CHAPTER 8 HEMATOLOGY IN THE AGED
CHAPTER 8 HEMATOLOGY IN THE AGED
MARSHALL A. LICHTMAN
WILLIAM J. WILLIAMS
Aging and Hematopoiesis
Serum Iron, Iron-Binding Capacity, and Ferritin Levels
Serum Erythropoietin Concentration
Serum Vitamin B12 and Folate Levels
Plasma Coagulation Factors
Erythrocyte Sedimentation Rate and C Reactive Protein
The Incidence of Clonal Hemopathies
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
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.
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
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.
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
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
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).
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.
Kinsella KG: Changes in life expectancy 1900–1990. Am J Clin Nutr 55:1196S, 1992.
Lansdorp PM: Self-renewal of stem cells. Biol Blood Marrow Transplantation 3:171, 1997.
Hayflick L: Mortality and immortality at the cellular level. A review. Biochemistry 62:1180, 1997.
Perillo NL, Walford RL, Newman MA, Effros RB: Human T lymphocytes possess a limited in vitro life span. Exp Gerontol 24:177, 1989.
Kirkland JL: The biochemistry of mammalian senescence. Clin Biochem 25:61, 1992.
Rubin H: Cell aging in vivo and vitro. Mech Ageing Dev 100:209, 1998.
Cudkowicz G, Upton AC, Shearer GM, Hughes WL: Lymphocyte content and proliferative capacity of serially transplanted mouse bone marrow. Nature 201:165, 1964.
Siminovitch L, Till JE, McCulloch EA: Decline in colony-forming ability of marrow cells subjected to serial transplantation into irradiated mice. J Cell Comp Physiol 64:23, 1964.
Yuhas JM, Storer JB: The effect of age on two modes of radiation death and on hematopoietic cell survival in the mouse. Radiat Res 32:596, 1967.
Davis ML, Upton AC, Satterfield LC: Growth and senescence of the bone marrow stem cell pool in RFM/Un mice. Proc Soc Exp Biol Med 137:1452, 1971.
Lajtha LB, Schofield R: Regulation of stem cell renewal and differentiation of possible significance in aging. Adv Gerontol Res 3:131, 1971.
Vos O, Dolans MJAS: Self-renewal of colony forming units (CFU) in serial bone marrow transplantation experiments. Cell Tissue Kinet 5:371, 1972.
Harrison DE: Normal production of erythrocytes by mouse marrow continuous for 73 months. Proc Natl Acad Sci USA 70:3184, 1973.
Relucke U, Burlington H, Cronkite EP, Laissue J: Hayflick’s hypothesis: an approach to in vivo testing. Fed Proc 34:71, 1975.
Harrison DE: Normal function of transplanted marrow cell lines from aged mice. J Gerontol 30:279, 1975.
Harrison DE: Defective erythropoietic responses of aged mice not improved by young marrow. J Gerontol 30:286, 1975.
Mauch P, Botnick LE, Hannon EC, et al: Decline in bone marrow proliferative capacity as a function of age. Blood 60:245, 1982.
Inoui T, Cronkite EP: The influence of in vivo incubation of aged murine spleen colony-forming units on their proliferative capacity. Mech Ageing Dev 23:177, 1983.
Boggs DR, Saxe DF, Boggs SS: Aging and hematopoiesis. II. The ability of bone marrow cells from young aged mice to cure and maintain cure in W/W. Transplantation 37:300k, 1984.
Lipschitz DA, Udupa KB, Milton KY, Thompson CO: Effect of age on hematopoiesis in man. Blood 63:502, 1984.
Udupa KB, Lipschitz DA: Erythropoiesis in the aged mouse. II. Response to stimulation in vitro. J Lab Clin Med 103:581, 1984.
Boggs DR, Patrene KD: Hematopoiesis and aging. III. Anemia and a blunted erythropoietic response to hemorrhage in aged mice. Am J Hematol 19:327, 1985.
Williams LH, Udupa KB, Lipschitz DA: Evaluation of the effect of age on hematopoiesis in the C57BL/6 mouse. Exp Hematol 14:827, 1986.
