Page 160 - Williams Hematology ( PDFDrive )

134 Part III: Epochal Hematology Chapter 9: Hematology in Older Persons 135

noted with age. 200–203 To date, a longitudinal data set describing altera- correlation for adverse outcomes was stronger with D-dimer than
tions in platelet number with advancing age has not been produced nor IL-6. In this, and other studies, 234–236 D-dimer and other markers of
233
are there conclusive studies describing age-associated changes in plate- activated coagulation were associated with limitation in a wide variety
let function. of functional domains, including independent activities of daily living
(IADL), lower-extremity function, and performance on cognitive test-
AGING AND COAGULATION ing. The age-associated changes in coagulation markers occur earlier
Coagulation Factors and Aging than other aging biomarkers, and hence it has been argued that they
A number of proteins critical to clot formation and fibrinolysis change in could be early predictors of those elderly at increased risk for functional
237
characteristic ways with advancing age. 204–206 Plasma concentrations of decline.
factor VII coagulant activity and antigen, 204–208 and factor VIIIC, 191,206,209 This age-associated prominence of coagulation factors has also
as well as von Willebrand factor, 191,209 fibrinogen, 191,206,208,210 fibrinopep- been reproduced in animals. For example, when stress associated with
tide A, 191,206,207 and tissue plasminogen activator antigen 191,211–213 increase physical restraint was compared in aged versus young C57BL/6J mice,
with age. In healthy centenarians, levels of activated factor VII, activation significantly increased expression of PAI-1 mRNA was noted in almost
238
peptides of prothrombin, factors IX and X, and thrombin–antithrombin all the tissues in older mice. Similar results were seen for expression of
238
complex concentration were increased, which are signs of higher-than- tissue factor mRNA in aged mice. In both these experimental models
expected coagulation enzyme activity. Age-associated increases in an increase in microthrombi was noted with clots distributed through
206
levels of protein C occur in both sexes. Aging is also associated with multiple organ systems in the older mice.
increasing levels of free protein S. In contrast, antithrombin tends to In humans, both the presence of depression and/or psychological
204
239–241
decrease with age in males and increases with age in females following stress are associated with increased coagulation and decreased
242
menopause. Higher D-dimer and plasmin–antiplasmin complexes fibrinolytic activity. In elderly subjects without cardiovascular dis-
214
indicate an accompanying increase in fibrinolytic activity. 206,215 In con- ease, physical exhaustion, a characteristic frequently used to distinguish
trast, plasma tissue-plasminogen activator inhibitor levels increase with frail from nonfrail individuals, was associated with significant increases
increasing age, as do levels of thrombin-activatable fibrinolysis inhibitor in both inflammatory and coagulation factors as assessed by fibrinogen,
239
in women and its proenzyme form, procarboxypeptidase U, in both C-reactive protein, and white cell levels. Frail and prefrail subjects
216
sexes. These latter findings are suggestive of a possible age-dependent from the Cardiovascular Health Study had significantly higher levels of
217
compromise in fibrinolytic activity. Thus, procoagulant and, in some fibrinogen, factor VIII, and D-dimer levels as compared to the nonfrail
218
studies, fibrinolytic activities appear to be increased in older subjects by group. The association with frailty persisted even after adjusting for the
243
both in vitro 206,219,220 and in vivo studies, 190,221 but the changes in fibrino- presence of cardiovascular disease and diabetes. Frailty is also associ-
lytic activity are inconsistent. Older patients may show an exaggerated ated with increased risk of venous thromboembolism when compared
anticoagulant response to warfarin. 222 to nonfrail individuals of the same age, especially in association with
increased factor VIII levels. 244
Aging as a Prothrombotic State
Activation of the coagulation system and increase in procoagulant
markers are associated with the pathogenesis of atherosclerosis. 223,224 AGING AND IMMUNITY
However, procoagulant markers, most notably D-dimer, fibrinogen, Whether related to primary processes of aging or not, the thymus gland
225
and factor VIII, also increase with advancing age, and may, in fact, undergoes a very characteristic pattern of involution beginning well in
226
correlate better with aging than with cardiovascular disease. 223,224 In a advance of other phenotypic changes attributed to aging (see Figs. 9–1
study examining 1729 participants age 70 years and older in the Estab- and 9–2; Chap. 6). Among the consequences are a decreased gener-
245
lished Populations for the Epidemiological Study of the Elderly (EPESE) ation of naïve T cells. Despite this, the total lymphocyte count does
246
cohort, increasing age was associated with high D-dimer levels. For not decline greatly because peripheral T cells are capable of expanding
example, 23 percent of the participants age 90 to 99 years had high to fill the T-cell niche in the absence of generation of new T cells. How-
D-dimer levels (>600 mcg/L) compared to 13 percent in the 80- to ever, when they do so, the repertoire for antigen recognition becomes
89-year-old age group and 7 percent in the 70- to 79-year-old age less comprehensive. Thymic involution may result from the aging T-cell
247
group. Investigators measured fibrinogen concentrations in healthy progenitor population, from the defects in rearrangement of T-cell
215
subjects ages 19 to 96 years and found levels to be significantly higher receptor β genes, 248,249 from loss of self-peptide expressing thymic epi-
251
250
in participants older than age 60 years when compared to younger sub- thelium, and/or from the loss of thymic trophic cytokines. Thy-
jects. Healthy individuals across the life span had fibrinogen levels mic epithelial cells produce a variety of colony-stimulating factors and
227
increased by 25 mg/dL per decade of life, and levels as high as 320 mg/ hematopoietic cytokines, such as IL-1, IL-3, IL-6, IL-7, transforming
dL were found in more than 80 percent of people older than 65 years growth factor-β, oncostatin M, and leukemia inhibitory factor, 252–254
of age. Other markers of activated coagulation, such as plasmino- which influence the complex process of T-cell production. It is pro-
228
gen activating inhibitor-I (PAI-1) and factor VIII also increased with posed that thymic atrophy and decreased thymopoiesis is an active pro-
age. 209,229,230 Thus, it is now apparent that aging is associated with markers cess and mediated by the upregulation of thymosuppressive cytokines
of activated coagulation. In this context, it is notable that the incidence (leukemia inhibitory factor, IL-6, and oncostatin M), which results in
of venous thrombosis and pulmonary emboli increases dramatically in the altered peripheral lymphatic tissue T-lymphocyte function with
geriatric populations. 231,232 Bleeding complications from anticoagulation aging. 255
therapy are also increased in older patients. No interventional study has There is a notable shift in the overall blood T-cell population
256
identified an at-risk population of normal-age subjects without prior toward lymphocytes with memory T-cell markers, and many of
257
thrombosis in whom prophylactic anticoagulation is of value. these are thought to have attained replicative senescence. With the
decreasing numbers of naïve T cells in the peripheral lymphatic tissue
Coagulation and Functional Decline and increasing memory T cells reaching senescence, elderly persons
In the EPESE study, increases in D-dimer and interleukin (IL)-6 were have difficulties responding to old and new antigens and demonstrate
215
related to increases in both morbidity and mortality. In fact, the impaired reactions to vaccinations. The decreased efficacy of vaccines
Kaushansky_chapter 09_p0129-0142.indd 135 17/09/15 6:16 pm