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are increased in ageing individuals. Memory T-cell clones also increase and are directed toward a few epitopes of common viruses, such as cytomegalovirus and Epstein-Barr virus.41,42

a quantitative gradient in inflammation: high levels of IL-6 (a pro-inflammatory cytokine often used as a measure of inflammation), for example, are associated with an increased risk of frailty in the elderly.43 In healthy centenerians this low-grade inflammatory response is associated with anti-inflamm-ageing, i.e. with biological mechanisms that control inflammation.39,40

Comments and Perspectives There seems to be

Anti-inflammatory agents have traditionally been commonly used in antithrombotic therapy: both aspirin and heparins possess anti-inflammatory activity.45,46

However, aspirin, is often used at

antiplatelet dosages that do not elicit an anti-inflammatory effect (i.e. do not inhibit cyclo-oxygenase-2 [COX-2]).47

Added to this, the The natural conclusion from these

experimental observations is that excess inflammation is a noxious impediment to healthy ageing. It is not currently known whether this low-grade chronic inflammation and coagulation activation is directly linked to the increasing incidence of thrombosis, both arterial and venous, with age (the risk doubles for every decade after 40 years of age).44

It is likely, however, that in ageing – as in the chronic

diseases mentioned – persistent inflammation is a predisposing factor for thrombosis. It is also plausible that other intervening precipitating factors common in the elderly population, such as cardiovascular disease, cancer and metabolic derangement, trigger the thrombotic events.

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2. Lowe GD, Common risk factors for both arterial and venous thrombosis, Br J Haematol, 2008;140:488–95.

3. Buckley DI, Fu R, Freeman M, et al., C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force, Ann Intern Med, 2009;151:483–95.

4. Folsom AR, Lutsey PL, Astor BC, et al., C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort, Thromb Haemost, 2009;102:615–9.

5. Franchini M, Veneri D, Lippi G, Inflammation and hemostatis: a bidirectional interation, Clin Lab, 2007;53:63–7.

6. Von Hundelhausen P, Weber C, Platelets as immune cells. Bridging inflammation and cardiovascular disease, Circ Res, 2007;100:27–40.

7. Peerschke EIB, Yin W, Ghebrehiwet B, Platelet mediated complement activation, Adv Exp Med Biol, 2008; 632:81–91.

8. Antoniades C, Bakogiannis C, Tousoulis D, et al., The CD40/CD40 ligand system. Linking inflammation with atherothrombosis, J Am Coll Cardiol, 2009;54:669–77.

9. Massberg S, Enders G, Leiderer R, et al., Platelet-endothelial cell interactions during ischemia/reperfusion: The role of P-selectin, Blood, 1998;92:507–15.

10. Von Hundelshausen P, Weber KS, Huo Y, et al., RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium, Circulation, 2001;103:1772–7.

11. Danese S, de la Motte C, Sturm A, et al., Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients, Gastroenterology, 2003;124:1249–64.

12. Lee SP, Ataga KI, Orringer EP, et al., Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation, Arterioscler Thromb Vasc Biol, 2006;26:1626–31.

13. Sowa JM, Crist SA, Ratliff TL, et al., Platelet influence on T- and B-cell responses, Arch Immunol Ther Exp (Warsz), 2009;57:235–41.

14. Silverstein RL, Inflammation, atherosclerosis, and arterial thrombosis: Role of scavenger receptor CD36, Clev Clin J Med, 2009;76(Suppl. 2):S27–S30.

15. Ghosh A, Li W, Febbraio M, et al., Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice, J Clin Invest, 2008;118:1934–43.

16. Nakata M, Yada T, Soejima N, et al., Leptin promotes aggregation of human platelets via the long form of its receptor, Diabetes, 1999;48:426–9.

anti-inflammatory properties of heparin are exploited mostly in the acute phase of thrombosis, since patients are soon placed on oral anticoagulants. Anti-inflammatory drugs, in association with antithrombotics, have the potential to interrupt the complex interactions shown in Figure 1. Moreover, as mechanisms linking inflammation, coagulation and immunity are unravelled, new therapeutic targets are emerging. Little is known about the complex pro-inflammatory/anti- inflammatory balances that exist in chronic inflammation. The importance of an individual’s genetic background in terms of inflammatory and immune responses is just now beginning to be appreciated. Research in this area is moving forward fast. It is also focusing on the important role of neutrophils in thrombotic events, especially in the arteries. New therapeutic strategies will hopefully be born from the results of this exciting ongoing research. n

17. Martin SS, Qasim A, Reilly MP, Leptin resistance, J Am Coll Cardiol, 2008;52:1201–10.

18. Westerbacka J, Yki-Järvinen H, Turpeinen A, et al., Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity, Arterioscler Thromb Vasc Biol, 2002;22:167–72.