Stead NW: Defective mononuclear cell support of erythropoiesis in the elderly. Am J Med Sci 293:85, 1987.
Hirota Y, Okamura S, Kimura N, et al: Haematopoiesis in the aged as studied by in vitro colony assay. Eur J Haematol 40:83, 1988.
Schofield R, Dexter TM, Lord BI, Tasta NG: Comparison of haemopoiesis in young and old mice. Mech Ageing Dev 34:1, 1986.
Boggs D, Patrene K, Steinberg H: Aging and hematopoiesis. VI. Neutrophilia and other leukocyte changes in aged mice. Exp Hematol 14:372, 1986.
Williams LH, Udupa KB, Lipschitz DA: Evaluation of the effect of age on hematopoiesis in the C57BL/6 mouse. Exp Hematol 14:827, 1986.
Maggio-Price L, Wolf NS, Priestley GV, et al: Evaluation of stem cell reserve using serial bone marrow transplantation and competitive repopulation in a murine model of chronic hemolytic anemia. Exp Hematol 16:653, 1988.
Baldwin JG: Hematopoietic function in the elderly. Arch Intern Med 148:2544, 1988.
Harrison DE, Astle CM, Stone M: Numbers and functions of transplantable primitive immunohematopoietic stem cells: effects of age. J Immunol 142:3833, 1989.
Lee MA, Segal GM, Bagby GC: The hematopoietic microenvironment in the elderly: defects in IL-1-induced CSF expression in vitro. Exp Hematol 17:952, 1989.
Tejero C, Testa NG, Hendry JH: Decline in cycling of granulocyte-macrophage colony-forming cells with increasing age in mice. Exp Hematol 17:66, 1989.
Sharp A, Zipori D, Toledo J, et al: Age related changes in hemopoietic capacity of bone marrow cells. Mech Ageing Dev 48:91, 1989.
Morrison SJ, Wandycz AM, Akashi K, et al: The aging of hematopoietic stem cells. Nat Med 2:1011, 1996.
Boggs SA, Patrene KD, Austin CA, et al: Latent deficiency of the hematopoietic microenvironment of aged mice as revealed in W/Wv mice given +l/+ cells. Exp Hematol 19:683, 1991.
Keating A: The hematopoietic stem cell in elderly patients with leukemia. Leukemia 10(suppl 1):530, 1996.
Shank WA Jr, Balducci L: Recombinant hemopoietic growth factors: comparative hemopoietic response in younger and older subjects. J Am Geriatr Soc 40:151, 1992.
Chatta GS, Andrews RG, Rodger E, et al: Hematopoietic progenitors and aging: alterations in granulocyte precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol 48:M207, 1993.
Chatta GS, Price TH, Dale DC, et al: The effects of in vivo rhG-CSF on the neutrophil response in healthy young and elderly volunteers. Blood 84:2923, 1994.
Egusa Y, Fujiwara Y, Syahrrudin E, et al: Effect of age on human peripheral blood stem cells. Oncol Rep 5:398, 1998.
Custer RP, Ahlfeldt FE: Studies on the structure and function of the bone marrow. J Lab Clin Med 17:960, 1932.
Hartsock RJ, Smith EB, Petty CS: Normal variations with aging on the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. Am J Clin Pathol 43:326, 1965.
Kricun ME: Red-yellow marrow conversion: its effect on location of some solitary bone lesions. Skeletal Radiol 14:10, 1985.
Ricci C, Cova M, Kang YS, et al: Normal age-related patterns of cellular and fatty bone marrow distribution in the axial skeleton: MR imaging study. Radiology 177:83, 1990.
Callander ST, Spray GH: Latent pernicious anemia. Br J Haematol 8:230, 1962.
Beutler E, Drennan W, Block M: The bone marrow and liver in iron-deficiency anemia: a histopathologic study of sections with special reference to the stainable iron content. J Lab Clin Med 43:427, 1954.
