 4 months.21837 The more premature the infant, the higher the MCV. A newborn with an MCV of less than 94 fL should be evaluated for α-thalassemia or iron deficiency.141

Mean cell hemoglobin. 

MCH is 30 to 42 pg in healthy neonates and 27 to 41 pg in premature infants.1837

Mean cell hemoglobin concentration. 

The average MCHC is the same for full-term infants, premature infants, and adults: approximately 33 g/dL.

Red blood cell distribution width. 

The red blood cell distribution width is elevated in newborns, with a reference interval of 14.2% to 17.8% the first 30 days of life. After that it gradually decreases and reaches the adult reference interval by 6 months of age.25

Anemia in infants and children

Nutritional deficiencies in infants and children can result in iron deficiency anemia and, rarely, in megaloblastic anemia (Chapters 20 and 21), 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.

Iron deficiency anemia. 

Iron deficiency anemia is the most common pediatric hematologic disorder and the most frequent cause of anemia in childhood.47 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.48 However, the prevalence is still 2% in toddlers 1 to 2 years of age and 3% in children 3 to 5 years of age49 and is related to early introduction and excessive intake of whole cow’s milk.4250 Chapter 20 provides 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 intervals 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.51 Transferrin levels are also lower in neonates, increasing rapidly after birth and reaching adult levels at 6 months.51 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. 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 (). Leukocytosis is typical at birth for full-term and preterm infants, with a wide reference interval.Table 45-218 There is an excess of segmented neutrophils and bands, and an occasional metamyelocyte, with no evidence of disease. The absolute neutrophil count rises within the first 8 to 12 hours following birth and then declines by 12 hours to a constant level.2185556

TABLE 45-2

Leukocyte Count Reference Intervals by Age*

 

NEUTROPHILS

 

EOSINOPHILS

MONOCYTES

TOTAL WBC COUNT

Age

Mean

Range

%

Mean

Range

%

Mean

%

Mean

%

Mean

Range

Birth

4.0

2.0–6.0

4.2

2.0–7.3

0.1

0.6

12 hr

11.0

7.8–14.5

4.2

2.0–7.3

0.1

0.6

24 hr

9.0

7.0–12.0

4.2

2.0–7.3

0.1

0.6

1–4 wk

3.6

1.8–5.4

5.6

2.9–9.1

0.2

0.7

6 mo

3.8

1.0–8.5

32

7.3

4.0–13.5

61

0.3

3

0.6

5

11.9

6.0–17.5

1 yr

3.5

1.5–8.5

31

7.0

4.0–10.5

61

0.3

3

0.6

5

11.4

6.0–17.5

2 yr

3.5

1.5–8.5

33

6.3

3.0–9.5

59

0.3

3

0.5

5

10.6

6.0–17.0

4 yr

3.8

1.5–8.5

42

4.5

2.0–8.0

50

0.3

3

0.5

5

9.1

5.5–15.5

6 yr

4.3

1.5–8.0

51

3.5

1.5–7.0

42

0.2

3

0.4

5

8.5

5.0–14.5

8 yr

4.4

1.5–8.0

53

3.3

1.5–6.8

39

0.2

2

0.4

4

8.3

4.5–13.5

10 yr

4.4

1.8–8.0

54

3.1

1.5–6.5

38

0.2

2

0.4

4

8.1

4.5–13.5

16 yr

4.4

1.8–8.0

57

2.8

1.2–5.2

35

0.2

3

0.4

5

7.8

4.5–13.0

* 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. WBC, white blood cell.

‡ Dashes indicate insufficient data for a reliable estimate.

Data 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 45-2 and the inside front cover for the leukocyte reference intervals for healthy 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 45-3). Newborn females have absolute neutrophil counts averaging 2000 cells/μL 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.5556 There is some evidence that absolute neutrophil counts are lower in healthy black children than in white children.5758

TABLE 45-3

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

* Reference intervals 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 healthy at the time the count was obtained and for the preceding and subsequent 48 hours. There was no difference in the reference intervals when values were stratified by infant birth weight or gestational age.

