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CHAPTER 8 HEMATOLOGY IN THE AGED

CHAPTER 8 HEMATOLOGY IN THE AGED
Williams Hematology

CHAPTER 8 HEMATOLOGY IN THE AGED

MARSHALL A. LICHTMAN
WILLIAM J. WILLIAMS

Aging and Hematopoiesis

Marrow Cellularity

Chromosome Studies

Erythrocytes

Serum Iron, Iron-Binding Capacity, and Ferritin Levels

Serum Erythropoietin Concentration

Serum Vitamin B12 and Folate Levels

Leukocytes

Immune Responses

Platelets

Plasma Coagulation Factors

Erythrocyte Sedimentation Rate and C Reactive Protein

The Incidence of Clonal Hemopathies
Chapter References

The hematopoietic system is modestly affected by aging, and these effects become particularly notable after age 65. There is a continuous decrease in the volume of the hematopoietic marrow with age, which does not cause significant alterations in either granulocyte, monocyte, or platelet counts, although a slight (£1.0 g/dl) decrease in population mean hemoglobin concentration in men occurs. The recruitment of neutrophils in response to exogenous stimuli is slightly decreased, but the response to infection does not appear impaired. Neutrophil function is not significantly decreased with age of the subject. Although the population mean vitamin B12 and folate levels decrease with age, these changes do not result in decreased hematopoiesis as judged by blood counts, except in individual patients with significant deficiencies. Anemia in older individuals should be evaluated in the same manner as anemia in younger individuals. Certain coagulation proteins are altered significantly with aging, and a propensity to accelerated coagulation and compensatory fibrinolysis is present, leading to a new steady state. Decreased immune cell function is the most consistent change in older persons and perhaps the most important functionally. Although there is a tendency to decreased lymphocyte counts in the blood, the major effects are mediated by dysregulation of T lymphocyte function, perhaps as a result of the prolonged period since thymic atrophy in older subjects. This change affects both cellular immune functions and antibody responses to antigens because of the T helper cell function required. Many studies of aging have to be interpreted in the light of inadequate population samples for study, the difficulty and therefore the rarity of using longitudinal as contrasted with cross-sectional analyses, the small sample sizes after stratification for gender and decade of age, and the need to study smaller age intervals in the 8th through 10th decades of life because of more dramatic changes over short intervals at these ages.

Acronyms and abbreviations that appear in this chapter include: BPG, bisphosphoglycerate; EPO, erythropoietin; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-monocyte colony stimulating factor; IL, interleukin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; SEER, National Cancer Institute Surveillance Epidemiology End Results.