Mangolas SC, Jilka RL: Bone marrow, cytokines, and bone remodelling. N Engl J Med 332:305, 1995.
Nowinski GP, Van Dyke DL, Tilley BC, et al: The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not with reproductive history. Am J Hum Genet 46:1101, 1990.
Stone JF, Sandberg AA: Sex chromosome aneuploidy and aging. Mutat Res 338:107, 1995.
United Kingdom Cancer Cytogenetics Group: Loss of Y chromosome from normal and neoplastic bone marrow. Genes, Chromosomes, Cancer 5:83, 1992.
Ramsey MJ, Moore DH II, Briner JF, et al: The effects of age and lifestyle factors on the accumulation of cytogenetic damage as measured by chromosome painting. Mutat Res 338:95, 1995.
Bolognesi C, Abbondandolo A, Barale R, et al: Age-related increase of baseline frequencies of sister chromatid exchanges, chromosome aberrations, and micronuclei in human lymphocytes. Cancer Epidemiol Biomark Prevent 6:249, 1997.
Grist SA, McCarron M, Kutlaca A, et al: In vivo human somatic mutation: frequency and spectrum with age. Mutat Res 266:189, 1992.
Catalan J, Autio K, Wessman M, et al: Age-associated micronuclei containing centromeres and the X chromosome in lymphocytes of women. Cytogen Cell Genet 68:11, 1995.
Frenck RW Jr, Blackburn EH, Shannon KM: The rate of telomere sequence loss in human leukocyte varies with age. Proc Natl Acad Sci USA 95:5607, 1998.
Notario R, Cimmino A, Tabarini D, et al. In vivo telomere dynamics of human hematopoietic stem cells. Proc Natl Acad Sci USA 94:13782, 1997.
Batliwalla F, Monteiro J, Serrano D, Gregorson PK: Oligoclonality of CD8+ T cells in health and disease: aging, infection, or immune regulation. Hum Immunol 48:68, 1996.
McDonough JR, Hames CG, Garrison GE, et al: The relationship of hematocrit to cardiovascular states of health in the negro and white population of Evans County, Georgia. J Chron Dis 18:243, 1965.
McLennan WJ, Andrews GR, Macleod C, Caird FI: Anaemia in the elderly. Q J Med 42:1, 1973.
Zauber NP, Zauber AG: Hematologic data of healthy very old people. JAMA 257:2181, 1987.
Nilsson-Ehle H, Jagenburg R, Landahl S, et al: Decline of blood haemoglobin in the aged: a longitudinal study of an urban Swedish population from age 70 to 81. Br J Haematol 71:437, 1989.
Salive ME, Cornoni-Huntley J, Guralnik JM, et al: Anemia and hemoglobin level in older persons: relationship with age, gender, and health status. J Am Geriatr Soc 40:489, 1992.
Cruickshank JM: Some variations in the normal haemoglobin concentration. Br J Haematol 18:523, 1970.
Elwood PC, Shinton NK, Wilson CD, et al: Haemoglobin, vitamin B12 and folate levels in the elderly. Br J Haematol 21:557, 1971.
Zaino EC: Blood counts in the nonagenarian. NY State J Med 81:1199, 1981.
Sansoni P, Cossarizza A, Brianti V, et al: Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 82:2767, 1993.
Nilsson-Ehle H, Jagenburg R, Landahl S, et al: Haematological abnormalities and reference intervals in the elderly: a cross-sectional comparative study of three Swedish population samples aged 70, 75 and 81 years. Acta Med Scand 224:595, 1988.
Yip R, Johnson C, Dallman PR: Age-related changes in laboratory values used in the diagnosis of anemia and iron deficiency. Am J Clin Nutr 39:427, 1984.
Jernigan JA, Gudat JC, Blake JL, et al: Reference values for blood findings in relatively fit elderly persons. J Am Geriatr Soc 28:308, 1980.
Kelly A, Munan L: Haematologic profile of natural populations: red cell parameters. Br J Haematol 35:153, 1977.
