669
Inflammatory Response and Thrombosis in Older Individuals Jeffrey Schlaudecker, MD, MEd1
Richard Becker, MD2
1 Office of Geriatric Medicine, University of Cincinnati College of
Medicine, Cincinnati, Ohio 2 Division of Cardiovascular Health and Disease, Heart, Lung, and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio
Address for correspondence Richard Becker, MD, Division of Cardiovascular Health and Disease, Heart, Lung, and Vascular Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0542, Cincinnati, OH 45267-0542 (e-mail: [email protected]).
Abstract
Keywords
► thrombosis ► chronic inflammation ► frailty
The available evidence suggests that immunosenescence induces organismal proinflammatory responses. The chronic inflammation seen in advancing age stratifies persons into aging phenotypes. Even with adjustment for confounders, elevated inflammatory cytokines significantly decrease the odds of successful aging. This chronic inflammation seen in advancing age has varied causes, including comorbid illness, adipose tissue mass, diet, socioeconomic status, body mass index, gender, age, and physical activity. Aging can therefore be thought of as an acquired thrombophilia of increasing inflammation, impaired fibrinolytic potential, and a hypercoagulable state, out of proportion to physiological needs. Factors ranging from genetic to environmental contribute to the prothrombotic tendency of aging adults, especially those with concomitant frailty, to experience a decline in health status.
There is a clear and well-documented relationship between aging and thrombosis involving the venous and arterial circulatory systems. Some have referred to this phenomenon as “thrombotic preparedness” stemming from vascular fragility and a tendency toward bruising and bleeding with aging. In support of this position is an upregulation of coagulation proteins, diminished fibrinolytic capacity, and endothelial dysfunction with impaired regenerative capacity in older adults.1,2 Herein, we summarize the current literature on thrombosis and aging, with a specific emphasis on inflammation and inflammatory responses as pivotal mediators.
Aging in Humans In biology, senescence is the state or process of aging. Cellular senescence is a phenomenon where isolated cells demonstrate a limited ability to divide, whereas organismal senescence is the cumulative aging of organisms. After several decades of efficient cellular renewal, organismal senescence is typified by the declining ability to respond to stress, increasing homeostatic imbalance, and the increased risk of
published online August 24, 2014
Issue Theme Age-Related Changes in Thrombosis and Hemostasis; Guest Editors: Hau C. Kwaan, MD, FRCP, Brandon J. McMahon, MD, and Elaine M. Hylek, MD, MPH.
disease. Aging and longevity are determined by a complex interplay of environmental and genetic factors. In humans, cellular senescence has been attributed to the shortening of telomeres with each successive cell cycle. When telomeres become too short, the cells die and organs become inefficient due to a progressive lack of regenerative and reparative capacity. While cell and organismal senescence are the hallmark of aging, their relationship with inflammation has not, until recently, been clarified. The available evidence suggests that immunosenescence, possibly mediated by miRNA-associated failure to regulate immune recognition induces proinflammatory responses and attenuates resolution once aging provoked networks are initiated (summarized in the study by Olivieri et al3).
Is Inflammation a Part of the Natural Process of Aging? Senescence of the immune system and cellular senescence both contribute to rising inflammation with age. This inflammation is manifested in part by increased C-reactive protein (CRP), erythrocyte sedimentation rate, and other
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DOI http://dx.doi.org/ 10.1055/s-0034-1387882. ISSN 0094-6176.
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Semin Thromb Hemost 2014;40:669–674.
