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
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
21. Januar 2003 (online)

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.

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
  • 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
  • 3 Martinelli I. Risk factors for venous thromboembolism.  Thromb Haemost . 2001;  86 395-403
  • 4 Heit J A, Silverstein M D, Mohr D N. The epidemiology of venous thromboembolism in the community.  Thromb Haemost . 2001;  86 452-463
  • 5 American Heart Association 2001 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association 2000
  • 6 National Center for Health Statistics. Advanced Report of Final Mortality Statistics, 1987.  Hyattsville, MD: Public Health Service 1989
  • 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
  • 8 Tracy R P, Bovill E G. Thrombosis and cardiovascular risk in the elderly.  Arch Pathol Lab Med . 1992;  16 1307-1312
  • 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
  • 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
  • 11 Meade T, North W R, Chakrabarti R. Haemotatic function and cardiovascular death: elderly results of a prospective study.  Lancet . 1980;  1 1050-1054
  • 12 Stone M, Thorp J. Plasma fibrinogen-a major coronary risk factor.  J R Coll Gen Pract . 1985;  35 565-569
  • 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
  • 14 Kannel W, Wolf P, Castelli W. Fibrinogen and risk of cardiovascular disease: the Framingham study.  JAMA . 1987;  285 1183-1186
  • 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
  • 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
  • 17 Kannel W, D'Agustino R, Belanger A. Update on fibrinogen as a cardiovascular risk factor.  Ann Epidemiol . 1992;  2 457-466
  • 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
  • 19 Ershler W B. Interleukin-6: A cytokine for gerontologists.  J Am Geriatr Soc . 1993;  41 176-181
  • 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
  • 21 Brozovíc M, Chakrabarti R, Stirling Y. Factor V in an industrial population.  Br J Haematol . 1976;  33 543-550
  • 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
  • 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
  • 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
  • 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
  • 26 Sweeney J D, Hoerning L A. Age dependent effect on the level of factor IX.  Am J Clin Pathol . 1993;  687-688
  • 27 Ofosu F A, Craven S, Dewar L. Age-related changes in factor VII proteolysis in vivo.  Br J Haemotol . 1996;  94 407-412
  • 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
  • 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
  • 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
  • 31 Mari D, Mannucci P M, Coppola R. Hypercoagulability in centenarians: the paradox of successful aging.  Blood . 1995;  85 3144-3149
  • 32 Ofosu F A, Craven S, Dewar L. Age-related changes in factor VII proteolysis in vivo.  Br J Haematol . 1996;  94 407-412
  • 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
  • 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
  • 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
  • 36 Gleerup G, Winther K. The effect of ageing on platelet function and fibrinolytic activity.  Angiology . 1995;  46 715-718
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 44 Juhan-Vague I, Alessi M C. PAI-1, obesity, insulin resistance and risk of cardiovascular events.  Thromb Haemost . 1997;  78 656-660
  • 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
  • 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
  • 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
  • 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
  • 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
  • 50 Bajzar L, Manuel R, Nesheim M. Purification and characterization of TAFI, a thrombin-activatable fibrinolysis inhibitor.  J Biol Chem . 1995;  270 14477-1448
  • 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
  • 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
  • 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
  • 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
  • 55 Kurachi K, Kurachi S. Genetic mechanisms of age regulation of blood coagulation. Factor IX model.  Arterioscler Thromb Vasc Biol . 2002;  20 902-906
  • 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
  • 57 Samani N J, Boultby R, Butler R, Thompson J R, Goodall A H. Telomere shortening in atherosclerosis.  Lancet . 2001;  358 472-473
  • 58 Solum N O. Procoagulant expression in platelets and defects leading to clinical disorders.  Arterioscler Thromb Vasc Biol . 1999;  19 2841-2846
  • 59 Jørgensen K A, Dyerberg J, Olessen A S, Stoffersen E. Acetylsalicylic acid, bleeding time and age.  Thromb Res . 1980;  19 799-805
  • 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
  • 61 Kasjanovova D, Balaz V. Age-related changes in human platelet function in vitro.  Mech Ageing Dev . 1986;  37 175-182
  • 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
  • 63 Reilly I AG, FitzGerald G A. Eicosagnoid biosynthesis and platelet function with advancing age.  Thromb Res . 1986;  41 545-554
  • 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
  • 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
  • 66 Prisco D, Rogasi G, Matucci M. Age related changes in platelet lipid composition.  Thromb Res . 1986;  44 427-437
  • 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
  • 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
  • 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
  • 70 Kiechl S, Willeit J. The natural course of atherosclerosis. Part II: vascular remodeling.  Arterioscler Thromb Vasc Biol . 1999;  19 1491-1498
  • 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
  • 72 Wang M, Lakatta E G. Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging.  Hypertension . 2002;  39 865-873
  • 73 Lee R T, Libby P. The unstable atheroma.  Arterioscler Thromb Vasc Biol . 1997;  17 1859-1867
  • 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
  • 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
  • 76 Otsuka H, Nakase H, Nagata K. Effect of age on cerebral venous circulation disturbances in the rat.  J Neurosurg . 2000;  93 298-304
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 86 Taddei S, Virdis A, Ghiadoni L. Age-related reduction of NO availability and oxidative stress in humans.  Hypertension . 2001;  38 274-279
  • 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
  • 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
  • 89 Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis.  Circ Res . 2001;  88 756-762
  • 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
  • 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
  • 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
  • 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
  • 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
  • 95 Mannick J B, Hausladen A, Liu L. Fas-induced caspase denitrosylation.  Science . 1999;  284 651-654
  • 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
  • 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
  • 98 Bombeli T, Karsan A, Tait J F, Harlan J M. Apoptotic vascular endothelial cells become procoagulant.  Blood . 1997;  89 2429-2442
  • 99 Miyazaki H, Matsuoka H, Cooke J P. Endogenous nitric oxide synthase inhibitor. A novel marker of atherosclerosis.  Circulation . 1999;  99 1141-1146
  • 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
  • 101 Corpas E, Harman S M, Blackman M R. Human growth hormone and human aging.  Endocrinol Rev . 1993;  14 20-39
  • 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
  • 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
  • 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
  • 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
  • 106 Ershler W B. Interleukin-6: a cytokine for gerontologists.  J Am Geriatr Soc . 1993;  41 176-181
  • 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
  • 108 Heinrich P C, Castell J V, Andus T. Interleukin-6 and the acute phase response.  Biochem J . 1990;  265 621-636
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 116 Saito H, Papaconstantinou J. Age-associated differences in cardiovascular inflammatory gene induction during endotoxic stress.  J Biol Chem . 2001;  276 29307-29312
  • 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
  • 118 Burstein S A. Effects of interleukin 6 on megakaryocytes and on canine platelet function.  Stem Cells . 1994;  12 386-393
  • 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
  • 120 Stouthard J M, Levi M, Hack C E. Interleukin-6 stimulates coagulation, not fibrinolysis in humans.  Thromb Haemost . 1996;  76 738-742
  • 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
  • 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
  • 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
  • 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
  • 125 Esmon C T. Does inflammation contribute to thrombotic events?.  Haemostasis . 2000;  30 34-40
  • 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
  • 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
  • 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
  • 129 Moustapha A, Robinson K. Homocysteine: An emerging age-related cardiovascular risk factor.  Geriatrics . 1999;  54 49-63
  • 130 Durand P, Prost M, Loreau N, Lussier-Cacan S, Blache D. Impaired homocysteine metabolism and atherothrombotic disease.  Lab Invest . 2001;  81 645-672
  • 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
  • 132 Kario K, Matsuo T, Kobayashi H. Heparin cofactor II deficiency in the elderly: comparison with antithrombin III.  Thromb Res . 1992;  66 489-498
  • 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
  • 134 Schachter F, Faure-Delanef L. Genetic associations with human longevity at the APOE and ACE loci.  Nat Genet . 1994;  6 29-32
  • 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
  • 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
  • 137 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem . 2000;  275 1521-1524
  • 138 Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application.  Thromb Haemost . 2001;  86 23-33
  • 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
  • 140 Nagi Y, Tasaki H, Takatsu H. Homocysteine inhibits angiogenesis in vitro and in vivo.  Biochem Biophys Res Commun . 2001;  281 726-731
  • 141 Duan J, Murohara T, Ikeda H. Hyperhomocysteinemia impairs angiogenesis in response to hindlimb ischemia.  Arterioscler Thromb Vasc Biol . 2000;  20 2579-2585
  • 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
  • 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
  • 144 Campbell N R, Hull R D, Brant R. Aging and heparin-related bleeding.  Arch Intern Med . 1996;  156 857-860
  • 145 Rosenson R S, Tangney C C. Antiatherothombotic properties of statins. Implications for cardiovascular event reduction.  JAMA . 1998;  279 1643-1650
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 153 Grundy S M. Statin therapy in older persons: pertinent issues.  Arch Intern Med . 2002;  162 1329-1331
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 160 McGill H C, McMahan C A, Herderick E E. Obesity accelerates the progression of atherosclerosis in young men.  Circulation . 2002;  105 2712-2718
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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