Htoo MSH, Kofkoff RL, Freedman ML: Erythrocyte parameters in the elderly: an argument against new geriatric normal values. J Am Geriatr Soc 27:547, 1979.
Lipschitz DA, Mitchell CO, Thompson C: The anemia of senescence. Am J Hematol 11:47, 1981.
Marx JJM: Normal iron absorption and decreased red cell iron uptake in the aged. Blood 53:204, 1979.
Garry PJ, Goodwin JS, Hunt WC: Iron status and anemia in the elderly: new findings and a review of previous studies. J Am Geriatr Soc 31:389, 1983.
Timiras ML, Brownstein H: Prevalence of anemia and correlation of hemoglobin with age in a geriatric screening clinic population. J Am Geriatr Soc 35:639, 1987.
Baldwin JG: Hematopoietic function in the elderly. Arch Intern Med 148:2544, 1988.
Glass GA, Gershon D, Gershon H: Some characteristics of the human erythrocyte as a function of donor and cell age. Exp Hematol 13:1122, 1978.
Sheibon E, Gershon H: Recognition and sequestration of young and old erythrocytes from young and elderly human donors: in vitro studies. J Lab Clin Med 121:493, 1993.
Purcell Y, Brozovic B: Red cell 2,3-diphosphoglycerate concentration in man decreases with age. Nature 241:511, 1974.
Kalofoutis A, Paterakis S, Koutselenis A, Spanos V: Relationship between erythrocyte 2,3-diphosphoglycerate and age in a normal population. Clin Chem 22:1918, 1976.
Detraglia M, Cook FB, Stasiw DM, Cerny LC: Erythrocyte fragility in aging. Biochim Biophys Acta 345:213, 1974.
Araki K, Rifkind JM: Age dependent changes in osmotic hemolysis of human erythrocyte. J Gerontol 35:499, 1980.
Pirrie R: The influence of age upon serum iron in normal subjects. J Clin Path 5:10, 1952.
Powell DEB, Thomas JH, Mills P: Serum iron in elderly hospital patients. Gerontol Clin (Basel) 10:21, 1968.
Rechenberger J: über die Eisenbildungskapazität des Blutserums in den verscheidenen Lebensaltern. Z Alternsforsch 9:98, 1955.
Powell DEB, Thomas JH: The iron-binding capacity of serum in elderly hospital patients. Gerontol Clin (Basel) 11:36, 1969.
Cook JD, Finch CA, Smith NJ: Evaluation of the iron status of a population. Blood 48:449, 1976.
Guyatt GH, Patterson C, Ali M, et al: Diagnosis of iron deficiency anemia in the elderly. Am J Med 88:205, 1990.
Mori M, Murai Y, Hirai M, et al: Serum erythropoietin titers in the aged. Mech Ageing Dev 46:105, 1988.
Powers JS, Lichtenstein MJ, Collins JC, et al: Serum erythropoietin in healthy older persons. J Am Geriatr Soc 37:388, 1989.
Powers JS, Krantz SB, Collins JC, et al: Erythropoietin response to anemia as a function of age. J Am Geriatr Soc 39:30, 1991.
Kario K, Matsuo T, Nakao K: Serum erythropoietin levels in the elderly. Gerontology 37:345, 1991.
Pasqualetti P, Casale R: No influence of aging on the circadian rhythm of erythropoietin in healthy subjects. Gerontology 43: 206, 1997.
Henderson JG, Strachen RW, Swanson Beck J, et al: The antigastrin-antibody test as a screening procedure for vitamin B12 deficiency in psychiatric practice. Lancet 2:809, 1966.
Schilling RF, Fairbanks VF, Miller R, et al: “Improved” vitamin B12 assays: a report on two commercial kits. Clin Chem 29:582, 1983.
Cooper BA, Fehedy V, Blanshay P: Recognition of deficiency of vitamin B12 using measurement of serum concentration. J Lab Clin Med 107:447, 1986.
Thompson WG, Babitz L, Cassino C, et al: Evaluation of current criteria used to measure vitamin B12 levels. Am J Med 82:291, 1987.