Modified from Luchtman-Jones L, Wilson DB: The blood and hematopoietic system. In Martin RJ, Fanaroff AA, Walsh MC, editors: Fanaroff and Martin’s neonatal-perinatal medicine, ed 9, Philadelphia, 2011, Elsevier Mosby, p 1325.

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.59There is no significant difference in the absolute neutrophil count of infants by birth weight or gestational age; however, very low-birth-weight infants have a significantly lower limit (1.0 × 109/L) compared with larger infants.

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.62

Neutrophilia. 

Neutrophilia refers to an increase in the absolute number of neutrophils to greater than 8.0 × 109/L. Morphologic changes associated with infection include Döhle bodies, vacuoles, and toxic granulation.63

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 intervals.

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.1320 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 cells6465 and are frequently referred to as “baby” or “kiddie” lymphocytes. They vary in diameter from 10 to 20 μm, have scant cytoplasm and condensed but homogeneous nuclear chromatin, and may have small, indistinct nucleoli (Figures 45-3and 45-4. 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 (Chapter 32).6970

Image 

FIGURE 45-3 Peripheral blood film from a healthy newborn showing a benign lymphocyte (×1000).

Image 

FIGURE 45-4 Peripheral blood film from a healthy 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.25

Neonatal hematologic response to infection. 

The immune response of newborns is considered “immature,” with decreased responsiveness to agonists. This distinct immune response is postulated to be related to the demands of the fetal environment and the need to avoid response to maternal antigens.71 Sepsis in neonates is a common cause of morbidity, particularly in premature and low-birth-weight infants. Defective B cell response against polysaccharide agents, as well as abnormal cytokine release by neutrophils and monocytes, has been implicated. 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.81 Newborns with bacterial infections frequently have neutrophil counts within or below the reference interval with a shift to the left. Thus many practitioners depend on the band count and its derived immature-to-total neutrophil ratio as an indicator of sepsis in neonates,82 although CD64 index, C-reactive protein, and procalcitonin levels have been suggested as more sensitive markers of sepsis in infants and children.8283

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 45-4).8485 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.8687 Platelets of a newborn infant show great variation in size and shape. Neonatal thrombocytopenia is discussed in Chapter 40.

TABLE 45-4

Platelet Count Reference Intervals for Full-Term and Preterm Infants

Age

Platelet Count (× 109/L; mean ± 1 SD)

Preterm infants, 27–31 wk

275 ± 60

Preterm infants, 32–36 wk

290 ± 70

Term infants

310 ± 68

Healthy child/adult

300 ± 50

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

SD, Standard deviation.

Neonatal hemostasis

The physiology of the hemostatic system in infants and children is different from that in adults (Chapter 37). 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.8889 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, and antithrombin) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) that cleaves ultra-long von Willebrand factor multimers are reduced to about 30% to 40% at birth. Antithrombin reaches adult values by 3 months, whereas protein C does not reach adult levels until after 6 months.88 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 1 (PAI-1) are increased (Table 45-5).89 The hemostatic components are not only changing in concentration over the first few weeks to months of life, but their values are also dependent on the gestational age of the child, and premature infants have different values at birth than term infants (Table 45-6).

TABLE 45-5

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

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.

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.

TABLE 45-6

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

0.50–1.48

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.

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.

Bleeding and thrombosis

The reference intervals for the prothrombin time and partial thromboplastin time for neonates extend higher than those for adults; however, these values reach adult reference intervals by 6 months (Table 45-5). 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.90

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.91Central venous catheters, cancer, and chemotherapy are the most common risk factors in both of these groups. Hemorrhagic and thrombotic disorders are discussed in Chapters 38 and 39, respectively.