In 1998, individuals 65 years of age or older accounted for 12.7 percent of the population of the United States; this group is expected to grow to 23.0 percent of the population by the year 2040. Currently, there are 4.0 million people in the United States who are 85 years old or older.1 Data from 1985 through 1989 indicate that life expectancy at age 65 is 14 years for males and 18 years for females in most developed countries.2 As a result, physicians are increasingly caring for older patients and are being called upon to interpret hematologic data in the context of the age of the patient. Age-related effects on cellular DNA results in a dramatic increase in the incidence of clonal hematopoietic diseases, especially leukemia, lymphoma, myeloma, and closely related diseases in the decades after age 50. In addition, the decrease in immune function has an impact on vaccine use and resistance to infection in older individuals.
AGING AND HEMATOPOIESIS
Throughout embryogenesis and early infancy nearly all cells of the body have mitotic capacity. Subsequently, certain cells of the body lose their ability to divide (e.g., nervous tissue, muscles).3 Others continue to divide until full growth has been achieved. Thereafter, cells usually do not divide at a significant rate except under conditions of stress, when they become capable of rapid cell division. These cells are said to be “potentially mitotic” or “discontinuous replicators,” as exemplified by hepatic cells and renal tubular cells.3 Cells of organs that require continuous self-renewal, such as the marrow, the scalp hair follicles, and the gastrointestinal mucosa, are continuously mitotic throughout life.3
Studies of diploid human cells maintained in continuous culture have led to the assertion that there is a limit to the number of divisions a cell may undergo,4,5 and 6 a state of replication senescence, which may be related in part to telomere shortening.7 However, there is no evidence of exhaustion of marrow stem cells with extreme aging. The proliferative capacity of marrow cells from older animals and humans has been studied by a variety of techniques, both in vivo and in vitro.8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40 and 41 Most studies indicate that marrow can sustain normal blood cell counts in older animals,27,28,29 and 30,32,35,42 but the reserve capacity may be limited during periods of exaggerated demand.11,14,15,19,22,23 and 24,29,199 The hematopoietic limitations observed in older animals could be intrinsic to marrow stem cells or to cells of the hematopoietic stroma and/or their cytokine production.17,28,32,33,35 The short-term hematopoietic responses to the growth factors granulocyte-monocyte colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and erythropoietin (EPO) are well maintained in older subjects,39,40 although the response of multipotential (CD34+) cells to granulocyte colony-stimulating factor (G-CSF) in culture in older patients is decreased, and the mobilization of neutrophils by G-CSF in vivo is diminished.40,41 There is no evidence, however, that the effects of aging on marrow proliferative capacity, or, ultimately on steady-state blood cell levels, are clinically significant within existing life-spans.12,14,15 and 16
MARROW CELLULARITY
The cellularity of the marrow decreases with aging, as estimated from studies of histologic sections.43,44 and 45 Magnetic resonance imaging confirms an age-related reduction in marrow cellularity.46 Studies of marrow from the anterior iliac crest demonstrate a progressive decrease in cellularity from 80–100 percent to about 50 percent over the first 30 years of life.47 Cellularity of about 40 percent has been found in sternal marrow from normal adults.48 In iliac crest marrow there is a plateau of about 50 percent cellularity to age 65, after which a decrease in cellularity to about 30 percent occurs over the succeeding decade.44 This latter decline may be due to an increase in fat related to osteoporosis, with reduction of the volume of cancellous bone, rather than to a decrease in hematopoietic cells.49 These changes may account for the more pronounced marrow hypocellularity in the subcortical zone.
CHROMOSOME STUDIES