Nilsson-Ehle H, Landahl S, Lindstedt G, et al: Low serum cobalamin levels in a population study of 70- and 75-year-old subjects: gastrointestinal causes and hematologic effects. Dig Dis Sci 34:716, 1989.
Lindenbaum J, Rosenberg IH, Wilson PWF, et al: Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 60:2, 1994.
Carmel R: Cobalamin, the stomach and aging. Am J Clin Nutr 66:750, 1997.
Carmel R, Sinow RM, Siegel ME, Samloff IM: Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels. Arch Intern Med 148:1715, 1988.
Scarlett JD, Read H, O’Dea K: Protein-bound cobalamin absorption declines in the elderly. Am J Hematol 39:79, 1992.
van Asselt DZ, van den Broek MJ, Lamers CB, et al: Free and protein-bound cobalamin absorption in healthy middle-aged and older subjects. J Amer Geriatr Soc 44:949, 1996.
Carmel R: Pernicious anemia. The expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med 148:1712, 1988.
Herbert V: Don’t ignore low serum cobalamin (vitamin B12) levels. Arch Intern Med 148:1705, 1988.
Carmel R, Sinow RM, Karnaze DS: Atypical cobalamin deficiency: subtle biochemical evidence of deficiency is commonly demonstrable in patients with megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption. J Lab Clin Med 109:454, 1987.
Pathy MS, Newcombe RG: Temporal variation of serum levels of vitamin B12, folate, iron, and total iron-binding capacity. Gerontology 26:34, 1980.
Girdwood RH, Thompson AD, Williamson J: Folate status in the elderly. Br Med J 2:670, 1967.
Osterlind PO, Alafuzoff I, Lofgren A-C, et al: Blood components in an elderly population. Gerontology 30:247, 1984.
Hall CA, Bardwell SA, Allen ES, Rappazzo ME: Variation in plasma folate levels among groups of healthy persons. Am J Clin Nutr 28:854, 1975.
Okuno T: Red cell size as measured by the Coulter model S. J Clin Pathol 25:599, 1972.
Okuno T: Smoking and blood changes. JAMA 225:1387, 1973.
Helman N, Rubenstein LS: The effects of age, sex, and smoking on erythrocytes and leukocytes. Am J Clin Pathol 63:35, 1975.
Caird FI, Andrews GR, Gallie TB: The leukocyte count in old age. Age and Ageing 1:239, 1972.
Conrad RA, Demoise CF, Scott WA, Makar M: Immunohematological studies of Marshall Islanders sixteen years after fallout radiation exposure. J Gerontol 26:28, 1971.
Diaz-Jouanen E, Strickland RG, Williams RC Jr: Studies of human lymphocytes in the newborn and the aged. Am J Med 58:620, 1975.
MacKinney AA Jr: Effect of aging on the peripheral blood lymphocyte count. J Gerontol 33:213, 1978.
Jamil NAK, Millard RE: Studies of T, B, and “null” blood lymphocytes in normal persons of different age groups. Gerontology 27:79, 1981.
Polednak AP: Age changes in differential leukocyte count among female adults. Hum Biol 50:30, 1978.
Allan RN, Alexander MK: A sex difference in the leukocyte count. J Clin Pathol 21:691, 1968.
Cruickshank JM, Alexander MK: The effect of age, sex, parity, haemoglobin level, and oral contraceptive preparations on the normal leukocyte count. Br J Haematol 18:541, 1970.
Globerson A: T lymphocytes and aging. Int Arch Allergy Immunol 107:491, 1995.
Miller RA: The aging immune system. Science 273:70, 1996.
Wick G, Grubeck-Lobenstein B: The aging immune system: primary and secondary alterations of immune reactivity in elderly. Exp Gerontol 32:401,1997.
Thomas JH, Powell DEB: Blood Disorders in the Elderly, p 18. John Wright and Sons, Bristol, UK, 1971.
Thorbjarharson B, Loehr WJ: Acute appendicitis in patients over the age of sixty. Surg Gynecol Obstet 125:1277, 1967.