Geriatric hematology and hemostasis

In 2010, there were 40 million people in the United States aged 65 and over, accounting for 13% of the population. The older population in 2030 is projected to be twice as large as in 2000, growing from 35 million to 75 million and representing 20% of the total U.S. population.96 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 19.2 more years—almost 5 years longer than people aged 65 in 1960. In 2009, the life expectancy of people who survived to age 85 was 7 years for women and 5.9 years for men.96

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: the “young-old,” aged 65 to 74; the “old-old,” aged 74 to 84; and the “very old,” aged 85 and older.97 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 intervals 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.98 This section focuses on hematologic changes in the elderly and discusses hematologic reference intervals 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. These changes may be due to a reduction in the volume of cancellous (trabecular or spongy) bone, along with an increase in fat, rather than to a decrease in hematopoietic tissue.101 Telomere shortening, which determines the number of divisions a cell undergoes, has not been definitively correlated to age-related hematopoietic stem cell exhaustion in humans102; however, it is speculated to be associated with hematopoietic stem cell differentiation.103

Assessment of hematologic parameters in healthy elderly adults

In 1930, Wintrobe published hematologic reference intervals 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 intervals, 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 intervals 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 intervals for healthy elderly individuals with and without evidence of underlying disease.

Red blood cells

Most RBC parameters (e.g., RBC count, indices, and RDW) for 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.104 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.105106 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.107 Characteristically, the lowest hemoglobin levels are found in the oldest patients (Table 45-7).

TABLE 45-7

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

 
 

277 ± 21

361 ± 38

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, Halter JB, et al: Principles of geriatric medicine and gerontology, ed 5, New York, 2003, McGraw-Hill, p 767.

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.106 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 50.107

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.108 The adverse changes that occur in the function of the immune system with age are called immunosenescence.109 Although all components of immunity are affected, T cells appear to be the most susceptible.110 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.111112 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. 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.111112116117

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 signaling.108

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.108 Recent studies provide evidence for defects in the toll-like receptor (TLR) function in monocytes and macrophages in older individuals.108 The TLRs play a crucial role in the immune response.118

Platelets

The platelet count does not significantly change 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.119120Thrombocytopenia may be drug induced or secondary to marrow infiltration of metastatic cancer, lymphoma, or leukemia (Chapter 40). Thrombocytosis can be categorized into primary and secondary (Chapter 40). Essential thrombocythemia is a myeloproliferative neoplasm characterized by sustained proliferation of megakaryocytes, resulting in platelet counts of 450 × 109/L or greater (Chapter 33).121 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.

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.125126 Although anemia in the elderly is typically mild, it has been associated with substantial morbidity and mortality.127128 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% in men and 10.2% in women. This proportion doubles in those aged 85 and above.126 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.129

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. Unexplained anemia, anemia due to hematologic malignancies, iron deficiency anemia, anemia related to therapy for nonhematologic malignancies, and anemia of chronic inflammation are the most common causes of anemia in the elderly.130

Ineffective erythropoiesis and hypoproliferation are also seen in the elderly. Ineffective erythropoiesis is associated with vitamin B12 or folate deficiency, myelodysplastic syndrome, sideroblastic anemia, and thalassemia. Hypoproliferative anemia often occurs secondary to iron deficiency, vitamin B12 or folate deficiency, renal failure, hypothyroidism, chronic inflammation, or endocrine disease.130131 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. Table 45-8 indicates the types of anemia suggested by MCV and RDW results. 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 45-8

Classification of Geriatric Anemia Based on Typical 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

High

Early iron deficiency anemia Mixed deficiency anemia (e.g., vitamin B12 and iron) 

Sideroblastic anemia

Low

Normal

Anemia of chronic inflammation (some)

High

Iron deficiency anemia

High

Normal

Anemia associated with myelodysplastic syndrome

High

Vitamin B12 deficiency anemia Folate deficiency anemia 

Hemolytic anemia

Note that this classification is not absolute because there can be an overlap of RDW values among some of the conditions in each MCV category.