19. Anfossi G, Russo I, Trovati M, Platelet dysfunction in central obesity, Nutr Metab Cardiovasc Dis, 2009;19:440–9.

20. Brandt E, Ludwig A, Petersen F, et al., Platelet-derived CXC chemokines: old players in new games, Immunol Rev, 2000;177:204–16.

21. Gleissner CA, von Hundelshausen P, Ley K, Platelet chemokines in vascular disease, Arterioscler Thromb Vasc Biol, 2008;28:1920–7.

22. Dahlbäck B, Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases, J Intern Med, 2005;257:209–23.

23. Esmon CT, Crosstalk between inflammation and thrombosis, Maturitas, 2008;61(1-2):122–31.

24. Martorell L, Martínez-González J, Rodríguez C, et al., Thrombin and protease-activated receptors (PARs) in atherothrombosis, Thromb Haemost, 2008;99:305–15.

25. Maugeri N, Rovere-Querini P, Baldini M, et al., Translational mini-review series on immunology of vascular disease: Mechanisms of vascular inflammation and remodelling in systemic vasculitis, Clin Exper Immunol, 2009;156:395–404.

26. Trifiletti A, Scamardi R, Bagnato GF, et al., Hemostatic changes in vasculitides, Thromb Res, 2009;124:252–5.

27. Faioni EM, Ferrero S, Fontana G, et al., Expression of endothelial protein C receptor and thrombomodulin in the intestinal tissue of patients with inflammatory bowel disease, Crit Care Med, 2004;32(5 Suppl.):S266–70.

28. Miehsler W, Reinisch W, Valic E, et al., Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism?, Gut, 2004;53:542–8.

29. Young E, The anti-inflammatory effects of heparin and related compounds, Thromb Res, 2008;122:743–52.

30. Yan SF, Mackman N, Kisiel W, et al., Hypoxia/hypoxemia- induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis, Arterioscler Thromb Vasc Biol, 1999;19:2029–35.

31. Sites WE, Froude II JW, Does the oxidation of methionine in thrombomodulin contribute to the hypercoagulable state of smokers and diabetics?, Med Hypotheses, 2007;68:811–21.

32. Iwanaga S, The molecular basis of innate immunity in the horseshoe crab, Curr Opin Immunol, 2002;14:87–95.

33. Opal SM, Esmon CT, Bench-to-bedside review: Functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of

sepsis, Crit Care, 2003;7:23–8.

34. Delvaeye M, Conway EM, Coagulation and innate immune responses: can we view them separately?, Blood, 2009;114:2367–74.

35. Bernard GR, Vincent JL, Laterre PF, et al.; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group, Efficacy and safety of recombinant human activated protein C for severe sepsis, N Engl J Med, 2001;344:699–709.

36. Warren BL, Eid A, Singer P, et al.; KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial, JAMA, 2001;286:1869–78.

37. Abraham E, Reinhart K, Opal S, et al.; OPTIMIST Trial Study Group, Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial, JAMA, 2003;290:238–47.

38. Kerschen EJ, Fernandez JA, Cooley BC, et al., Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C, J Exp Med, 2007;204:2439–48.

39. Franceschi C, Capri M, Monti D, et al., Inflamm and anti- inflammaging: A systemic perspective on aging and longevity emerged from studies in humans, Mech Ageing Dev, 2007;128:92–105.

40. Sergio G, Exploring the complex relations between inflammation and aging (inflamm-aging): anti-inflamm-aging remodeling of inflammaging, from robustness to frailty, Inflamm Res, 2008;57:558–63.

41. Mari D, Mannucci PM, Coppola R, et al., Hypercoagulability in centenarians: the paradox of successful aging, Blood, 1995;85(11):3144–9.

42. Ouyang Q, Wagner WM, Voehringer D, et al., Age-associated accumulation of CMV-specific CD8+T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1), Exp Gerontol, 2003;38:911–20.

43. Zanni F, Vescovini R, Biasini C, et al., Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+T cells in humans: a contribution to understand the reltionship between inflammation and immunosenescence, Exp Gerontol, 2003;38:981–7.

44. Anderson FA Jr, Spencer FA, Risk factors for venous thromboembolism, Circulation, 2003;107(23 Suppl. 1):I9–16.

45. Rao P, Knaus EE, Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond, J Pharm Pharm Sci, 2008;11:81s–110s.

46. Young E, The anti-inflammatory effects of heparin and related compounds, Thromb Res, 2008;122:743–53.

47. Patrono C, García Rodríguez LA, Landolfi R, et al., Low-dose aspirin for the prevention of atherothrombosis, N Engl J Med, 2005;353:2373–83.



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