Peitokallio P, Jauhiainen K: Acute appendicitis in the aged patients: study of 300 cases after the age of 60. Arch Surg 100:140, 1970.
Sasso RD, Hanna EA, Moore DL: Leukocyte and neutrophil counts in acute appendicitis. Am J Surg 120:563, 1970.
Fedullo AJ, Swinburne AJ: Relationship of patient age to clinical features and outcome for in-hospital treatment of pneumonia. J Gerontol 40:29, 1985.
Timaffy M: A comparative study of bone marrow function in young and old individuals. Gerontol Clin (Basel) 4:13, 1962.
Cream JJ: Prednisolone-induced granulocytosis. Br J Haematol 15:259, 1968.
Buchanan JP, Peters CA, Rasmussen CJ, Rothstein G: Impaired expression of haematopoietic growth factors: a candidate mechanism for the hematopoietic defect of aging. Exp Gerontol 31:135, 1996.
Corberand JX, Laharrague PF, Fillola G: Neutrophils of healthy aged humans are normal. Mech Ageing Dev 36:57, 1986.
Nagel JE, Han K, Coon PJ, et al: Age differences in phagocytosis by polymorphonuclear leukocytes measured by flow cytometry. J Leukoc Biol 39:399, 1986.
Emanuelli G, Lanzio M, Anfossi T, et al: Influence of age on polymorphonuclear leukocytes in vitro: phagocytic activity in healthy human subjects. Gerontology 32:308, 1986.
Lipschitz DA, Udupa KB, Boxer LA: The role of calcium in the age-related decline of neutrophil function. Blood 71:659, 1988.
Rao KMK, Curie MS, Padmanabhan J, Cohen HJ: Age-related alterations in actin cytoskeleton and receptor expression in human leukocytes. J Gerontol 47:B37, 1992.
Niwa Y, Ishimoto K, Kanoh T: Induction of superoxide dismutase in leukocytes by paraquat: correlation with age and possible predictor of longevity. Blood 76:835, 1990.
Dantew B, Spagnuolo PJ, Goldsmith GGH, Marino JA: Neutrophil adhesion in the elderly: inhibitory effects of plasma from elderly patients. Clin Immunol Immunopathol 54:247, 1990.
Markus HS, Toghill PJ: Impaired splenic function in elderly people. Age and Ageing 20:287, 1991.
Grubeck-Lobenstein: Changes in the aging immune system. Biologicals 25:205, 1997.
Yoshikawa TT: Perspective: aging and infectious diseases: past, present and future. J Infect Dis 176:1053, 1997.
Song L, Kim YH, Chopra RK, et al: Age-related effects in T cell activation and proliferation. Exp Gerontol 28:313, 1993.
Effros RB, Boucher N, Porter V, et al: Decline in CD2 T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol 29:60, 1994.
Grubeck-Lobenstein B, Lechner H, Trieb K: Long-term in vitro growth of human T cell clones: can postmitotic senescent cell population be defined? Int Arch Allergy Immunol 110:278, 1996.
Lechner H, Amort M, Steger MM, et al: Regulation of CD 95 (APO-1) expression and the induction of apoptosis in human T cells: changes in old age. Int Arch Allergy Immunol 110:238, 1996.
Cossarizza A, Ortolani C, Paganelli R, et al: CD4 isoform expression on CD4+ and CD8+ T cells throughout life, from newborn to centenarians. Implication for T cell memory. Mech Aging Dev 86:173, 1996.
Posnett DN, Sinka R, Kabak S, Russo C: Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammopathy.” J Exp Med 179:609, 1994.
Schwab R, Szabo P, Manavalan JS, et al: Expanded CD4+ and CD8+ T cell clones in elderly humans. J Immunol 158:4493, 1997.
Schulze DH, Goidl EA: Age-associated changes in antibody-forming cells (B cells). Proc Soc Exp Biol Med 196:253, 1991.