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. This hypoproliferative anemia is the most common form of anemia in the hospitalized geriatric population.140 The severity of the anemia generally correlates with the severity of the underlying disease.141 Hepcidin-induced inhibition of iron absorption in the intestines and iron mobilization from macrophages and hepatocytes, and impaired erythropoietin-dependent erythropoiesis triggered by inflammatory cytokines is involved in the pathogenesis of anemia of chronic inflammation (Chapter 20).142143

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.136 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 serum iron levels within the adult reference interval.

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 anti-inflammatory medications, gastritis, peptic ulcer disease, gastroesophageal reflux disease with esophagitis, colon cancer, and angiodysplasia. 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 20 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, thalassemia, and myelodysplastic syndrome. Sideroblastic anemias are characterized by impaired heme synthesis, and abnormal globin synthesis occurs in the thalassemias (Chapters 20 and 28). Megaloblastic anemia results from defective synthesis of deoxyribonucleic acid (DNA) (Chapter 21) with compromised cell division but normal cytoplasmic development (i.e., asynchrony). These megaloblastic cells are more prone to destruction in the bone marrow, which results in ineffective erythropoiesis. Two causes of megaloblastic anemia are vitamin B12 deficiency and folate deficiency. Myelodysplastic syndrome results in ineffective hematopoiesis due to mutations in hematopoietic stem cells and progenitor cells. It is more common in the elderly and is discussed below.

Vitamin b12 deficiency. 

Vitamin B12 (cobalamin) deficiency causes a megaloblastic disorder in 5% to 10% of the elderly.131 It may be difficult to detect because anemia is present in only about 60% of patients.150 Neurologic complications are found in 75% to 90% of individuals with clinically apparent vitamin B12 deficiency.151152 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.

Vitamin B12 deficiency in the elderly has been attributed to inadequate intestinal absorption of food-bound vitamin B12 rather than pernicious anemia or inadequate intake.143153 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 from food proteins and therefore cannot bind to intrinsic factor for absorption. In addition, the loss of gastric acid can result in bacterial overgrowth, particularly with Helicobacter pylori, which also interferes with vitamin B12 absorption.154155Inadequate 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.156 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.157 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 B12deficiency.158159 Chapter 21 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.160 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.161Alcoholic elderly patients are particularly prone to folic acid deficiency because alcohol interferes with folate absorption, enterohepatic recycling, metabolism, breakdown, and excretion (Chapter 21).162163

Hemolytic anemia

Hemolytic anemias are characterized by a shortened RBC survival time. The three major types of hemolytic anemias are those caused by immunologic mechanisms; those due to intrinsic defects, such as an RBC membrane defect, abnormal hemoglobins, or RBC enzyme defects; and those resulting from extrinsic factors, such as mechanical or lytic processes.132164 The elderly are at risk for drug-induced hemolytic anemia because they may take multiple medications. Drug-induced hemolytic anemia has been associated with high doses of antibiotics (penicillin, chloramphenicol, cephalosporins), several nonsteroidal anti-inflammatory drugs, quinidine, phenacetin, and others. Hemolytic axcollagen vascular diseases, infections, and chronic lymphocytic leukemia. The hemolytic anemias are discussed in Chapters 23 through 28 [Chapter 23 Chapter 24 Chapter 25 Chapter 26 Chapter 27 Chapter 28 ].

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 disorders 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/myeloproliferative neoplasms; and myeloid and lymphoid 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. Myelodysplastic syndrome is the most common hematologic malignancy in the elderly.130165 The incidence of myelodysplastic syndrome increases from 6.6 cases per 100,000 for individuals aged 60 to 64 to 20.9 per 100,000 for those aged 70 to 74, and is 51.2 per 100,000 for those age 85 and older.166 Typical features include progressive cytopenias, dyspoiesis in one or more cell lines, and an increase in blasts in the peripheral blood and bone marrow. Chapter 34 provides 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, chronic eosinophilic leukemia not otherwise classified, mastocytosis, chronic neutrophilic leukemia, and unclassifiable myeloproliferative neoplasms. The incidence of myeloproliferative neoplasms increases from 6.1 per 100,000 for individuals aged 60 to 64, to 11.5 per 100,000 for those aged 70 to 74, and to 15.8 per 100,000 for those 85 years of age and older.166 Chapter 33 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 of leukemia in the elderly (). 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, Table 45-9 especially men). Acute myelogenous leukemia (Chapter 35) and chronic lymphocytic leukemia (Chapter 36) show the most dramatic age-related increase in incidence.166