Three principal cytogenetic changes in hematopoietic cells have been identified in relationship to human aging: loss of chromosomes, increased micronucleus formation, and telomere shortening. There is an exponential increase during aging in the proportion of adult women whose phytohemagglutinin-stimulated blood lymphocytes display X chromosome aneuploidy as a result of X chromosome loss. Thus, the proportion of women with X chromosome aneuploidy increases from about 1 percent of women under age 25 years to about 15 percent of women over 45 years of age.50,51 This alteration is not evident, however, in marrow erythroid or granulocytic cells. Loss of the Y chromosome also increases with age and is a feature of marrow hematopoietic cells. Y chromosome loss is very unusual under age 50 years but occurs in about 10 percent of men beyond age 50 years, with a continuously increasing frequency each decade between 50 and 90 years of age.52 Loss of the Y chromosome in men with clonal hemopathies occurs at a rate expected in unaffected males of the same age and thus is an aging rather than a neoplastic phenomenon. Autosome loss increases in frequency with age. Smaller chromosomes are lost more frequently than larger chromosomes.51 An increase in stable aberrations of chromosomes, including insertions, translocations, and dicentric and acentric chromosome fragments, are evident with aging.53,54 An increase in somatic mutations occurs with age when studied in blood lymphocytes, but this may reflect an accumulation with time rather than an age-dependent increase in mutation rate.55
An increase in micronuclei is evident in the blood lymphocytes of older as compared with younger individuals.54 In women this phenomenon is directly correlated with X chromosome aneuploidy, since fluorescence in situ hybridization demonstrates lost portions of the X chromosome within micronuclei.51,56
The termini of chromosomes contain telomeres consisting of specific proteins and tandemly repeated sequences of DNA that have the base structure TTAGGG. Telomeres shorten during “aging” of cells in culture and in the cells of humans (and other species) as they age. Aging of hematopoietic tissues is complex because of the potential lengthy dormancy and the self-renewal capability of stem cells, whereas their derivative cells die and are replaced in relatively short periods of time. Telomere length has been examined in blood leukocytes. A shortening of telomere length with age of the host occurs but does so in a complex, not linear, fashion, which may have to do with the relative proliferative rate at the time of study.57,58 and 59
ERYTHROCYTES
HEMOGLOBIN LEVEL
Many population studies of hematologic variables in aging subjects suffer from several limitations: sampling is often done by convenience rather than random selection of a free-living, defined population; cross-sectional rather than cohort studies are conducted; and small sample sizes, especially after stratification for gender and decade of age, permit undue influence by a few deviant values. Most studies have shown that the mean hemoglobin level or hematocrit60,61,62,63 and 64 for a population of men falls slightly after middle age. Although statistically significant in some cases, mean hemoglobin levels decrease by less than 1.0 g/dl in the sixth through eighth decades.60,61,62,63,64,65 and 66 In a group of men age 96 to 106 years the mean hemoglobin level was 12.4 g/dl,67 but a later report of centenarians did not find a decrease in mean hemoglobin as compared with other men.68 In a group of men aged 84 to 98 years the mean hemoglobin level was 14.8 g/dl, only 0.8 g/dl less than that of a younger comparison group.62 The lowest levels, however, are found in the oldest patients.63,64,69 The hemoglobin levels in women may increase slightly with age60,65,70 or remain unchanged.71 Small mean decreases in hemoglobin levels in older women have been reported.61,63,64,66,67 In studies that have identified a decrease in hemoglobin level of both men and women, the decrease is less in women than in men. The narrowing of the difference in hemoglobin level between older men and woman may be the result of decreased androgen levels in older men and decreased estrogen levels in older women.
Iron deficiency and the anemia of chronic disease have usually been responsible for low hemoglobin levels in the majority of asymptomatic elderly people.61,69,73,74 Iron absorption is not impaired in the elderly, but utilization of orally administered iron for hemoglobin production is reduced.75 Since hemoglobin concentration does not decrease significantly with age, elderly patients with anemia should be evaluated for a cause (e.g., iron, folate, or vitamin B12 deficiency or underlying malignancy or renal disease, etc.) before ascribing it to age.76,77 and 78
Unexplained anemia is also frequently observed in studies of elderly people.61,69,74 One set of studies found that the red cells of older individuals separated in vitro had a greater proportion of dense cells in each density fraction, a greater proportion of reticulocytes, and an increase in autologous IgG antibodies per cell. In vitro erythrophagocytosis by macrophages was increased when red cells from older individuals were the target particles.79,80 The inference drawn was that shortened red cell survival may play a role in the unexplained mild decrease in hemoglobin concentration in some older individuals.