Powers DC: Immunological principles and emerging strategies of vaccination for the elderly. J Am Geriatr Soc 40:81, 1992.
McArthur WP, Bloom K, Taylor M, et al: Peripheral blood leukocyte populations in the elderly with and without periodontal disease. J Clin Periodontol 23:846, 1996.
Miyaji C, Watanabe H, Minagawa M, et al: Numerical and functional characteristics of lymphocyte subsets in centenarians. J Clin Immunol 17:420, 1997.
Ruiz M, Esparza B, Perez C, et al: CD8+ T cell subsets in aging. Immunol Invest 24:891, 1995.
McNerlan SE, Rea IM, Alexander HD, Morris TCM: Changes in natural killer cells, the CD57CD8 subset, and related cytokines in health aging. J Clin Immunol 18:31, 1998.
Moesgaard F, Nielsen ML, Larsen N, et al: Cell-mediated immunity assessed by skin testing (Multitest®). I. Normal values in healthy Danish adults. Allergy 42:591, 1987.
Stead WW, To T: Significance of the tuberculin skin test in elderly patients. Ann Intern Med 107:837, 1987.
Marrie TJ, Johnson S, Durant H: Cell-mediated immunity of healthy adult Nova Scotians in various age groups compared with nursing home and hospitalized senior citizens. J Allergy Clin Immunol 81:836, 1988.
Castle SC, Norman DC, Perls TT, et al: Analysis of cutaneous delayed-type hypersensitivity reaction and T cell proliferative response in elderly nursing home patients: an approach to identifying immunodeficient patients. Gerontology 36:217, 1990.
Wayne SJ, Rhyne RL, Garry PJ, Goodwin JS: Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60. J Gerontol 45:M45, 1990.
Lichtman MA, Vaughn JH, Hames CG: The distribution of serum immunoglobulins, anti-gamma G globulins (“rheumatoid factors”), and antinuclear antibodies in Evans County, Georgia. Arthr Rheum 10:204, 1967.
Axelsson U, Bachmann R, Hällén J: Frequency of pathological proteins (M-components) in 6995 sera from an adult population. Acta Med Scand 179:235, 1966.
Hällén J: frequency of “abnormal” serum globulins (M-components) in the aged. Acta Med Scand 173:737, 1963.
Van Rensburg EJ, Heyns A du P: The effect of age, arteriosclerosis and hypercholesterolemia on platelet function tests, in Thrombotic and Haemorrhagic Disorders, Springer-Verlag, 1990.
Zahavi J, Jones NRG, Leyton J, et al: Enhanced in vivo platelet “release reaction” in old healthy individuals. Thromb Res 17:329, 1980.
Fetkovska N, Amstein R, Ferraein F, et al: 5HT-kinetics and sensitivity of human blood platelets: variations with age, gender and platelet number. Thromb Haemost 60:486, 1988.
Kasjanovova D, Balaz V: Age-related changes in human platelet function in vitro. Mech Ageing Dev 37:175, 1986.
Winther K, Naesh O: Aging and platelet b-adrenoceptor function. Eur J Pharmacol 136:219, 1987.
Vericel E, Croset M, Sedivy P, et al: Platelets and aging. I. Aggregation, arachidonate metabolism and antioxidant status. Thromb Res 49:331, 1988.
Winther K, Naesh O: Platelet alpha-adrenoreceptor function and aging. Thromb Res 46:677, 1987.
Bastyr EJ, Kadrofske MM, Vinik AI: Platelet activity and phosphoinositide turnover increase with advancing age. Am J Med 88:601, 1990.
Wang H-Y, Bashore TR, Friedman E: Exercise reduces age-dependent decrease in platelet protein kinase C activity and translocation. J Gerontol 50A:M12, 1995.
Kario K, Matsuo T, Kobayashi H, et al: Close relationship between hemostatic factors and acute-phase reaction as normal aging process. J Am Geriatr Soc 44:614, 1996.
Mari D, Mannucci PM, Coppola R, et al: Hypercoagulability in centenarians: the paradox of successful aging. Blood 85:3144, 1995.