Inflammatory Response and Thrombosis in Older Individuals inflammatory markers. The associations between longterm CRP and interleukin 6 (IL-6) change with mortality, cardiovascular disease (CVD), or cognitive and physical impairment, and demonstrate that increases in these inflammatory cytokines confer higher risk.4 Comparing magnitude of change over time versus peak level of inflammatory marker revealed that peak level was more strongly associated with increased risk.4
Inflammatory Markers and Aging Phenotype Chronic inflammation seen in advancing age stratifies persons into aging phenotypes, and even with adjustment for confounders, elevated inflammatory cytokines significantly decrease the odds of successful aging.5 The chronic inflammation seen in advancing age has varied causes, including the overall burden of comorbid illness, adipose tissue mass, diet, socioeconomic status (SES), body mass index (BMI; the weight in kilograms divided by the height in meters), gender, age, and physical activity (►Fig. 1). This chronic inflammation decreases physical and cognitive performance, causes sarcopenia, and accurately predicts aging phenotype, including the syndrome of frailty.5 Although frailty has been defined in varied ways, the increased vulnerability later in life that it confers is well accepted. Several different frailty measures exist, but the significant correlation of these frailty indices with increasing CRP, IL-6, tumor necrosis factor α (TNF-α), and decreasing albumin has been demonstrated.6
Additive Effects of the Environment Diet Quality Overall diet in midlife accurately predicts future aging phenotype, according to a recent study.7 A cohort of 5,350 adults was followed for 16 years and baseline diet was assessed. Higher intakes of a traditional western diet were associated
Schlaudecker, Becker
with lower odds of ideal aging and higher risk of both cardiovascular and noncardiovascular death.7 It is also recognized that SES is linked to overall health status, and one important factor in this relationship is diet. Dietary fiber from fruits and vegetables make up a diet that is associated with lower CRP levels, whereas a diet high in saturated fats and refined grains may elevate CRP.8 A correlation between elevated CRP and measurement of total quality of diet tracked among 2,017 community dwelling US adults found that the micronutrient quality of the diet significantly inversely affected CRP level. The quality of the diet and CRP level was correlated for both whites and African Americans in this population-based prospective longitudinal epidemiologic study of low-income adults.8
Socioeconomic Status SES, diet, and health have a complicated interplay with fruit and vegetable consumption accounting for a significant effect on CRP, which is further influenced by education and income.9 Schafer et al found in a 2011 study that educational attainment and overall net worth, two common markers for SES, have a significant negative interaction with CRP as a marker for chronic inflammation.10 Elevated CRP levels are also associated with obesity, and the conjoint influence of these risk factors reveals both to be associated with elevated CRP levels. This analysis also highlighted the complicated relationship between CRP and SES, as when both markers of SES increased, representing lower SES, the relative impact of rising BMI was reduced.10 Persons within lower SES are exposed to more health risks, thus the relative contribution of BMI is less.
Physical Activity There exists a strong correlation with the increasing inflammatory cytokines of aging and functional status. Hamer et al
Fig. 1 Direct evidence relationships between discreet aging phenotypes and chronic inflammation.
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followed physical activity and inflammatory markers in a cohort study of 4,289 men and women.11 CRP, IL-6, and selfreported physical activity were followed over 10 years, demonstrating lower inflammatory markers in those adults with regular (2.5 h/week moderate to vigorous) physical activity. In addition, Tiainen et al evaluated physical performance and inflammatory markers in 197 nonagenarians, finding that high levels of CRP, IL-6, and IL-1 receptor antagonist (IL-1Ra) were associated with poor hand grip strength and lower physical performance status in daily tasks, even when adjusted for chronic disease, smoking, and physical exercise.12 This suggests that even in the oldest old, the association of inflammatory biomarkers and physical performance is evident.