ERYTHROCYTE 2,3-BISPHOSPHOGLYCERATE CONCENTRATION (2,3-BPG)
The erythrocyte 2,3-bisphosphoglycerate (2,3-BPG) level has been reported to fall with age from a mean value of 14.9 µmol/g hemoglobin at ages 18 to 24 to 13.9 µmol/g hemoglobin at ages 75 to 84.81,82 This decrease is statistically significant. It could account for a slight increase in oxygen affinity of hemoglobin, but is of doubtful physiologic significance.
OSMOTIC FRAGILITY
Erythrocyte osmotic fragility is increased in older individuals in comparison with younger subjects.83,84 This phenomenon is associated with an increased mean corpuscular volume (MCV) and decreased mean corpuscular hemoglobin concentration (MCHC) of the red cells of older people.84
SERUM IRON, IRON-BINDING CAPACITY, AND FERRITIN LEVELS
In individuals of both sexes with normal hemoglobin levels, and presumably with normal iron stores, the serum iron level falls after the ages of 20 to 30.70,85 In one study the values fell from a mean of about 130 µg/dl (28 µmol/liter) in males and 116 µg/dl (21 µmol/liter) for females to a mean at age 71 to 80 of about 75 µg/dl (13 µmol/liter) in men and 66 µg/dl (12 µmol/liter) in women.85 Levels of 50 µg/dl (9 µmol/liter) or less were found in 40 percent of men and women above the age of 50.86 The iron-binding capacity also falls in the elderly.70,87,88
Serum ferritin levels rise from a median of 25 µg/liter to 94 µg/liter in males in the third decade and then to a median of 124 µg/liter above age 45.89 Ferritin levels in females remain low until middle age and then increase from a median of 25 µg/liter to 89 µg/liter in women after menopause.89 Serum ferritin levels appear to reflect iron stores in elderly people.73,90
SERUM ERYTHROPOIETIN CONCENTRATION
Serum erythropoietin levels in nonanemic elderly individuals appear to be the same as those found in younger people,91,92 and 93 although elevated levels were found in one study94 and lower levels in another.95 Serum erythropoietin levels are generally inversely related to hemoglobin levels,91,92 and 93 suggesting that the erythropoietin response in the elderly is similar to that in younger individuals. The peak and trough of the diurnal variation in erythropoietin levels is the same in younger and older individuals.90
SERUM VITAMIN B12 AND FOLATE LEVELS
Low serum vitamin B12 levels are found in a significant number of older individuals who do not have clinical findings of vitamin B12 deficiency (i.e., anemia or a neurologic disorder).47,96,97,98,99,100,101 and 102 They are very nonspecific screening measurements. The absorption of pure vitamin B12 (“Schilling test”) is normal in older individuals,88 but absorption of protein-bound vitamin B12 may be reduced103 in such patients and also in apparently healthy adults over 55 years of age.104 Reexamination of this question, however, showed normal absorption of free and protein-bound cobalamin in older subjects.105 On the other hand, untreated patients with pernicious anemia may have only a moderate reduction in the serum vitamin B12 level and not have anemia or macrocytosis.106 These data require that reductions in the serum vitamin B12 level be evaluated carefully.106,107 and 108 Some individuals with low serum vitamin B12 levels have been followed for a 4-year period without developing anemia or other signs of vitamin B12 deficiency.109 Serum and urine methylmalonic acid and serum homocysteine assays may be helpful in assessing such patients. Patients with metabolically significant decreases in plasma vitamin B12 concentration will usually have elevated levels of methylmalonic acid and homocysteine, and their levels decrease to normal after vitamin B12 replacement (see Chap. 25).
Both serum66,101,107 and red cell66 folate levels were below the usual lower limit of normal (3 µg/liter) in a small proportion (3–7%) of both males and females over age 65. Low median values compared to those in young subjects were found for the plasma folate levels of a group of individuals in the eighth decade.108 Similarly low levels were also found, however, in young people who were clinically well and apparently on a normal diet,110,112 creating uncertainty regarding the “normal” level of serum folate and making the interpretation of these results difficult. None of the patients with low serum folate levels were anemic, and the significance of these findings is uncertain.