TABLE 45-9

SEER Incidence of Leukemia in the Elderly in the United States per 100,000 (2000–2010)*

Age at Diagnosis

All Leukemias

ALL

CLL

AML

CML

AMoL

65–69 yr

36.8

1.3

16.7

10.4

4.4

0.7

70–74 yr

49.4

1.4

21.9

14.9

5.7

0.9

75–79 yr

65.7

1.5

28.5

19.7

7.9

1.2

80–84 yr

77.8

1.6

32.4

23.2

9.7

1.4

≥85 yr

88.5

1.8

37.5

22.7

10.1

1.5

* Surveillance, Epidemiology, and End Results (SEER) Incidence Source: SEER 18 areas.

Adapted from Howlader N, Noone AM, Krapcho M, et al, editors: SEER cancer statistics review, 1975-2010, Bethesda, Md, 2010, National Cancer Institute. Based on November 2012 SEER data submission, posted to the SEER website in 2013. Available at: http://seer.cancer.gov/csr/1975_2010/. Accessed July 10, 2013.

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

Geriatric hemostasis

Age-related changes occur in the vascular and hemostatic systems, including alterations in platelets, coagulation, and fibrinolytic factors. These changes are thought to contribute to the increased incidence of thrombosis in the elderly. The rate of venous thromboembolism, for example, increases from 1 per 10,000 in the young (25 to 30 years of age) to 8 per 1000 in the elderly (85 years and older).167 Approximately 60% of venous thrombosis events occur in those aged 70 years and older (Chapter 39).168

Fibrinogen, factor V, factor VII, factor VIII, factor IX, factor XIII, high-molecular-weight kininogen, and prekallikrein increase in healthy individuals as they age.169 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),170 from 280 mg/dL to over 300 mg/dL. Elevated levels of factor VIII also have been associated with increased risk of venous thrombosis.171 Studies of the association between factor VII and venous thrombosis have yielded conflicting findings.169

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.

Platelets increase in activity with age, as evidenced by a decrease in bleeding time as males age from 11 to 70 years175 and an increase in markers of platelet activation, platelet β-thromboglobulin, and platelet factor 4.176 Increased platelet activity with aging is also associated with increased platelet phospholipids, which suggests an age-related increase in platelet transmembrane signaling.177

Many conventional risk factors associated with venous thrombosis are likely to also increase the risk of thrombosis in the elderly. These factors include immobility, malignant disease, comorbidities, and prescription drugs that influence coagulation or platelet function.143167

Summary

• The newborn infant, preadolescent child, and elderly adult exhibit profound hematologic differences from one another.

• Newborn hematologic parameters continue to change and evolve over the first few days, weeks, and months of life. Laboratory results must be assessed in light of gestational age, birth weight, and developmental differences between newborns and older infants.

• The erythrocytes of newborn infants are markedly macrocytic at birth. A condition known as physiologic anemia of infancy occurs after the first few weeks of life. Infants born prematurely also experience a decrease in hemoglobin concentration, which is termed physiologic anemia of prematurity.

• Iron deficiency is the most frequent cause of anemia in children.

• Fluctuations in the number of WBCs are common at all ages but are greatest in infants. Leukocytosis is typical at birth for healthy full-term and preterm infants, with a mean of 22 × 109 cells/L (range, 9 to 30 × 109cells/L) at 12 hours of life. There is an increase in segmented neutrophils, bands, and occasional metamyelocytes with no evidence of disease.