Haverkate F, Thompson SG, Duckert F: Haemostasis factors in angina pectoris: relation to gender, age and acute phase reaction: results from the ECAT Angina Pectoris Study Group. Thromb Haemost 73:561, 1995.
Balleisen L, Bailey J, Epping P-H, et al: Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population. I. Baseline data on the relation to age, gender, body weight, smoking, alcohol, pill-using, and menopause. Thromb Haemost 54:475, 1985.
Scarabin PY, Van Dreden P, Bonithon-Kop C, et al: Age-related changes in factor VII activation in healthy women. Clin Sci 75:341, 1988.
Conlan MG, Folsom AR, Finch A, et al: Associations of Factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. Thromb Haemost 70:380, 1993.
Ernst E, Rosch KL: Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 118:956, 1993.
Bauer KA, Weiss LM, Sparrow D, et al: Aging associated changes in indices of thrombin generation and protein C activation in humans: normative aging study. J Clin Invest 80:1527, 1987.
Sundell B, Nilsson TK, Rainby M, et al: Fibrinolytic variables are related to age, sex, blood pressure, and body build measurements: a cross-sectional study in Norsjo, Sweden. J Clin Epidemiol 42:719, 1989.
Eliasson M, Evrin PE, Lundblad D, et al: Influence of gender, age, sampling time on fibrinolytic variables and fibrinogen. A population study. Fibrinolysis 7:316, 1993.
Siegert G, Bergmann S, Jaross W: Influence of age, gender and lipoprotein metabolism parameters on the activity of plasminogen activator inhibitor and the fibrinogen concentration. Fibrinolysis 6 (suppl 3):47, 1992.
Cawkwell RC: Patient’s age and the activated partial thromboplastin time test. Thromb Haemost 39:780, 1978.
Ibbotson SH, Tate GM, Davies JA: Thrombin activity by intrinsic activation of plasma in-vitro accelerates with increasing age of the donor. Thromb Haemost 67:377, 1992.
Kario K, Matsuo T, Kobayashi H: Which factors affect high D-dimer levels in the elderly? Thromb Res 62:501, 1991.
Gurwitz JH, Avorn J, Ross-Oegnan D, et al: Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 116:901, 1992.
Boyd RV, Hoffbrand BI: Erythrocyte sedimentation rate in elderly hospital in-patients. Br Med J 1:901, 1966.
Böttiger LE, Svedberg CA: Normal erythrocyte sedimentation rate and age. Br Med J 2:85, 1967.
Sharland DE: Erythrocyte sedimentation rate: the normal range in the elderly. J Am Geriatr Soc 28:346, 1980.
Sparrow D, Rowe JW, Silbert JE: Cross-sectional and longitudinal changes in the erythrocyte sedimentation rate in man. J Gerontol 36:180, 1981.
Shearn MA, Kang IY: Effect of age and sex on the erythrocyte sedimentation rate. J Rheumatol 13:297, 1986.
Katz PR, Gutman SJ, Richman G, et al: Erythrocyte sedimentation rate and C-reactive protein compared in the elderly. Clin Chem 35:466, 1989.
Katz PR, Karuza J, Gutman SI, et al: A comparison between erythrocyte sedimentation rate (ESR) and selected acute-phase proteins in the elderly. Am J Clin Pathol 94:637, 1990.
Ballou SP, Lozanski GP, Hadder S, et al: Quantitative and qualitative alterations of acute phase proteins in healthy elderly persons. Age and Ageing 25:224, 1996.
Caswell M, Pike LA, Bull BS: Effect of patients’ age on tests of the acute-phase response. Arch Pathol Lab Med 117:906, 1993.
Globerson A: Hematopoietic stem cells and aging. Exp Gerontol 34:137, 1999.
Pawelec G, Solana R, Remarque E, Mariani E: Impact of aging on innate immunity. J Leuk Biol 64:703, 1998.
Solana R, Alonso MC, Pena J: Natural killer cells in healthy aging. Exp Gerontol 34:435, 1999.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn