Semin Thromb Hemost 2010; 36(4): 452-457
DOI: 10.1055/s-0030-1254054
© Thieme Medical Publishers

The Prothrombotic State in Rheumatoid Arthritis: An Additive Risk Factor for Adverse Cardiovascular Events

Radjesh J. Bisoendial1 , Marcel Levi2 , Paul-Peter Tak1 , Eric S. G Stroes3
  • 1Department of Clinical Immunology and Rheumatology, University of Amsterdam, The Netherlands
  • 2Department of Internal Medicine, University of Amsterdam, The Netherlands
  • 3Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands
Further Information

Publication History

Publication Date:
07 July 2010 (online)

ABSTRACT

Rheumatoid arthritis (RA) has been recognized to increase cardiovascular morbidity and mortality independent of established risk factors. The chronic inflammatory state, a hallmark of RA, is considered an autonomous risk factor, whereas components of innate and adaptive immunity are believed to contribute to the onset of acute cardiovascular events. Several studies have suggested that RA confers a prothrombotic state featured by abnormalities in coagulation and fibrinolytic systems together with an altered state of platelet reactivity. It is conceivable that these findings may be partly instrumental for the observed increased risk for adverse cardiovascular events in RA. Therapeutic strategies aimed at attenuating the inflammatory disease activity and intervening at the point of cross-talk between mediators of inflammation and thrombogenesis may help reduce cardiovascular disease burden in patients with RA.

REFERENCES

  • 1 Solomon D H, Karlson E W, Rimm E B et al.. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis.  Circulation. 2003;  107(9) 1303-1307
  • 2 Wolfe F, Mitchell D M, Sibley J T et al.. The mortality of rheumatoid arthritis.  Arthritis Rheum. 1994;  37(4) 481-494
  • 3 Naranjo A, Sokka T, Descalzo M A QUEST-RA Group et al. Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study.  Arthritis Res Ther. 2008;  10(2) R30
  • 4 Bisoendial R J, Stroes E S, Tak P P. Where the immune response meets the vessel wall.  Neth J Med. 2009;  67(8) 328-333
  • 5 Libby P. Inflammation in atherosclerosis.  Nature. 2002;  420(6917) 868-874
  • 6 Blanco-Colio L M, Muñoz-García B, Martín-Ventura J L et al.. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors decrease Fas ligand expression and cytotoxicity in activated human T lymphocytes.  Circulation. 2003;  108(12) 1506-1513
  • 7 Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis.  Circ Res. 2001;  88(8) 756-762
  • 8 Björkerud S, Björkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability.  Am J Pathol. 1996;  149(2) 367-380
  • 9 Flynn P D, Byrne C D, Baglin T P, Weissberg P L, Bennett M R. Thrombin generation by apoptotic vascular smooth muscle cells.  Blood. 1997;  89(12) 4378-4384
  • 10 Butenas S, Orfeo T, Mann K G. Tissue factor in coagulation: Which? Where? When?.  Arterioscler Thromb Vasc Biol. 2009;  29(12) 1989-1996
  • 11 Creager M A, Lüscher T F, Cosentino F, Beckman J A. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I.  Circulation. 2003;  108(12) 1527-1532
  • 12 MacCallum P K, Rudnicka A R, Rumley A, Meade T W, Lowe G D. Low-intensity warfarin reduces thrombin generation and fibrin turnover, but not low-grade inflammation, in men at risk of myocardial infarction.  Br J Haematol. 2004;  127(4) 448-450
  • 13 McEntegart A, Capell H A, Creran D, Rumley A, Woodward M, Lowe G D. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis.  Rheumatology (Oxford). 2001;  40(6) 640-644
  • 14 Wållberg-Jonsson S, Cvetkovic J T, Sundqvist K G, Lefvert A K, Rantapää-Dahlqvist S. Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis.  J Rheumatol. 2002;  29(5) 875-882
  • 15 Ingegnoli F, Fantini F, Favalli E G et al.. Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: effects of tumor necrosis factor-alpha blockade.  J Autoimmun. 2008;  31(2) 175-179
  • 16 Angiolillo D J, Bernardo E, Sabaté M et al.. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease.  J Am Coll Cardiol. 2007;  50(16) 1541-1547
  • 17 Harrison P, Keeling D. Platelet hyperactivity and risk of recurrent thrombosis.  J Thromb Haemost. 2006;  4(12) 2544-2546
  • 18 Riddle J M, Bluhm G B, Pitchford W C et al.. A comparative study of platelet reactivity in arthritis.  Ann N Y Acad Sci. 1981;  370 22-29
  • 19 Wang F, Wang N S, Yan C G, Li J H, Tang L Q. The significance of platelet activation in rheumatoid arthritis.  Clin Rheumatol. 2007;  26(5) 768-771
  • 20 Mac Mullan P A, Peace A J, Madigan A M, Tedesco A F, Kenny D, McCarthy G M. Platelet hyper-reactivity in active inflammatory arthritis is unique to the adenosine diphosphate pathway: a novel finding and potential therapeutic target.  Rheumatology (Oxford). 2010;  49(2) 240-245
  • 21 Levi M, van der Poll T. The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients.  Semin Thromb Hemost. 2008;  34(5) 459-468
  • 22 Kobayashi S, Inoue N, Ohashi Y et al.. Interaction of oxidative stress and inflammatory response in coronary plaque instability: important role of C-reactive protein.  Arterioscler Thromb Vasc Biol. 2003;  23(8) 1398-1404
  • 23 Sattler K J, Woodrum J E, Galili O et al.. Concurrent treatment with renin-angiotensin system blockers and acetylsalicylic acid reduces nuclear factor kappaB activation and C-reactive protein expression in human carotid artery plaques.  Stroke. 2005;  36(1) 14-20
  • 24 Torzewski J, Torzewski M, Bowyer D E et al.. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries.  Arterioscler Thromb Vasc Biol. 1998;  18(9) 1386-1392
  • 25 Yasojima K, Schwab C, McGeer E G, McGeer P L. Generation of C-reactive protein and complement components in atherosclerotic plaques.  Am J Pathol. 2001;  158(3) 1039-1051
  • 26 Turk J R, Carroll J A, Laughlin M H et al.. C-reactive protein correlates with macrophage accumulation in coronary arteries of hypercholesterolemic pigs.  J Appl Physiol. 2003;  95(3) 1301-1304
  • 27 Sun H, Koike T, Ichikawa T et al.. C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.  Am J Pathol. 2005;  167(4) 1139-1148
  • 28 Inoue T, Kato T, Uchida T et al.. Local release of C-reactive protein from vulnerable plaque or coronary arterial wall injured by stenting.  J Am Coll Cardiol. 2005;  46(2) 239-245
  • 29 Verma S, Wang C H, Li S H et al.. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis.  Circulation. 2002;  106(8) 913-919
  • 30 Venugopal S K, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells.  Circulation. 2002;  106(12) 1439-1441
  • 31 Mineo C, Gormley A K, Yuhanna I S et al.. FcgammaRIIB mediates C-reactive protein inhibition of endothelial NO synthase.  Circ Res. 2005;  97(11) 1124-1131
  • 32 Qamirani E, Ren Y, Kuo L, Hein T W. C-reactive protein inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by activating p38 kinase and NAD(P)H oxidase.  Arterioscler Thromb Vasc Biol. 2005;  25(5) 995-1001
  • 33 Venugopal S K, Devaraj S, Jialal I. C-reactive protein decreases prostacyclin release from human aortic endothelial cells.  Circulation. 2003;  108(14) 1676-1678
  • 34 Cermak J, Key N S, Bach R R, Balla J, Jacob H S, Vercellotti G M. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor.  Blood. 1993;  82(2) 513-520
  • 35 Paffen E, Vos H L, Bertina R M. C-reactive protein does not directly induce tissue factor in human monocytes.  Arterioscler Thromb Vasc Biol. 2004;  24(5) 975-981
  • 36 Cirillo P, Golino P, Calabrò P et al.. C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation.  Cardiovasc Res. 2005;  68(1) 47-55
  • 37 Devaraj S, Xu D Y, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis.  Circulation. 2003;  107(3) 398-404
  • 38 Singh U, Devaraj S, Jialal I. C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells. Evidence that C-reactive protein is a procoagulant.  Arterioscler Thromb Vasc Biol. 2005;  25(10) 2216-2221
  • 39 Grad E, Golomb M, Koroukhov N et al.. Aspirin reduces the prothrombotic activity of C-reactive protein.  J Thromb Haemost. 2009;  7(8) 1393-1400
  • 40 Bisoendial R J, Kastelein J J, Peters S L et al.. Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects.  J Lipid Res. 2007;  48(4) 952-960
  • 41 Meek R L, Urieli-Shoval S, Benditt E P. Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: implications for serum amyloid A function.  Proc Natl Acad Sci U S A. 1994;  91(8) 3186-3190
  • 42 Zhao Y, Zhou S, Heng C K. Impact of serum amyloid A on tissue factor and tissue factor pathway inhibitor expression and activity in endothelial cells.  Arterioscler Thromb Vasc Biol. 2007;  27(7) 1645-1650
  • 43 Cai H, Song C, Endoh I et al.. Serum amyloid A induces monocyte tissue factor.  J Immunol. 2007;  178(3) 1852-1860
  • 44 He R, Sang H, Ye R D. Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R.  Blood. 2003;  101(4) 1572-1581
  • 45 Bauer K A, ten Cate H, Barzegar S, Spriggs D R, Sherman M L, Rosenberg R D. Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans.  Blood. 1989;  74(1) 165-172
  • 46 van der Poll T, Büller H R, ten Cate H et al.. Activation of coagulation after administration of tumor necrosis factor to normal subjects.  N Engl J Med. 1990;  322(23) 1622-1627
  • 47 Anderson H D, Rahmutula D, Gardner D G. Tumor necrosis factor-alpha inhibits endothelial nitric-oxide synthase gene promoter activity in bovine aortic endothelial cells.  J Biol Chem. 2004;  279(2) 963-969
  • 48 Nawroth P P, Bank I, Handley D, Cassimeris J, Chess L, Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1.  J Exp Med. 1986;  163(6) 1363-1375
  • 49 Faust S N, Levin M, Harrison O B et al.. Dysfunction of endothelial protein C activation in severe meningococcal sepsis.  N Engl J Med. 2001;  345(6) 408-416
  • 50 Jansen P M, Boermeester M A, Fischer E et al.. Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia.  Blood. 1995;  86(3) 1027-1034
  • 51 Stouthard J M, Levi M, Hack C E et al.. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans.  Thromb Haemost. 1996;  76(5) 738-742
  • 52 Lauw F N, Dekkers P E, te Velde A A et al.. Interleukin-12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees.  J Infect Dis. 1999;  179(3) 646-652
  • 53 Portielje J E, Kruit W H, Eerenberg A J et al.. Interleukin 12 induces activation of fibrinolysis and coagulation in humans.  Br J Haematol. 2001;  112(2) 499-505
  • 54 Hermann A, Rauch B H, Braun M, Schrör K, Weber A A. Platelet CD40 ligand (CD40L)—subcellular localization, regulation of expression, and inhibition by clopidogrel.  Platelets. 2001;  12(2) 74-82
  • 55 Pignatelli P, Cangemi R, Celestini A et al.. Tumour necrosis factor alpha upregulates platelet CD40L in patients with heart failure.  Cardiovasc Res. 2008;  78(3) 515-522
  • 56 So A K, Varisco P A, Kemkes-Matthes B et al.. Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways.  J Thromb Haemost. 2003;  1(12) 2510-2515
  • 57 Busso N, Morard C, Salvi R, Péclat V, So A. Role of the tissue factor pathway in synovial inflammation.  Arthritis Rheum. 2003;  48(3) 651-659
  • 58 Busso N, Hamilton J A. Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis.  Arthritis Rheum. 2002;  46(9) 2268-2279

Radjesh BisoendialM.D. Ph.D. 

Department Internal Medicine (F-4), Academic Medical Center

University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Email: r.j.bisoendial@amc.uva.nl

    >