ranging from phagocytosis, degranulation of antimicrobial enzymes, and generator of reactive oxygen species that have direct antimicrobial effects. In distinct contrast, the dysregulation of neutrophils is associated with inflammation, tissue injury, and the genesis of neutrophil extracellular traps (NETs)—extracellular DNA and histones forming a highly prothrombotic lattice. While the direct effect of aging and frailty or NET formation and thrombosis is under investigation, the recognized relationship between immaturity of neutrophils and impaired NET formation and the proinflammatory environment that typifies aging suggests that an effect is likely.26
Gender Differences
While frailty is common with aging and, as previously summarized, tracks with inflammation and thrombosis, the progressive increase of body weight in the United States must not be understated, including among persons older than 70 years. Obesity is rapidly becoming a global epidemic of unparalleled proportion. Changes in BMI have accelerated rapidly in the past 5 years among children, adolescents, and adults. BMI is associated with increased all-cause mortality and mortality from CVD, with the greatest overall risks for adults (ages 19–84 years) in the 35.0 to 39.9 (hazards ratio [HR], 1.88) and 40.0 to 49.9 (HR, 2.51) categories. Obesity has been associated with increased visceral fat, including nonalcoholic fatty liver damage. In this disorder, coagulation factors VIII-, IX-, XI-, and XII-related activities are increased independent of age and gender.27 In addition, obesity is a risk factor for chronic venous insufficiency and venous thromboembolism. Individuals with a BMI > 30 kg/m 2 have decreased lower extremity venous peak velocity, mean velocity, velocity amplitudes (peak velocityminimum velocity), and shear stress.28 Overall, obese individuals are twofold more likely to experience venous thromboembolism than nonobese individuals, particularly if obesity is accompanied by decreased muscle strength or inherited thrombophilias, including the factor V Leiden and prothrombin gene mutations.29,30 In addition to its association with several atherogenic states, including type 2 diabetes mellitus, systemic hypertension and dyslipidemia, obesity, in-and-of itself, appears to be both proatherogenic and prothrombotic. Obesity is an independent risk factor for deep vein thrombosis and pulmonary embolism.31,32 Data from the National Hospital Discharge Survey support a twofold to threefold increased risk for both obese men and women, particularly in those individuals younger than 40 years.33 Beyond traditional risk factors for atherothrombosis observed frequently among obese individuals, one most consider additional acquired metabolic abnormalities and contributing disease states (reviewed in Poirier et al34). Accumulating evidence indicates that obesity represents a state of low-grade inflammation which, in turn, leads to insulin resistance—both are associated strongly with systemic markers of inflammation and atherosclerosis.35 Adipose tissue itself is composed of several cell types, including lipid-laden
Innate Immunity and Thrombosis Neutrophils are highly specialized participants in both host defenses and immune surveillance, with unique properties
Inflammation and Obesity
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The male survival disadvantage at all ages and across species suggests a biological base.13 A nationally representative community sample evaluated subgroups by sex and age and found that both descriptive and multivariate regression analyses showed highly significant differences for all markers and indices of physiological dysregulation, including metabolic disorder and chronic inflammation.14 The relationship between coagulation and inflammation among older adults has been a subject of interest for the past two decades.15–18 In the Framingham Offspring Study, significantly higher levels of fibrinogen, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (t-PA) antigen were observed across increasing deciles of age after adjustment for traditional cardiovascular risk factors.15 Increased levels of factor VIII, fibrinogen, fibrin-degradation products, factor XIa-α1-antitrypsin, and CRP were observed in frail compared with nonfrail subjects participating in the Cardiovascular Health Study.17 A similar relationship between inflammation and frailty has been demonstrated.19 The association between elevated levels of D-dimer, a marker of fibrin formation and its subsequent degradation, and IL-6 with diminishing functional status and survival suggests that frailty may represent an intermediate phenotype of prognostic significance.20 The concomitant impact of age, environmental stress, and chronic inflammation on intrinsic fibrinolytic activity mediated by heightened expression of PAI-1, the major inhibitor of t-PA, has been a proposed as a contributing mechanism for both venous and arterial thrombosis in older adults.21,22 Inherited mutations in the PAI1 promoter region, may only be of clinical relevance with advancing age.23 Acquired factors that contribute to PAI-1 induction and risk for myocardial infarction include vessel injury, platelet activation, and inflammatory markers. Each correlates and tracks closely with increased age.24,25 Aging is an acquired thrombophilia characterized by heightened inflammation, impaired fibrinolytic potential, and a systemic state of “thrombotic preparedness” that is far out of proportion to physiological needs.