The MCV increases slightly but significantly with age.62,70,71,72,73,113,114 and 115 Cigarette smoking may also cause an increase in the MCV,114,115 and it has been reported that older persons who smoke may have a MCV of 100 fl or more in the absence of any demonstrable cause of macrocytosis.115
LEUKOCYTES
TOTAL AND DIFFERENTIAL LEUKOCYTE COUNT
There is no consistent, significant variation in the total leukocyte count in older subjects. Normal leukocyte and neutrophil counts were found in nonagenarian67 and centenarian populations.68 Some investigators have found that above age 65 the total leukocyte count tends to be lower in both sexes,69 due primarily to a decrease in the lymphocyte count.116,117,118,119,120 and 121 Others have reported a decrease in the leukocyte count due to a fall in the lymphocyte and the neutrophil count in women, but not in men, over age 50.22,123 The absolute lymphocyte count has also been reported to be unchanged in the aged.124,125 and 126
LEUKOCYTE RESPONSE TO INFECTION
Medical lore has it that the leukocyte count does not rise as high in response to infection in elderly individuals as in young people and that often the principal manifestation of a leukocyte response is an increase in the number of band forms in an otherwise normal leukocyte count.127,128 However, in two series of cases of acute appendicitis and one of pneumonia, the leukocytosis of patients over age 60 was the same as that found in younger patients.129,130 The leukocyte count and the proportion of neutrophils rise much less in response to bacterial pyrogen in individuals over age 70 than in young adults.131 Similarly, the neutrophilic leukocytosis that occurs 5 h after the oral administration of 40 mg prednisolone is diminished in patients over 55 years of age.132 These observations suggest a diminished marrow granulocyte reserve in the elderly and/or a decrease in hematopoietic growth factor release.133 The decreased responsiveness of older individuals to granulocyte colony-stimulating factor-induced release of neutrophils from the marrow supports these suppositions.40,41 Leukocyte function and serum opsonic capacity is well preserved in elderly individuals,134,135 but defects in phagocytic ability136,137 and diminished responses to chemotactic peptides138,139 and to oxidative stress140 have been documented. Defects in neutrophil function in elderly subjects may be due to inhibitory substances detected in plasma.141 Splenic function in elderly subjects may be impaired, as evidenced by an increase in the percentage of pitted erythrocytes in the blood.142
IMMUNE RESPONSES
There is compelling experimental evidence that a decrease in immune function mediated by lymphocytes is the most significant change with aging.200 Thymus involution occurs after puberty, and total thymic atrophy occurs by late middle age. With these changes, thymic-mediated T lymphocyte development disappears, and older individuals are dependent on their existing T lymphocyte pool to mediate T cell–dependent immune responses.124,125 and 126,143,144
T cells in older subjects have impaired responsiveness to mitogens and antigens,145,146 in part due to a decrease in expression of CD28 costimulator on the cell surface.146 The clonal expansion of T cells in culture is decreased, suggesting an inadequate response to antigen stimulation. Clones do not reach full development because of fewer doublings when T cells are obtained from older individuals.147,148 In the absence of thymic function, the number of naive T cells decreases in older individuals and memory T cells are the predominant type.149 Spontaneous T cell clonal expansion is a feature of older individuals and may occur among CD4+150,151 and CD8+ cell subsets.151 Although likened to benign monoclonal gammopathy, the T cell clones may be stable and less prone to malignant progression.151
B lymphocyte function is dependent on T cell accessory roles, and the decreased ability to generate antibody responses, especially to primary antigens,126,152,153 may be the result of T cell inadequacies rather than an intrinsic fault of B lymphocytes. The response to T cell–dependent antigens is characterized by the formation of low-affinity antibodies and anti-idiotypic autoantibodies.153 Although variable from study to study, total B lymphocyte,68,154 T lymphocyte,68,154 and T lymphocyte subset68,155,156 concentrations in the blood have been found to be decreased in older individuals. Natural killer cells are increased in number, but their function is disturbed.68,154,157,201 Not unexpectedly, delayed hypersensitivity reactions are reduced in the elderly.158,159,160 and 161 These immunologic deficits are correlated with overall mortality in individuals over age 60.162
