Infection and Inflammation as Risk Factors for Thrombosis and Atherosclerosis

Abstract

Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to gross activation of coagulation that may result in localized thrombotic complications or systemic intravascular fibrin deposition. Systemic inflammation results in activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory cytokines, immune cells, and the endothelium play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice-versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Similar mechanisms appear to play a role in the development of atherosclerosis and related arterial thrombosis. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy.

Keywords

infection - inflammation - thrombosis - atherosclerosis - coagulation - endothelium - cytokines

• References

• 1 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341 (8) 586-592
• 2 Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999; 340 (3) 207-214
• 3 Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res 2003; 60 (1) 26-39
• 4 Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular coagulation. Thromb Haemost 1999; 82 (2) 695-705
• 5 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2, Suppl) S26-S34
• 6 Esmon CT, Fukudome K, Mather T , et al. Inflammation, sepsis, and coagulation. Haematologica 1999; 84 (3) 254-259
• 7 Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997; 27 (1) 3-9
• 8 Østerud B, Bjørklid E. The tissue factor pathway in disseminated intravascular coagulation. Semin Thromb Hemost 2001; 27 (6) 605-617
• 9 Taylor Jr FB. Response of anticoagulant pathways in disseminated intravascular coagulation. Semin Thromb Hemost 2001; 27 (6) 619-631
• 10 ten Cate JW, van der Poll T, Levi M, ten Cate H, van Deventer SJ. Cytokines: triggers of clinical thrombotic disease. Thromb Haemost 1997; 78 (1) 415-419
• 11 Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 29 (7, Suppl) S28-S34 , discussion S34–S35
• 12 Levi M, ten Cate H, van der Poll T. Endothelium: interface between coagulation and inflammation. Crit Care Med 2002; 30 (5, Suppl) S220-S224
• 13 Vallet B. Microthrombosis in sepsis. Minerva Anestesiol 2001; 67 (4) 298-301
• 14 Levi M, van der Poll T, ten Cate H. Tissue factor in infection and severe inflammation. Semin Thromb Hemost 2006; 32 (1) 33-39
• 15 Taylor Jr FBJ, Chang A, Ruf W , et al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33 (3) 127-134
• 16 Levi M, ten Cate H, Bauer KA , et al. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93 (1) 114-120
• 17 van der Poll T, Levi M, Hack CE , et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179 (4) 1253-1259
• 18 Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med 2002; 8 (11) 1257-1262
• 19 Osterud B, Rao LV, Olsen JO. Induction of tissue factor expression in whole blood: lack of evidence for the presence of tissue factor expression in granulocytes. Thromb Haemost 2000; 83 (6) 861-867
• 20 Franco RF, de Jonge E, Dekkers PE , et al. The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood 2000; 96 (2) 554-559
• 21 Rauch U, Bonderman D, Bohrmann B , et al. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood 2000; 96 (1) 170-175
• 22 Østerud B, Bjørklid E. Sources of tissue factor. Semin Thromb Hemost 2006; 32 (1) 11-23
• 23 Löwenberg EC, Meijers JC, Levi M. Platelet-vessel wall interaction in health and disease. Neth J Med 2010; 68 (6) 242-251
• 24 Osterud B. Tissue factor expression by monocytes: regulation and pathophysiological roles. Blood Coagul Fibrinolysis 1998; 9 (Suppl 1) S9-S14
• 25 Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 2004; 10 (4) 171-178
• 26 Neumann FJ, Marx N, Gawaz M , et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation 1997; 95 (10) 2387-2394
• 27 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
• 28 Levi M. Antithrombin in sepsis revisited. Crit Care 2005; 9 (6) 624-625
• 29 Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109 (22) 2698-2704
• 30 Kobayashi M, Shimada K, Ozawa T. Human recombinant interleukin-1 beta- and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells. J Cell Physiol 1990; 144 (3) 383-390
• 31 Levi M, van der Poll T. Recombinant human activated protein C: current insights into its mechanism of action. Crit Care 2007; 11 (Suppl 5) S3
• 32 Esmon CT. Role of coagulation inhibitors in inflammation. Thromb Haemost 2001; 86 (1) 51-56
• 33 Levi M, de Jonge E, van der Poll T. Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation. Crit Care Med 2001; 29 (7 Suppl) S90-S94