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Inflammatory Response and Thrombosis in Older Individuals mature adipocytes, vascular stromal cells, and macrophages. Co-culture of differentiated 3T3-L1 adipocytes and macrophages result in a marked upregulation of proinflammatory cytokines such as TNFα and downregulation of the antiinflammatory and antiatherothrombotic cytokine adiponectin.36 Moreover, the inflammatory changes are augmented by adipose vascular stromal fraction, suggesting that inflammatory mediators participate in a maladaptive “paracrine loop” between adipocytes and macrophages. Inflammation-sensitive plasma proteins (fibrinogen, orosomucoid, α1-antitrypsin, haptoglobin, ceruloplasmin) increase steadily with BMI, and correlate with cardiovascular death, myocardial infarction, and stroke.37 Soluble CD40L, a marker of inflammation, platelet activation, and prothrombotic potential, is elevated among obese patients, declining along with fasting insulin, monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity c-reactive protein (hs-CRP) levels after bariatric surgery-associated weight loss.38 Similarly, circulating procoagulant microparticles have been documented in obesity, with levels threefold to fourfold higher than agematched, nonobese controls.39 The relationship between obesity and thrombosis supports one or more commonalities, with inflammation and metabolic abnormalities representing a likely point of interface. VWF plasma concentrations increase uniformly with inflammatory states. The gene rs1063856 is associated with VWF plasma levels and incident venous thrombosis.40 VWF gene expression is upregulated in omental tissue from morbidly obese patients undergoing bariatric surgery, particularly those with type 2 diabetes mellitus.41 Freedman et al, based on preliminary microarray data and candidate genes identified in the medical literature to be associated with CVD, measured expression of 48 genes by high throughput technology on 1,846 participants in the Framingham offspring cohort.42 Several inflammatory transcripts, including intercellular adhesion molecule 1 (ICAM-1), interferon (IFN)-gamma, interleukin (IL-1R1), IL-6, myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), TNF, tolllike receptors-2 (TLR-2), and TLR-4 were associated with BMI. Upon further analysis, a majority of the transcripts were specific to platelets, with few leukocyte transcripts showing a significant association. While genes significantly associated with BMI are known to stimulate NFκB activity or are expressed following activation of this pathway, a majority, with the exception of CCL2 are platelet-expressed transcripts. Considering the available data, one may conclude that obesity is a metabolic/inflammatory disorder associated with a heightened risk for thrombosis; however, not all obese individuals express the thrombosis phenotype. The question then becomes whether inflammation is required or represents a pathobiologic interface between obesity and thrombosis and to what degree heritability participates. Alternatively stated, thrombosis is a heritable phenotype determined by the presence of inflammation acquired through obesity as a primary environmental disorder.
Metabolic Syndrome Metabolic syndrome consists of a constellation of cardiovascular risk factors that include abdominal obesity, hyperlipidemia, Seminars in Thrombosis & Hemostasis
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hypertension, and impaired glucose tolerance, and is extremely common in persons older than 70 years.43 A prospective cohort study of 3,075 adults aged 70 to 79 years evaluated the interplay between metabolic syndrome, physical performance, the inflammatory biomarkers CRP and IL-6, and demographic covariates, and found that the presence of metabolic syndrome was significantly associated with poorer physical performance, partially accounted for by modest elevations of inflammatory biomarkers.44 Adipose tissue releases inflammatory cytokines in a proportional relationship with overall amount of adipose tissue, and these inflammatory markers predict mortality independently in older persons.45,46 Given the recognition that inflammatory cytokines accelerate body composition typical of the aging process, obesity-related cytokine elevation may increase vulnerability to debility and other consequences of this inflammatory cascade.47 Inflammation is independently associated with total and abdominal adiposity, as well as elevation of CRP and IL-6, as evaluated among 500 older adults in a multicenter single-blind randomized clinical trial.48,49
Immobility, Inflammation, and Thrombosis Venous thrombosis is common in older adults. While immobility and inactivity are potential hallmarks of advancing age, many have questioned whether this represents a sufficient explanation for the observation. Indeed, conditions associated with immobility, including hospitalization, surgery, trauma, and fractures—each associated with a local and/or systemic inflammatory state may represent a major contributor to the risk of thromboembolism.50 Infections, including those related to community acquired bacteria and viruses are associated with a heightened (threefold–fourfold) short-term (< 30 days) risk for the thromboembolic-based myocardial infarction and stroke—particularly among older patients.51,52
Conclusions There is a relationship between aging, inflammation, and inflammatory responses that provides a foundation for thrombosis as a collective phenotype of organismal senescence. Several factors, ranging from genetic to environmental, contribute to the prothrombotic tendency of aging adults, particularly those with concomitant frailty, to experience a decline in health status. The mechanisms that differentiate frailty, obesity, and metabolic syndrome as risk conditions for thrombosis require further investigation.