Serum immunoglobulin M and G concentrations do not change significantly in older subjects. Serum IgA levels increase with age.163 An increased prevalence of autoantibodies (e.g., anti-IgG rheumatoid factor) occurs in older people.118,152,163 Monoclonal plasma immunoglobulins (essential monoclonal gammopathy) are found with increasing frequency with age, reaching three percent in people over age 70 and nearly six percent in those from 80 to 89164,165 (see Chap 105).
PLATELETS
The platelet count does not change with age.68,69 Increased plasma levels of two platelet a-granule constituents, b-thromboglobulin and platelet factor 4, have been found in individuals over 65 years of age in comparison with younger individuals.166,167 Enhanced in vitro reactivity to platelet-aggregating agents has been observed.168,169,170,171,172 and 173 Decreased platelet membrane protein kinase C activity and translocation to the cytosol after platelet activation was noted in platelets from older subjects.174
PLASMA COAGULATION FACTORS
Several studies have emphasized the changes in the level of proteins involved in the formation or dissolution of fibrin.175,176 and 177 Plasma concentrations of factor VII coagulant activity and antigen,175,176,177,178 and 179 and factor VIIIC,175,176,180 as well as von Willebrand factor,175,180 fibrinogen,175,176,178,181 fibrinopeptide A,175,176,182 and tissue plasminogen activator antigen175,183 are increased with age. Fibrinogen level has been found to be a risk factor for thrombotic vascular disease.181 In healthy centenarians, levels of activated factor VII, activation peptides of prothrombin, factors IX and X, and thrombin-antithrombin complex concentration were increased, signs of higher-than-expected coagulation enzyme activity.176 Higher D-dimer and plasmin-antiplasmin complexes indicate an accompanying increase in fibrinolytic activity.176 Thus, coagulant and fibrinolytic activities appear to be increased in the older subjects by both in vitro,176,184,185,186 and 187 and in vivo studies.182,188 Older patients may show an exaggerated anticoagulant response to warfarin.189
ERYTHROCYTE SEDIMENTATION RATE AND C REACTIVE PROTEIN
The erythrocyte sedimentation rate increases significantly with age.62,190,191,192 and 193 Mean values of 14 mm/h (Westergren) and individual values as high as 69 mm/h were found in apparently well women age 70 to 89 years who were followed for 3 to 11 years.193 The erythrocyte sedimentation rate is of limited value in detecting disease in elderly patients. Estimation of levels of acute-phase proteins appears to offer no advantage over the erythrocyte sedimentation rate.195,196 The C-reactive protein content of serum also is mildly elevated in older individuals without an apparent inflammatory process.197,198
THE INCIDENCE OF CLONAL HEMOPATHIES
Several hematologic diseases are increased in frequency with age; for example, pernicious anemia. The notable increase in clonal (neoplastic) diseases of hematopoiesis is shown in Figure 8-1, which depicts the rate of occurrence of the leukemias (the aggregate of the four major types), lymphoma, and myeloma at 5-year intervals. The inclusion of acute lymphocytic leukemia, which has a mode at about 3.5 years and then increases in frequency again after middle age, does not dampen the dramatic age-dependent incidence rate. The curves do not provide insight into the cause of the relationship, which could reflect the accumulated injury resulting from external factors, the accumulated effects of spontaneous somatic mutations, or some combination of these events.

FIGURE 8-1 The abscissa depicts age in intervals of 5 years. The ordinate represents the incidence per 100,000 Americans of myeloma, lymphoma, and leukemia. The rates for each of the four major leukemias and the various subtypes of lymphoma are aggregated. The increment at 0 to 4 years among the leukemias reflects a mode in acute lymphocytic leukemia at that age. These data were obtained from the National Cancer Institute Surveillance Epidemiology End Results (SEER) Program.

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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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2 comments on “CHAPTER 8 HEMATOLOGY IN THE AGED

  1. Execelent info my friend, ganar dinero con encuestas online I just didn’t know what you published, fantastic share. como ganar dinero con encuestas

  2. Zlonis M: The mystique of the erythrocyte sedimentation rate – a reappraisal of one of the oldest laboratory tests still in use. Clin Lab Med 1993;13:787-800.

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