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Semin Thromb Hemost 2002; 28(6): 555-568
DOI: 10.1055/s-2002-36700
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Aging and Thrombosis

Wade R. Wilkerson, David C. Sane
  • Department of Internal Medicine, Section of Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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Publication History

Publication Date:
21 January 2003 (online)

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ABSTRACT

Advanced age is associated with a dramatic increase in the rates of venous and arterial thrombotic events. Increases in fibrinogen, factors VIII and IX, and other coagulation proteins, without a proportional increase in anticoagulant factors, likely contribute to this risk. Recent studies have delineated a role for genomic elements in controlling age-related expression of some coagulation proteins. Enhanced platelet activity as well as molecular and anatomic changes in the vessel wall also contribute to the thrombotic propensity. Advanced age is associated with elevated interleukin-6 (IL-6) and C-reactive protein levels, indicating an inflammatory state that may be an important stimulus for thrombus formation in the elderly. Despite evidence of a prothrombotic state, many elderly people do not experience clinical thrombotic events. It is possible that the increase in coagulation proteins and activation markers conveys a survival advantage, such as inhibiting tumor angiogenesis. The recent epidemic in obesity may heighten thrombotic risks in the elderly because adipose tissue is an important source of inflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1). As the population ages, further studies will be warranted to define the mechanisms for thrombosis in the elderly.

KEYWORD

Aging - thrombosis - inflammation - fibrinolysis - angiogenesis

REFERENCES

  • 1 Anderson F A, Wheeler H B, Goldberg R J. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism.  Arch Intern Med . 1991;  151 933-938
    CrossrefPubMedGoogle Scholar
  • 2 Silverstein M D, Heit J A, Mohr D N. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25 years population-based study.  Arch Intern Med . 1998;  158 585-593
    CrossrefPubMedGoogle Scholar
  • 3 Martinelli I. Risk factors for venous thromboembolism.  Thromb Haemost . 2001;  86 395-403
    PubMedGoogle Scholar
  • 4 Heit J A, Silverstein M D, Mohr D N. The epidemiology of venous thromboembolism in the community.  Thromb Haemost . 2001;  86 452-463
    PubMedGoogle Scholar
  • 5 American Heart Association 2001 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association 2000
    Google Scholar
  • 6 National Center for Health Statistics. Advanced Report of Final Mortality Statistics, 1987.  Hyattsville, MD: Public Health Service 1989
    Google Scholar
  • 7 Roger V L, Jacobsen S J, Weston S A. Trends in the incidence and survival of patients with hospitalized myocardial infarction, Olmsted County, Minnesota, 1979 to 1994.  Ann Intern Med . 2002;  136 341-348
    PubMedGoogle Scholar
  • 8 Tracy R P, Bovill E G. Thrombosis and cardiovascular risk in the elderly.  Arch Pathol Lab Med . 1992;  16 1307-1312
    PubMedGoogle Scholar
  • 9 Tracy R P, Bovill E G, Fried L P. The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study.  Ann Epidemiol . 1992;  2 509-519
    CrossrefPubMedGoogle Scholar
  • 10 Meade T W, North W R, Chakrabarti R, Haines A P, Stirling Y. Population-based distributions of haemostatic variables.  Br Med Bull . 1977;  33 283-288
    PubMedGoogle Scholar
  • 11 Meade T, North W R, Chakrabarti R. Haemotatic function and cardiovascular death: elderly results of a prospective study.  Lancet . 1980;  1 1050-1054
    PubMedGoogle Scholar
  • 12 Stone M, Thorp J. Plasma fibrinogen-a major coronary risk factor.  J R Coll Gen Pract . 1985;  35 565-569
    PubMedGoogle Scholar
  • 13 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K. Fibrinogen as a risk factor for stroke and myocardial infarction.  N Engl J Med . 1984;  311 501-505
    CrossrefPubMedGoogle Scholar
  • 14 Kannel W, Wolf P, Castelli W. Fibrinogen and risk of cardiovascular disease: the Framingham study.  JAMA . 1987;  285 1183-1186