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Inflammatory Response and Thrombosis in Older Individuals Jeffrey Schlaudecker, MD, MEd1
Richard Becker, MD2
1 Office of Geriatric Medicine, University of Cincinnati College of
Medicine, Cincinnati, Ohio 2 Division of Cardiovascular Health and Disease, Heart, Lung, and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio
Address for correspondence Richard Becker, MD, Division of Cardiovascular Health and Disease, Heart, Lung, and Vascular Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0542, Cincinnati, OH 45267-0542 (e-mail: [email protected]).
Abstract
Keywords
► thrombosis ► chronic inflammation ► frailty
The available evidence suggests that immunosenescence induces organismal proinflammatory responses. The chronic inflammation seen in advancing age stratifies persons into aging phenotypes. Even with adjustment for confounders, elevated inflammatory cytokines significantly decrease the odds of successful aging. This chronic inflammation seen in advancing age has varied causes, including comorbid illness, adipose tissue mass, diet, socioeconomic status, body mass index, gender, age, and physical activity. Aging can therefore be thought of as an acquired thrombophilia of increasing inflammation, impaired fibrinolytic potential, and a hypercoagulable state, out of proportion to physiological needs. Factors ranging from genetic to environmental contribute to the prothrombotic tendency of aging adults, especially those with concomitant frailty, to experience a decline in health status.
There is a clear and well-documented relationship between aging and thrombosis involving the venous and arterial circulatory systems. Some have referred to this phenomenon as “thrombotic preparedness” stemming from vascular fragility and a tendency toward bruising and bleeding with aging. In support of this position is an upregulation of coagulation proteins, diminished fibrinolytic capacity, and endothelial dysfunction with impaired regenerative capacity in older adults.1,2 Herein, we summarize the current literature on thrombosis and aging, with a specific emphasis on inflammation and inflammatory responses as pivotal mediators.
Aging in Humans In biology, senescence is the state or process of aging. Cellular senescence is a phenomenon where isolated cells demonstrate a limited ability to divide, whereas organismal senescence is the cumulative aging of organisms. After several decades of efficient cellular renewal, organismal senescence is typified by the declining ability to respond to stress, increasing homeostatic imbalance, and the increased risk of
published online August 24, 2014
Issue Theme Age-Related Changes in Thrombosis and Hemostasis; Guest Editors: Hau C. Kwaan, MD, FRCP, Brandon J. McMahon, MD, and Elaine M. Hylek, MD, MPH.
disease. Aging and longevity are determined by a complex interplay of environmental and genetic factors. In humans, cellular senescence has been attributed to the shortening of telomeres with each successive cell cycle. When telomeres become too short, the cells die and organs become inefficient due to a progressive lack of regenerative and reparative capacity. While cell and organismal senescence are the hallmark of aging, their relationship with inflammation has not, until recently, been clarified. The available evidence suggests that immunosenescence, possibly mediated by miRNA-associated failure to regulate immune recognition induces proinflammatory responses and attenuates resolution once aging provoked networks are initiated (summarized in the study by Olivieri et al3).
Is Inflammation a Part of the Natural Process of Aging? Senescence of the immune system and cellular senescence both contribute to rising inflammation with age. This inflammation is manifested in part by increased C-reactive protein (CRP), erythrocyte sedimentation rate, and other
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1387882. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Semin Thromb Hemost 2014;40:669–674.
Inflammatory Response and Thrombosis in Older Individuals inflammatory markers. The associations between longterm CRP and interleukin 6 (IL-6) change with mortality, cardiovascular disease (CVD), or cognitive and physical impairment, and demonstrate that increases in these inflammatory cytokines confer higher risk.4 Comparing magnitude of change over time versus peak level of inflammatory marker revealed that peak level was more strongly associated with increased risk.4
Inflammatory Markers and Aging Phenotype Chronic inflammation seen in advancing age stratifies persons into aging phenotypes, and even with adjustment for confounders, elevated inflammatory cytokines significantly decrease the odds of successful aging.5 The chronic inflammation seen in advancing age has varied causes, including the overall burden of comorbid illness, adipose tissue mass, diet, socioeconomic status (SES), body mass index (BMI; the weight in kilograms divided by the height in meters), gender, age, and physical activity (►Fig. 1). This chronic inflammation decreases physical and cognitive performance, causes sarcopenia, and accurately predicts aging phenotype, including the syndrome of frailty.5 Although frailty has been defined in varied ways, the increased vulnerability later in life that it confers is well accepted. Several different frailty measures exist, but the significant correlation of these frailty indices with increasing CRP, IL-6, tumor necrosis factor α (TNF-α), and decreasing albumin has been demonstrated.6
Additive Effects of the Environment Diet Quality Overall diet in midlife accurately predicts future aging phenotype, according to a recent study.7 A cohort of 5,350 adults was followed for 16 years and baseline diet was assessed. Higher intakes of a traditional western diet were associated
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with lower odds of ideal aging and higher risk of both cardiovascular and noncardiovascular death.7 It is also recognized that SES is linked to overall health status, and one important factor in this relationship is diet. Dietary fiber from fruits and vegetables make up a diet that is associated with lower CRP levels, whereas a diet high in saturated fats and refined grains may elevate CRP.8 A correlation between elevated CRP and measurement of total quality of diet tracked among 2,017 community dwelling US adults found that the micronutrient quality of the diet significantly inversely affected CRP level. The quality of the diet and CRP level was correlated for both whites and African Americans in this population-based prospective longitudinal epidemiologic study of low-income adults.8
Socioeconomic Status SES, diet, and health have a complicated interplay with fruit and vegetable consumption accounting for a significant effect on CRP, which is further influenced by education and income.9 Schafer et al found in a 2011 study that educational attainment and overall net worth, two common markers for SES, have a significant negative interaction with CRP as a marker for chronic inflammation.10 Elevated CRP levels are also associated with obesity, and the conjoint influence of these risk factors reveals both to be associated with elevated CRP levels. This analysis also highlighted the complicated relationship between CRP and SES, as when both markers of SES increased, representing lower SES, the relative impact of rising BMI was reduced.10 Persons within lower SES are exposed to more health risks, thus the relative contribution of BMI is less.
Physical Activity There exists a strong correlation with the increasing inflammatory cytokines of aging and functional status. Hamer et al
Fig. 1 Direct evidence relationships between discreet aging phenotypes and chronic inflammation.
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followed physical activity and inflammatory markers in a cohort study of 4,289 men and women.11 CRP, IL-6, and selfreported physical activity were followed over 10 years, demonstrating lower inflammatory markers in those adults with regular (2.5 h/week moderate to vigorous) physical activity. In addition, Tiainen et al evaluated physical performance and inflammatory markers in 197 nonagenarians, finding that high levels of CRP, IL-6, and IL-1 receptor antagonist (IL-1Ra) were associated with poor hand grip strength and lower physical performance status in daily tasks, even when adjusted for chronic disease, smoking, and physical exercise.12 This suggests that even in the oldest old, the association of inflammatory biomarkers and physical performance is evident.
ranging from phagocytosis, degranulation of antimicrobial enzymes, and generator of reactive oxygen species that have direct antimicrobial effects. In distinct contrast, the dysregulation of neutrophils is associated with inflammation, tissue injury, and the genesis of neutrophil extracellular traps (NETs)—extracellular DNA and histones forming a highly prothrombotic lattice. While the direct effect of aging and frailty or NET formation and thrombosis is under investigation, the recognized relationship between immaturity of neutrophils and impaired NET formation and the proinflammatory environment that typifies aging suggests that an effect is likely.26
Gender Differences
While frailty is common with aging and, as previously summarized, tracks with inflammation and thrombosis, the progressive increase of body weight in the United States must not be understated, including among persons older than 70 years. Obesity is rapidly becoming a global epidemic of unparalleled proportion. Changes in BMI have accelerated rapidly in the past 5 years among children, adolescents, and adults. BMI is associated with increased all-cause mortality and mortality from CVD, with the greatest overall risks for adults (ages 19–84 years) in the 35.0 to 39.9 (hazards ratio [HR], 1.88) and 40.0 to 49.9 (HR, 2.51) categories. Obesity has been associated with increased visceral fat, including nonalcoholic fatty liver damage. In this disorder, coagulation factors VIII-, IX-, XI-, and XII-related activities are increased independent of age and gender.27 In addition, obesity is a risk factor for chronic venous insufficiency and venous thromboembolism. Individuals with a BMI > 30 kg/m 2 have decreased lower extremity venous peak velocity, mean velocity, velocity amplitudes (peak velocityminimum velocity), and shear stress.28 Overall, obese individuals are twofold more likely to experience venous thromboembolism than nonobese individuals, particularly if obesity is accompanied by decreased muscle strength or inherited thrombophilias, including the factor V Leiden and prothrombin gene mutations.29,30 In addition to its association with several atherogenic states, including type 2 diabetes mellitus, systemic hypertension and dyslipidemia, obesity, in-and-of itself, appears to be both proatherogenic and prothrombotic. Obesity is an independent risk factor for deep vein thrombosis and pulmonary embolism.31,32 Data from the National Hospital Discharge Survey support a twofold to threefold increased risk for both obese men and women, particularly in those individuals younger than 40 years.33 Beyond traditional risk factors for atherothrombosis observed frequently among obese individuals, one most consider additional acquired metabolic abnormalities and contributing disease states (reviewed in Poirier et al34). Accumulating evidence indicates that obesity represents a state of low-grade inflammation which, in turn, leads to insulin resistance—both are associated strongly with systemic markers of inflammation and atherosclerosis.35 Adipose tissue itself is composed of several cell types, including lipid-laden
Innate Immunity and Thrombosis Neutrophils are highly specialized participants in both host defenses and immune surveillance, with unique properties
Inflammation and Obesity
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The male survival disadvantage at all ages and across species suggests a biological base.13 A nationally representative community sample evaluated subgroups by sex and age and found that both descriptive and multivariate regression analyses showed highly significant differences for all markers and indices of physiological dysregulation, including metabolic disorder and chronic inflammation.14 The relationship between coagulation and inflammation among older adults has been a subject of interest for the past two decades.15–18 In the Framingham Offspring Study, significantly higher levels of fibrinogen, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (t-PA) antigen were observed across increasing deciles of age after adjustment for traditional cardiovascular risk factors.15 Increased levels of factor VIII, fibrinogen, fibrin-degradation products, factor XIa-α1-antitrypsin, and CRP were observed in frail compared with nonfrail subjects participating in the Cardiovascular Health Study.17 A similar relationship between inflammation and frailty has been demonstrated.19 The association between elevated levels of D-dimer, a marker of fibrin formation and its subsequent degradation, and IL-6 with diminishing functional status and survival suggests that frailty may represent an intermediate phenotype of prognostic significance.20 The concomitant impact of age, environmental stress, and chronic inflammation on intrinsic fibrinolytic activity mediated by heightened expression of PAI-1, the major inhibitor of t-PA, has been a proposed as a contributing mechanism for both venous and arterial thrombosis in older adults.21,22 Inherited mutations in the PAI1 promoter region, may only be of clinical relevance with advancing age.23 Acquired factors that contribute to PAI-1 induction and risk for myocardial infarction include vessel injury, platelet activation, and inflammatory markers. Each correlates and tracks closely with increased age.24,25 Aging is an acquired thrombophilia characterized by heightened inflammation, impaired fibrinolytic potential, and a systemic state of “thrombotic preparedness” that is far out of proportion to physiological needs.