• Sepsis in neonates is a common cause of morbidity, particularly in premature and low-birth-weight infants. Defective B cell response against polysaccharide agents, as well as abnormal cytokine release by neutrophils and monocytes, have been implicated.

• Although hemostatic values are different in infants and children from those in adults, this population is not at increased risk of bleeding or thrombosis.

• There is a gradual decline in hemoglobin starting at middle age, and the mean level decreases by about 1 g/dL during the sixth through eighth decades.

• Although anemia is common in elderly patients, it is not a normal occurrence in the aging process. The cause of anemia may be multifactorial in elderly patients.

• Iron deficiency anemia, anemia of chronic inflammation, and megaloblastic anemia related to vitamin B12 deficiency are the most common anemias seen in the elderly.

• Immunosenescence refers to the adverse changes in the immune system associated with aging.

• The elderly experience an increased frequency of many neoplastic and malignant disorders, such as acute and chronic leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms.

• The elderly are at an increased risk of thrombosis associated with age-related changes in the vascular and hemostatic systems.

Now that you have completed this chapter, go back and read again the case study at the beginning and respond to the questions presented.

Review questions

Answers can be found in the Appendix.

1. The CBC results for children (aged 3 to 12 years) differ from those of adults chiefly in what respect?

a. NRBCs are present.

b. Notable polychromasia is seen, indicating increased reticulocytosis.

c. Platelet count is lower.

d. The percentage of lymphocytes is higher.

2. Physiologic anemia of infancy results from:

a. Iron deficiency caused by a milk-only diet during the early neonatal period

b. Increased oxygenation of blood and decreased erythropoietin

c. Replacement of active marrow with fat soon after birth

d. Hb F and its diminished oxygen delivery to tissues

3. The CBC report on a 3-day-old neonate who was born 6 weeks prematurely shows a decrease in hemoglobin compared with the value obtained 2 days earlier. Which of the following should be considered as an explanation for this result when no apparent source of hemolysis or bleeding is evident?

a. The sample was collected from a vein at the time that an intravenous line was inserted.

b. The sample was collected by heel puncture rather than finger puncture because of the infant’s small size.

c. The umbilical cord was clamped quickly to begin appropriate treatment for a preterm infant.

d. The infant has become dehydrated.

4. Morphologically, the hematogones in newborns are:

a. Similar to those seen in megaloblastic anemia

b. Easily confused with leukemic blasts

c. Monocytoid in appearance

d. Similar to adult lymphocytes

5. The most frequent cause of anemia in childhood is:

a. Vitamin B12 deficiency

b. Drug-related hemolysis

c. Iron deficiency

d. Folate deficiency

6. As age increases, the hemoglobin level of elderly adults:

a. Remains unchanged from that of middle-aged adults

b. Increases due to diminished respiration and poor tissue oxygenation

c. Decreases for reasons that are unclear

d. Becomes comparable to that of newborns

7. Which of the following are the most common anemias in the elderly population?

a. Megaloblastic anemia and iron deficiency anemia

b. Sideroblastic anemia and megaloblastic anemia

c. Myelophthisic anemia and anemia of chronic inflammation

d. Iron deficiency anemia and anemia of chronic inflammation

8. When iron deficiency is recognized in an elderly individual, the cause is usually:

a. An iron-deficient diet

b. Gastrointestinal bleeding

c. Diminished absorption

d. Impaired incorporation of iron into heme as a result of telomere loss

9. Which of the following conditions is least likely in an elderly individual?

a. Acute lymphoblastic leukemia

b. Multiple myeloma

c. Myelodysplasia

d. Chronic lymphocytic leukemia

10. The multiple medications used by the elderly makes this population more prone to:

a. Anemia of chronic inflammation

b. Megaloblastic anemia

c. Hemolytic anemia

d. Iron deficiency anemia

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