    PubMedGoogle Scholar
  • 15 Tracy R, Bovill E, Yanez D, for the CHS investigators. Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly: results from the Cardiovascular Heath Study.  Arterioscler Thromb Vasc Biol . 1995;  15 1269-1279
    PubMedGoogle Scholar
  • 16 Meade T. The epidemiology of haemostatic and other variables in coronary artery disease. In: Verstraete M, Vermylen J, Lijnen H, Arnout J, eds. Thrombosis and Haemostasis 1987 Leuven: International Society on Thrombosis and Haemostasis and Leuven University Press 1987: 37-59
    Google Scholar
  • 17 Kannel W, D'Agustino R, Belanger A. Update on fibrinogen as a cardiovascular risk factor.  Ann Epidemiol . 1992;  2 457-466
    PubMedGoogle Scholar
  • 18 Tracy R P. Hemostatic and inflammatory markers as risk factors for coronary disease in the elderly.  Am J Geriatr Cardiol . 2002;  11 93-100
    CrossrefPubMedGoogle Scholar
  • 19 Ershler W B. Interleukin-6: A cytokine for gerontologists.  J Am Geriatr Soc . 1993;  41 176-181
    CrossrefPubMedGoogle Scholar
  • 20 Gulledge A A, Rezaee F, Verheijen J H, Lord S T. A novel transgenic mouse model of hyperfibrinogenemia.  Thromb Haemost . 2001;  86 511-516
    PubMedGoogle Scholar
  • 21 Brozovíc M, Chakrabarti R, Stirling Y. Factor V in an industrial population.  Br J Haematol . 1976;  33 543-550
    PubMedGoogle Scholar
  • 22 Conlan M G, Folsom A R, Finch A. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study.  Thromb Haemost . 1993;  70 380-385
    PubMedGoogle Scholar
  • 23 Köster T, Blann D, Briët E, Vandenbroucke J P, Rosendaal F R. Role of clotting factor VIII and effect of von Willebrand factor on occurrence of deep-vein thrombosis.  Lancet . 1995;  345 152-155
    CrossrefPubMedGoogle Scholar
  • 24 Lowe G D, Rumley A, Woodward M. Epidemiology of coagulation factors, inhibitors and activation markers: the third Glasgow MONICA survey. I. Illustrative reference ranges by age, sex and hormone use.  Br J Haematol . 1997;  97 775-784
    CrossrefPubMedGoogle Scholar
  • 25 Tracy R P, Arnold A M, Ettinger W. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly. Results from the Cardiovascular Health Study.  Arterioscler Thromb Vasc Biol . 1999;  19 1776-1783
    CrossrefPubMedGoogle Scholar
  • 26 Sweeney J D, Hoerning L A. Age dependent effect on the level of factor IX.  Am J Clin Pathol . 1993;  687-688
    PubMedGoogle Scholar
  • 27 Ofosu F A, Craven S, Dewar L. Age-related changes in factor VII proteolysis in vivo.  Br J Haemotol . 1996;  94 407-412
    CrossrefPubMedGoogle Scholar
  • 28 Bauer K A, Weiss L M, Sparrow D, Vokonas P S, Rosenberg R D. Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study.  J Clin Invest . 1987;  80 1527-1534
    CrossrefPubMedGoogle Scholar
  • 29 Ariëns R A, Kohler H P, Mansfield M W, Grant P J. Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals. Relation to sex, age, smoking, and hypertension.  Arterioscler Thromb Vasc Biol . 1999;  19 2012-2016
    CrossrefPubMedGoogle Scholar
  • 30 Cushman M, Psaty B M, Macy E. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease.  Arterioscler Thromb Vasc Biol . 1996;  16 1163-1169
    PubMedGoogle Scholar
  • 31 Mari D, Mannucci P M, Coppola R. Hypercoagulability in centenarians: the paradox of successful aging.  Blood . 1995;  85 3144-3149
    PubMedGoogle Scholar
  • 32 Ofosu F A, Craven S, Dewar L. Age-related changes in factor VII proteolysis in vivo.  Br J Haematol . 1996;  94 407-412
    CrossrefPubMedGoogle Scholar
  • 33 Dolan G, Neal K, Cooper P, Brown P, Preston F E. Protein C, antithrombin III and plasminogen: effect of age, sex and blood group.  Br J Haematol . 1994;  86 798-803
    CrossrefPubMedGoogle Scholar
  • 34 Sakkinen P A, Cushman M, Psaty B M. Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.  Thromb Haemost . 1998;  80 134-139
    PubMedGoogle Scholar
  • 35 Ariëns R A, Coppola R, Potenza I, Mannucci P M. The increase with age of the components of the tissue factor coagulation pathway is gender-dependent.  Blood Coagul Fibrinolysis . 1995;  6 433-437
    CrossrefPubMedGoogle Scholar