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Inflammatory Response and Thrombosis in Older Individuals mature adipocytes, vascular stromal cells, and macrophages. Co-culture of differentiated 3T3-L1 adipocytes and macrophages result in a marked upregulation of proinflammatory cytokines such as TNFα and downregulation of the antiinflammatory and antiatherothrombotic cytokine adiponectin.36 Moreover, the inflammatory changes are augmented by adipose vascular stromal fraction, suggesting that inflammatory mediators participate in a maladaptive “paracrine loop” between adipocytes and macrophages. Inflammation-sensitive plasma proteins (fibrinogen, orosomucoid, α1-antitrypsin, haptoglobin, ceruloplasmin) increase steadily with BMI, and correlate with cardiovascular death, myocardial infarction, and stroke.37 Soluble CD40L, a marker of inflammation, platelet activation, and prothrombotic potential, is elevated among obese patients, declining along with fasting insulin, monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity c-reactive protein (hs-CRP) levels after bariatric surgery-associated weight loss.38 Similarly, circulating procoagulant microparticles have been documented in obesity, with levels threefold to fourfold higher than agematched, nonobese controls.39 The relationship between obesity and thrombosis supports one or more commonalities, with inflammation and metabolic abnormalities representing a likely point of interface. VWF plasma concentrations increase uniformly with inflammatory states. The gene rs1063856 is associated with VWF plasma levels and incident venous thrombosis.40 VWF gene expression is upregulated in omental tissue from morbidly obese patients undergoing bariatric surgery, particularly those with type 2 diabetes mellitus.41 Freedman et al, based on preliminary microarray data and candidate genes identified in the medical literature to be associated with CVD, measured expression of 48 genes by high throughput technology on 1,846 participants in the Framingham offspring cohort.42 Several inflammatory transcripts, including intercellular adhesion molecule 1 (ICAM-1), interferon (IFN)-gamma, interleukin (IL-1R1), IL-6, myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), TNF, tolllike receptors-2 (TLR-2), and TLR-4 were associated with BMI. Upon further analysis, a majority of the transcripts were specific to platelets, with few leukocyte transcripts showing a significant association. While genes significantly associated with BMI are known to stimulate NFκB activity or are expressed following activation of this pathway, a majority, with the exception of CCL2 are platelet-expressed transcripts. Considering the available data, one may conclude that obesity is a metabolic/inflammatory disorder associated with a heightened risk for thrombosis; however, not all obese individuals express the thrombosis phenotype. The question then becomes whether inflammation is required or represents a pathobiologic interface between obesity and thrombosis and to what degree heritability participates. Alternatively stated, thrombosis is a heritable phenotype determined by the presence of inflammation acquired through obesity as a primary environmental disorder.
Metabolic Syndrome Metabolic syndrome consists of a constellation of cardiovascular risk factors that include abdominal obesity, hyperlipidemia, Seminars in Thrombosis & Hemostasis
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hypertension, and impaired glucose tolerance, and is extremely common in persons older than 70 years.43 A prospective cohort study of 3,075 adults aged 70 to 79 years evaluated the interplay between metabolic syndrome, physical performance, the inflammatory biomarkers CRP and IL-6, and demographic covariates, and found that the presence of metabolic syndrome was significantly associated with poorer physical performance, partially accounted for by modest elevations of inflammatory biomarkers.44 Adipose tissue releases inflammatory cytokines in a proportional relationship with overall amount of adipose tissue, and these inflammatory markers predict mortality independently in older persons.45,46 Given the recognition that inflammatory cytokines accelerate body composition typical of the aging process, obesity-related cytokine elevation may increase vulnerability to debility and other consequences of this inflammatory cascade.47 Inflammation is independently associated with total and abdominal adiposity, as well as elevation of CRP and IL-6, as evaluated among 500 older adults in a multicenter single-blind randomized clinical trial.48,49
Immobility, Inflammation, and Thrombosis Venous thrombosis is common in older adults. While immobility and inactivity are potential hallmarks of advancing age, many have questioned whether this represents a sufficient explanation for the observation. Indeed, conditions associated with immobility, including hospitalization, surgery, trauma, and fractures—each associated with a local and/or systemic inflammatory state may represent a major contributor to the risk of thromboembolism.50 Infections, including those related to community acquired bacteria and viruses are associated with a heightened (threefold–fourfold) short-term (< 30 days) risk for the thromboembolic-based myocardial infarction and stroke—particularly among older patients.51,52
Conclusions There is a relationship between aging, inflammation, and inflammatory responses that provides a foundation for thrombosis as a collective phenotype of organismal senescence. Several factors, ranging from genetic to environmental, contribute to the prothrombotic tendency of aging adults, particularly those with concomitant frailty, to experience a decline in health status. The mechanisms that differentiate frailty, obesity, and metabolic syndrome as risk conditions for thrombosis require further investigation.
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