  • 36 Gleerup G, Winther K. The effect of ageing on platelet function and fibrinolytic activity.  Angiology . 1995;  46 715-718
    CrossrefPubMedGoogle Scholar
  • 37 Mehta J, Mehta P, Lawson D, Saldeen T. Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations.  J Am Coll Cardiol . 1987;  9 263-268
    CrossrefPubMedGoogle Scholar
  • 38 Healy A M, Gelehrter T D. Induction of plasminogen activator inhibitor-1 in HepG2 human hepatoma cells by mediators of the acute phase response.  J Biol Chem . 1994;  269 19095-19100
    PubMedGoogle Scholar
  • 39 Koike C, Hayakawa Y, Niiya K, Sakuragawa N, Sasaki H. The production of heparin cofactor II is not regulated by inflammatory cytokines in human hepatoma cells: comparison with plasminogen activator inhibitor type-1.  Thromb Haemost . 1996;  75 298-302
    PubMedGoogle Scholar
  • 40 Seki T, Gelehrter T D. Interleukin-1 induction of type-1 plasminogen activator inhibitor (PAI-1) gene expression in the mouse hepatocyte line, AML 12.  J Cell Physiol . 1996;  168 648-656
    CrossrefPubMedGoogle Scholar
  • 41 Loskutoff D J, Samad F. The adipocyte and haemostatic balance in obesity: studies of PAI-1.  Arterioscler Thromb Vasc Biol . 1998;  18 1-6
    CrossrefPubMedGoogle Scholar
  • 42 Juhan-Vague I, Alessi M C, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis.  Diabetologia . 1991;  34 457-462
    CrossrefPubMedGoogle Scholar
  • 43 Cushman M, Lemaitre R N, Kuller L H. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study.  Arterioscler Thromb Vasc Biol . 1999;  19 493-498
    CrossrefPubMedGoogle Scholar
  • 44 Juhan-Vague I, Alessi M C. PAI-1, obesity, insulin resistance and risk of cardiovascular events.  Thromb Haemost . 1997;  78 656-660
    PubMedGoogle Scholar
  • 45 Yamamoto K, Takeshita K, Shimokawa T. Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals.  Proc Natl Acad Sci USA . 2002;  99 890-895
    CrossrefPubMedGoogle Scholar
  • 46 Eren M, Painter C A, Atkinson J B, Declerck P J, Vaughn D E. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1.  Circulation . 2002;  106 491-496
    CrossrefPubMedGoogle Scholar
  • 47 Sakkinen P A, Wahl P, Cushman M, Lewis M R, Tracy R P. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome.  Am J Epidemiol . 2000;  152 897-907
    CrossrefPubMedGoogle Scholar
  • 48 Sakkinen P A, Cushman M, Psaty B M. Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.  Arterioscler Thromb Vasc Biol . 1999;  19 499-504
    CrossrefPubMedGoogle Scholar
  • 49 Tracy R P, Psaty B M, Macy E. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.  Arterioscler Thromb Vasc Biol . 1997;  17 2167-2176
    PubMedGoogle Scholar
  • 50 Bajzar L, Manuel R, Nesheim M. Purification and characterization of TAFI, a thrombin-activatable fibrinolysis inhibitor.  J Biol Chem . 1995;  270 14477-1448
    CrossrefPubMedGoogle Scholar
  • 51 Schatteman K A, Goossens F J, Scharpe S S, Neels H M, Hendriks D F. Assay of procarboxypeptidase U, a novel determinant of the fibrinolytic cascade, in human plasma.  Clin Chem . 1999;  45 807-813
    PubMedGoogle Scholar
  • 52 Juhan-Vague I, Renucci J F, Grimaux M. Thrombin-activatable fibrinolysis inhibitor antigen levels and cardiovascular risk factors.  Arterioscler Thromb Vasc Biol . 2000;  20 2156-2161
    PubMedGoogle Scholar
  • 53 Vlieg A VH, van der Linden K I, Bertina R M, Rosendaal F R. High levels of factor IX increase the risk of venous thrombosis.  Blood . 2000;  95 3678-3682
    PubMedGoogle Scholar
  • 54 Chotteau-Lelièvre A, Desbiens X, Pekzar H, Defossez P-A, de Launoit Y. Differential expression patterns of the PEA3 group transcription factors through murine embryonic development.  Oncogene . 1997;  15 937-952
    CrossrefPubMedGoogle Scholar
  • 55 Kurachi K, Kurachi S. Genetic mechanisms of age regulation of blood coagulation. Factor IX model.  Arterioscler Thromb Vasc Biol . 2002;  20 902-906
    PubMedGoogle Scholar
  • 56 Zhang K, Kurachi S, Kurachi K. Genetic mechanisms of age regulation of protein C and blood coagulation.  J Biol Chem . 2002;  277 4532-4540
    CrossrefPubMedGoogle Scholar
  • 57 Samani N J, Boultby R, Butler R, Thompson J R, Goodall A H. Telomere shortening in atherosclerosis.  Lancet . 2001;  358 472-473
    CrossrefPubMedGoogle Scholar
  • 58 Solum N O. Procoagulant expression in platelets and defects leading to clinical disorders.  Arterioscler Thromb Vasc Biol . 1999;  19 2841-2846
    PubMedGoogle Scholar
  • 59 Jørgensen K A, Dyerberg J, Olessen A S, Stoffersen E. Acetylsalicylic acid, bleeding time and age.  Thromb Res . 1980;  19 799-805
    CrossrefPubMedGoogle Scholar
  • 60 Zahavi J, Jones N AG, Leyton J, Dubiel M, Kakkar V V. Enhanced in vivo "platelet reaction" in old healthy individuals.  Thromb Res . 1980;  17 329-336
    CrossrefPubMedGoogle Scholar
  • 61 Kasjanovova D, Balaz V. Age-related changes in human platelet function in vitro.  Mech Ageing Dev . 1986;  37 175-182
    CrossrefPubMedGoogle Scholar
  • 62 Bastyr 3rd J E, Kadrofske M M, Vinik A I. Platelet activity and phosphoinositide turnover increase with advancing age.  Am J Med . 1990;  88 601-606
    CrossrefPubMedGoogle Scholar
  • 63 Reilly I AG, FitzGerald G A. Eicosagnoid biosynthesis and platelet function with advancing age.  Thromb Res . 1986;  41 545-554
    CrossrefPubMedGoogle Scholar
  • 64 Modesti P A, Fortini A, Abbate R, Gensini G F. Age related changes of platelet prostacyclin receptors in humans.  Eur J Clin Invest . 1985;  15 204-208
    CrossrefPubMedGoogle Scholar
  • 65 Renuad S, De Backer G, Thevenon C. Platelet fatty acids and function in two distinct regions of Belgium: relationship to age and dietary habits.  J Intern Med . 1991;  229 79-88
    PubMedGoogle Scholar
  • 66 Prisco D, Rogasi G, Matucci M. Age related changes in platelet lipid composition.  Thromb Res . 1986;  44 427-437
    CrossrefPubMedGoogle Scholar
  • 67 Lakotta E G, Mitchell J H, Pomerance A, Rowe G G. Human aging: changes in structure and function.  J Am Coll Cardiol . 1987;  10 42A-47A
    PubMedGoogle Scholar
  • 68 Hanon O, Luong V u, Mourad J J. Aging, carotid artery distensibility, and the Ser422Gly elastic gene polymorphism in humans.  Hypertension . 2001;  38 1185-1189
    PubMedGoogle Scholar
  • 69 Lajemi M, Labat C, Gautier S. Angiotensin II type 1 receptor -153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects.  J Hypertension . 2001;  19 407-413
    PubMedGoogle Scholar
  • 70 Kiechl S, Willeit J. The natural course of atherosclerosis. Part II: vascular remodeling.  Arterioscler Thromb Vasc Biol . 1999;  19 1491-1498
    CrossrefPubMedGoogle Scholar
  • 71 Schoenhagen P, Vince D G, Ziada K M. Relation of matrix-metalloproteinase 3 found in coronary lesion samples retrieved by directional coronary atherectomy to intravascular ultrasound observations on coronary remodeling.  Am J Cardiol . 2002;  89 1354-1359
    CrossrefPubMedGoogle Scholar
  • 72 Wang M, Lakatta E G. Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging.  Hypertension . 2002;  39 865-873
    CrossrefPubMedGoogle Scholar
  • 73 Lee R T, Libby P. The unstable atheroma.  Arterioscler Thromb Vasc Biol . 1997;  17 1859-1867
    PubMedGoogle Scholar
  • 74 Loftus I M, Naylor A R, Bell P R, Thompson M M. Plasma MMP-9: a marker of carotid plaque instability.  Eur J Vasc Endovasc Surg . 2001;  21 17-21
    CrossrefPubMedGoogle Scholar
  • 75 Fronek A, Criqui M H, Denenberg J, Langer R D. Common femoral vein dimensions and hemodynamics including Valsalva response as a function of sex, age, and ethnicity in a population study.  J Vasc Surg . 2001;  33 1050-1056
    CrossrefPubMedGoogle Scholar
  • 76 Otsuka H, Nakase H, Nagata K. Effect of age on cerebral venous circulation disturbances in the rat.  J Neurosurg . 2000;  93 298-304
    CrossrefPubMedGoogle Scholar
  • 77 Feyzi E, Saldeen T, Larsson E, Lindahl U, Salmivirta M. Age-dependent modulation of heparan sulfate structure and function.  J Biol Chem . 1998;  273 13395-13398
    CrossrefPubMedGoogle Scholar
  • 78 Atha D H, Stephens A W, Rosenberg R D. Evaluation of critical groups required for the binding of heparin to antithrombin.  Proc Natl Acad Sci USA . 1984;  81 1030-1034
    PubMedGoogle Scholar
  • 79 Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K. Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin.  Blood . 1999;  93 157-164
    PubMedGoogle Scholar
  • 80 Yamauchi T, Umeda F, Inoguchi T, Nawata H. Antithrombin III stimulates prostacyclin production by cultured aortic endothelial cells.  Biochem Biophy Res Commun . 1989;  163 1404-1411
    CrossrefPubMedGoogle Scholar
  • 81 Jörres A, Dinter H, Topley N. Inhibition of tumor necrosis factor production in endotoxin-stimulated human mononuclear leukocytes by the prostacyclin analogue iloprost: cellular mechanisms.  Cytokine . 1997;  9 119-125
    CrossrefPubMedGoogle Scholar
  • 82 Slungaard A, Key N S. Platelet factor 4 stimulates thrombomodulin protein C-activating cofactor activity. A structure-function analysis.  J Biol Chem . 1994;  269 25549-25556
    PubMedGoogle Scholar
  • 83 Celermajer D S, Sorensen K E, Spiegelhalter D J. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women.  J Am Coll Cardiol . 1994;  24 471-476
    PubMedGoogle Scholar
  • 84 Celermajer D S, Sorensen K E, Bull C, Robinson J, Deanfield J E. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interactions.  J Am Coll Cardiol . 1994;  24 1468-1474
    CrossrefPubMedGoogle Scholar
  • 85 Chou T-C, Yen M-H, Li C-Y, Ding Y-A. Alterations of nitric oxide synthase expression with aging and hypertension.  Hypertension . 1998;  31 643-648
    CrossrefPubMedGoogle Scholar
  • 86 Taddei S, Virdis A, Ghiadoni L. Age-related reduction of NO availability and oxidative stress in humans.  Hypertension . 2001;  38 274-279
    PubMedGoogle Scholar
  • 87 Wilcox J N, Subramanian R R, Sundell C L. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels.  Arterioscler Thromb Vasc Biol . 1997;  17 2479-2488
    CrossrefPubMedGoogle Scholar
  • 88 Tschudi M R, Barton M, Bersinger N A. Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery.  J Clin Invest . 1996;  98 899-905
    PubMedGoogle Scholar
  • 89 Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis.  Circ Res . 2001;  88 756-762
    CrossrefPubMedGoogle Scholar
  • 90 Garg U C, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells.  J Clin Invest . 1989;  83 1774-1777
    CrossrefPubMedGoogle Scholar
  • 91 Radomski M W, Palmer R M, Moncada S. The anti-aggregating properties of vascular endothelium: Interactions between prostacyclin and nitric oxide.  Br J Pharmacol . 1987;  92 639-646
    CrossrefPubMedGoogle Scholar
  • 92 Bath P M, Hassall D G, Gladwin A M, Palmer R M, Martin J F. Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro.  Arterioscler Thromb . 1991;  11 254-260
    PubMedGoogle Scholar
  • 93 Hogg N, Kalyanaraman B, Joseph J, Struck A, Partasaraty S. Inhibition of low-density lipoprotein oxidation by nitric oxide.  FEBS Lett . 1993;  334 170-174
    CrossrefPubMedGoogle Scholar
  • 94 Dimmeler S, Haendeler J, Nehls M, Zeiher A M. Suppression of apoptosis by nitric oxide via inhibition of interleukin-1β-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases.  J Exp Med . 1997;  185 601-608
    CrossrefPubMedGoogle Scholar
  • 95 Mannick J B, Hausladen A, Liu L. Fas-induced caspase denitrosylation.  Science . 1999;  284 651-654
    CrossrefPubMedGoogle Scholar
  • 96 Li J, Billiar T R, Talanian R V, Kim Y M. Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation.  Biochem Biophys Res Commun . 1997;  240 419-424
    CrossrefPubMedGoogle Scholar
  • 97 Hoffmann J, Haendeler J, Aicher A. Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli. Important role of nitric oxide.  Circ Res . 2001;  89 709-715
    PubMedGoogle Scholar
  • 98 Bombeli T, Karsan A, Tait J F, Harlan J M. Apoptotic vascular endothelial cells become procoagulant.  Blood . 1997;  89 2429-2442
    PubMedGoogle Scholar
  • 99 Miyazaki H, Matsuoka H, Cooke J P. Endogenous nitric oxide synthase inhibitor. A novel marker of atherosclerosis.  Circulation . 1999;  99 1141-1146
    CrossrefPubMedGoogle Scholar
  • 100 Boger R H, Bode-Boger S M. Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases.  Semin Thromb Haemost . 2000;  26 539-545
    PubMedGoogle Scholar
  • 101 Corpas E, Harman S M, Blackman M R. Human growth hormone and human aging.  Endocrinol Rev . 1993;  14 20-39
    CrossrefPubMedGoogle Scholar
  • 102 Chugh S S, Blackshear J L, Shen W K, Hammill S C, Gersh B J. Epidemiology and natural history of atrial fibrillation: clinical implications.  J Am Coll Cardiol . 2001;  37 371-378
    CrossrefPubMedGoogle Scholar
  • 103 Hart R G, Halperin J L. Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention.  Ann Intern Med . 1999;  131 688-695
    PubMedGoogle Scholar
  • 104 Hart R G, Pearce L A, Rothbort R L. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy.  J Am Coll Cardiol . 2000;  35 183-187
    CrossrefPubMedGoogle Scholar
  • 105 Papanicolau D A, Wilder R L, Manolagas S C, Chrousos G P. The pathophysiologic roles of interleukin-6 in human disease.  Ann Intern Med . 1998;  128 127-137
    PubMedGoogle Scholar
  • 106 Ershler W B. Interleukin-6: a cytokine for gerontologists.  J Am Geriatr Soc . 1993;  41 176-181
    CrossrefPubMedGoogle Scholar
  • 107 Ershler W B, Sun W H, Binkley N. Interleukin-6 and aging: Blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction.  Lymphokine Cytokine Res . 1993;  12 225-230
    PubMedGoogle Scholar
  • 108 Heinrich P C, Castell J V, Andus T. Interleukin-6 and the acute phase response.  Biochem J . 1990;  265 621-636
    PubMedGoogle Scholar
  • 109 Bataille R, Klein B. C-reactive protein levels as a direct indicator of interleukin-6 levels in humans in vivo.  Arthritis Rheumatol . 1992;  35 982-983
    PubMedGoogle Scholar
  • 110 Mestries J-C, Kruithof E KO, Gascon M-P. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons.  Eur Cytokine Network . 1994;  5 275-281
    PubMedGoogle Scholar
  • 111 Niessen R W, Lamping R J, Jansen P M. Antithrombin acts as a negative acute phase protein as established with studies on HepG2 cells and in baboons.  Thromb Haemost . 1997;  78 1088-1092
    PubMedGoogle Scholar
  • 112 Ferrucci L, Harris T B, Guralnik J M. Serum IL-6 level and the development of disability in older persons.  J Am Geriatr Soc . 1999;  47 639-646
    PubMedGoogle Scholar
  • 113 Harris T B, Ferrucci L, Tracy R P. Associations of elevated interleukin-6 and C-reactive protein levels in mortality in the elderly.  Am J Med . 1999;  106 506-512
    CrossrefPubMedGoogle Scholar
  • 114 Delpedro A D, Barjavel M J, Mamdouh Z, Faure S, Bakouche O. Signal transduction in LPS-activated aged and young monocytes.  J Interferon Cytokine Res . 1998;  18 429-437
    PubMedGoogle Scholar
  • 115 Belmin J, Bernard C, Corman B. Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats.  Am J Physiol . 1995;  268 H2288-H2293
    PubMedGoogle Scholar
  • 116 Saito H, Papaconstantinou J. Age-associated differences in cardiovascular inflammatory gene induction during endotoxic stress.  J Biol Chem . 2001;  276 29307-29312
    CrossrefPubMedGoogle Scholar
  • 117 Soslau G, Morgan D A, Jaffe J S, Brodsky I, Wang Y. Cytokine mRNA expression in human platelets and a megakaryocytic cell line and cytokine modulation of platelet function.  Cytokine . 1997;  9 405-411
    CrossrefPubMedGoogle Scholar
  • 118 Burstein S A. Effects of interleukin 6 on megakaryocytes and on canine platelet function.  Stem Cells . 1994;  12 386-393
    PubMedGoogle Scholar
  • 119 van der Poll T, Levi M, Hack E. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees.  J Exp Med . 1994;  179 1253-1259
    CrossrefPubMedGoogle Scholar
  • 120 Stouthard J M, Levi M, Hack C E. Interleukin-6 stimulates coagulation, not fibrinolysis in humans.  Thromb Haemost . 1996;  76 738-742
    PubMedGoogle Scholar
  • 121 Pepys M B, Baltz M L. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein.  Adv Immunol . 1983;  34 141-142
    PubMedGoogle Scholar
  • 122 Cermak J, Key N S, Bach R R. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor.  Blood . 1993;  82 513-520
    PubMedGoogle Scholar
  • 123 Yasojima K, Schwab C, McGeer E G, McGeer P L. Generation of C-reative protein and complement components in atherosclerotic plaques.  Am J Pathol . 2001;  158 1039-1051
    CrossrefPubMedGoogle Scholar
  • 124 Torzewski M, Rist C, Mortensen R F. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis.  Arterioscler Thromb Vasc Biol . 2000;  20 2094-2099
    CrossrefPubMedGoogle Scholar
  • 125 Esmon C T. Does inflammation contribute to thrombotic events?.  Haemostasis . 2000;  30 34-40
    CrossrefPubMedGoogle Scholar
  • 126 Wen F Q, Watanabe K, Yoshida M. Inhibitory effects of interleukin-6 on release of PGI2 by cultured human pulmonary artery smooth muscle cells.  Prostaglandins . 1996;  52 93-102
    CrossrefPubMedGoogle Scholar
  • 127 Ritchie D G, Levy B A, Adams M A, Fuller G M. Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.  Proc Natl Acad Sci USA . 1982;  79 1530-1534
    PubMedGoogle Scholar
  • 128 Wang Y, Fuller G M. The putative role of fibrin fragments in the biosynthesis of fibrinogen by hepatoma cells.  Biochem Biophys Res Commun . 1991;  175 562-567
    CrossrefPubMedGoogle Scholar
  • 129 Moustapha A, Robinson K. Homocysteine: An emerging age-related cardiovascular risk factor.  Geriatrics . 1999;  54 49-63
    PubMedGoogle Scholar
  • 130 Durand P, Prost M, Loreau N, Lussier-Cacan S, Blache D. Impaired homocysteine metabolism and atherothrombotic disease.  Lab Invest . 2001;  81 645-672
    PubMedGoogle Scholar
  • 131 Selhub J, Pacques P F, Wilson P WF, Rush D, Rosenberg I H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population.  JAMA . 1993;  270 2693-2698
    CrossrefPubMedGoogle Scholar
  • 132 Kario K, Matsuo T, Kobayashi H. Heparin cofactor II deficiency in the elderly: comparison with antithrombin III.  Thromb Res . 1992;  66 489-498
    CrossrefPubMedGoogle Scholar
  • 133 Mannucci P M, Mari D, Merati G. Gene polymorphisms predicting high plasma levels of coagulation and fibrinolysis proteins.  Arterioscler Thromb Vasc Biol . 1997;  17 755-759
    PubMedGoogle Scholar
  • 134 Schachter F, Faure-Delanef L. Genetic associations with human longevity at the APOE and ACE loci.  Nat Genet . 1994;  6 29-32
    PubMedGoogle Scholar
  • 135 Thun M J, Wingo P A. Cancer epidemiology. In: Bast RC Jr, Kute DW, Pollock RE, et al., eds. Cancer Medicine, 5th ed Hamilton, Ontario: BC Decker 2000: 283-297
    Google Scholar
  • 136 Kreisle R A, Stebler B A, Ershler W B. Effect of host age on tumor-associated angiogenesis in mice.  J Natl Cancer Inst . 1990;  82 44-47
    PubMedGoogle Scholar
  • 137 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem . 2000;  275 1521-1524
    CrossrefPubMedGoogle Scholar
  • 138 Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application.  Thromb Haemost . 2001;  86 23-33
    PubMedGoogle Scholar
  • 139 Jang J J, Ho H-KV, Kwan H H, Fajardo L F, Cooke J P. Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine.  Circulation . 2000;  102 1414-1419
    CrossrefPubMedGoogle Scholar
  • 140 Nagi Y, Tasaki H, Takatsu H. Homocysteine inhibits angiogenesis in vitro and in vivo.  Biochem Biophys Res Commun . 2001;  281 726-731
    CrossrefPubMedGoogle Scholar
  • 141 Duan J, Murohara T, Ikeda H. Hyperhomocysteinemia impairs angiogenesis in response to hindlimb ischemia.  Arterioscler Thromb Vasc Biol . 2000;  20 2579-2585
    PubMedGoogle Scholar
  • 142 White R H, McBurnie M A, Manolio T. Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort.  Am J Med . 1999;  106 165
    CrossrefPubMedGoogle Scholar
  • 143 Gurwitz J H, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy.  Ann Intern Med . 1992;  116 901-904
    CrossrefPubMedGoogle Scholar
  • 144 Campbell N R, Hull R D, Brant R. Aging and heparin-related bleeding.  Arch Intern Med . 1996;  156 857-860
    CrossrefPubMedGoogle Scholar
  • 145 Rosenson R S, Tangney C C. Antiatherothombotic properties of statins. Implications for cardiovascular event reduction.  JAMA . 1998;  279 1643-1650
    CrossrefPubMedGoogle Scholar
  • 146 Cipollone F, Mezzetti A, Porreca E. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia. Effects of statin therapy.  Circulation . 2002;  106 399-402
    CrossrefPubMedGoogle Scholar
  • 147 Ray J G, Mamdani M, Tsuyuki R T. Use of statins and the subsequent development of deep vein thrombosis.  Arch Intern Med . 2001;  161 1405-1410
    CrossrefPubMedGoogle Scholar
  • 148 Herrington D M, Vittinghoff E, Lin F. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS).  Circulation . 2002;  105 2962-2967
    CrossrefPubMedGoogle Scholar
  • 149 Lemaitre R N, Furberg C D, Newman A B. Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.  Arch Intern Med . 1998;  158 1761-1768
    CrossrefPubMedGoogle Scholar
  • 150 Benner J S, Glynn R J, Mogun H. Long-term persistence in use of statin therapy in elderly patients.  JAMA . 2002;  288 455-461
    CrossrefPubMedGoogle Scholar
  • 151 Jackevicius C A, Mamdani M, Tu J V. Adherence with statin therapy in elderly patients with and without acute coronary syndromes.  JAMA . 2002;  288 462-467
    CrossrefPubMedGoogle Scholar
  • 152 Lemaitre R N, Psaty B M, Heckbert S R. Therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study.  Arch Intern Med . 2002;  162 1395-1400
    CrossrefPubMedGoogle Scholar
  • 153 Grundy S M. Statin therapy in older persons: pertinent issues.  Arch Intern Med . 2002;  162 1329-1331
    CrossrefPubMedGoogle Scholar
  • 154 Wannamethee S G, Lowe G DO, Whincup P H. Physical activity and hemostatic and inflammatory variables in elderly men.  Circulation . 2002;  105 1785-1790
    CrossrefPubMedGoogle Scholar
  • 155 Geffken D F, Cushman M, Burke G. Association between physical activity and markers of inflammation in a healthy elderly population.  Am J Epidemiol . 2001;  153 242-250
    CrossrefPubMedGoogle Scholar
  • 156 Stratton J, Chandler W L, Schwartz R S. Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults.  Circulation . 1991;  83 1692-1697
    CrossrefPubMedGoogle Scholar
  • 157 Gonzales F, Mañas M, Seiquer I. Blood platelet function in healthy individuals of different ages. Effects of exercise and exercise conditioning.  J Sports Med Phys Fitness . 1996;  36 112-116
    PubMedGoogle Scholar
  • 158 Taddei S, Galetta F, Virdis A. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes.  Circulation . 2000;  101 2896-2901
    CrossrefPubMedGoogle Scholar
  • 159 Mokdad A H, Serdula M K, Dietz W H. The spread of the obesity epidemic in the United States, 1991-1998.  JAMA . 1999;  282 1519-1522
    CrossrefPubMedGoogle Scholar
  • 160 McGill H C, McMahan C A, Herderick E E. Obesity accelerates the progression of atherosclerosis in young men.  Circulation . 2002;  105 2712-2718
    CrossrefPubMedGoogle Scholar
  • 161 Mavri A, Alessi M C, Bastelica D. Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss.  Diabetologia . 2001;  44 2025-2031
    CrossrefPubMedGoogle Scholar
  • 162 Shimomura I, Funahashi T, Takahashi M. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.  Nature Med . 1996;  2 800-803
    CrossrefPubMedGoogle Scholar
  • 163 Chung H Y, Kim H J, Kim J W, Yu B P. The inflammation hypothesis of aging. Molecular modulation by calorie restriction.  Ann NY Acad Sci . 2001;  928 327-335
    PubMedGoogle Scholar
  • 164 Ershler W B, Sun W H, Binkley N. Interleukin-6 and aging: Blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction.  Lymphokine Cytokine Res . 1993;  12 225-230
    PubMedGoogle Scholar
  • 165 Yudkin J S, Kumari M, Humphries S E, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?.  Atherosclerosis . 2000;  148 209-214
    CrossrefPubMedGoogle Scholar
  • 166 Kern P A, Saghizadeh M, Ong J M. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase.  J Clin Invest . 1995;  95 2111-2119
    CrossrefPubMedGoogle Scholar
  • 167 Loskutoff D J, Samad F. The adipocyte and hemostatic balance in obesity: studies of PAI-1.  Arterioscler Thromb Vasc Biol . 1998;  18 1-6
    CrossrefPubMedGoogle Scholar
  • 168 Mohamed-Ali V, Goodrick S, Rawesh A. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo.  J Clin Endocrinol Metabol . 1997;  82 4196-4200
    CrossrefPubMedGoogle Scholar
  • 169 Yudkin J S, Stehouwer C DA, Emeis J J, Coppack S W. C-reactive protein in healthy subjects: association with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?.  Arterioscler Thromb Vasc Biol . 1999;  19 972-978
    CrossrefPubMedGoogle Scholar
  • 170 Fried S K, Bunkin D A, Greenberg A S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.  J Clin Endocrinol Metabol . 1998;  83 847-850
    CrossrefPubMedGoogle Scholar
  • 171 Pieper C F, Rao K M, Currie M S, Harris T B, Chen H J. Age, functional status, and racial differences in plasma D-dimer levels in community-dwelling elderly persons.  J Gerontol A Biol Sci Med Sci . 2000;  55 M649-M657
    PubMedGoogle Scholar