• 34 Esmon CT. The regulation of natural anticoagulant pathways. Science 1987; 235 (4794) 1348-1352
• 35 Esmon CT. The endothelial cell protein C receptor. Thromb Haemost 2000; 83 (5) 639-643
• 36 Pérez-Casal M, Downey C, Fukudome K, Marx G, Toh CH. Activated protein C induces the release of microparticle-associated endothelial protein C receptor. Blood 2005; 105 (4) 1515-1522
• 37 Mesters RM, Helterbrand J, Utterback BG , et al. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med 2000; 28 (7) 2209-2216
• 38 Vary TC, Kimball SR. Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol 1992; 262 (2 Pt 1) C445-C452
• 39 Eckle I, Seitz R, Egbring R, Kolb G, Havemann K. Protein C degradation in vitro by neutrophil elastase. Biol Chem Hoppe Seyler 1991; 372 (11) 1007-1013
• 40 Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163 (3) 740-745
• 41 Faust SN, Levin M, Harrison OB , et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345 (6) 408-416
• 42 García de Frutos P, Alim RI, Härdig Y, Zöller B, Dahlbäck B. Differential regulation of alpha and beta chains of C4b-binding protein during acute-phase response resulting in stable plasma levels of free anticoagulant protein S. Blood 1994; 84 (3) 815-822
• 43 Taylor Jr FBJ, Dahlback B, Chang AC , et al. Role of free protein S and C4b binding protein in regulating the coagulant response to Escherichia coli . Blood 1995; 86 (7) 2642-2652
• 44 Taylor Jr FBJ, Stearns-Kurosawa DJ, Kurosawa S , et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95 (5) 1680-1686
• 45 de Pont AC, Bakhtiari K, Hutten BA , et al. Endotoxaemia induces resistance to activated protein C in healthy humans. Br J Haematol 2006; 134 (2) 213-219
• 46 Biemond BJ, Levi M, Ten Cate H , et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Lond) 1995; 88 (5) 587-594
• 47 Biemond BJ, Friederich PW, Koschinsky ML , et al. Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo. Circulation 1997; 96 (5) 1612-1615
• 48 Schleef RR, Bevilacqua MP, Sawdey M, Gimbrone Jr MAJ, Loskutoff DJ. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. J Biol Chem 1988; 263 (12) 5797-5803
• 49 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest 1991; 88 (4) 1346-1353
• 50 Yamamoto K, Loskutoff DJ. Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator. J Clin Invest 1996; 97 (11) 2440-2451
• 51 ten Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis. Crit Care Med 2000; 28 (9, Suppl) S9-S11
• 52 Hermans PW, Hibberd ML, Booy R , et al; Meningococcal Research Group. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Lancet 1999; 354 (9178) 556-560
• 53 Westendorp RG, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 1999; 354 (9178) 561-563
• 54 Brandtzaeg P, Joø GB, Brusletto B, Kierulf P. Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 1990; 57 (2) 271-278
• 55 Mesters RM, Flörke N, Ostermann H, Kienast J. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost 1996; 75 (6) 902-907
• 56 Zimmerhackl LB, Rosales A, Hofer J , et al. Enterohemorrhagic Escherichia coli O26:H11-associated hemolytic uremic syndrome: bacteriology and clinical presentation. Semin Thromb Hemost 2010; 36 (6) 586-593
• 57 Karpman D, Sartz L, Johnson S. Pathophysiology of typical hemolytic uremic syndrome. Semin Thromb Hemost 2010; 36 (6) 575-585
• 58 van Gorp EC, Suharti C, ten Cate H , et al. Review: infectious diseases and coagulation disorders. J Infect Dis 1999; 180 (1) 176-186
• 59 Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000; 406 (6797) 782-787
• 60 Anas AA, Wiersinga WJ, de Vos AF, van der Poll T. Recent insights into the pathogenesis of bacterial sepsis. Neth J Med 2010; 68 (4) 147-152
• 61 Tromp M, Tjan DH, van Zanten AR , et al. The effects of implementation of the Surviving Sepsis Campaign in the Netherlands. Neth J Med 2011; 69 (6) 292-298
• 62 Vos FJ, Bleeker-Rovers CP, Sturm PD , et al. Endocarditis: effects of routine echocardiography during Gram-positive bacteraemia. Neth J Med 2011; 69 (7) 335-340
• 63 Bhamarapravati N. Hemostatic defects in dengue hemorrhagic fever. Rev Infect Dis 1989; 11 (Suppl 4) S826-S829
• 64 Heller MV, Marta RF, Sturk A , et al. Early markers of blood coagulation and fibrinolysis activation in Argentine hemorrhagic fever. Thromb Haemost 1995; 73 (3) 368-373
• 65 Mohanty D, Ghosh K, Nandwani SK , et al. Fibrinolysis, inhibitors of blood coagulation, and monocyte derived coagulant activity in acute malaria. Am J Hematol 1997; 54 (1) 23-29
• 66 Chuttani K, Tischler MD, Pandian NG, Lee RT, Mohanty PK. Diagnosis of cardiac tamponade after cardiac surgery: relative value of clinical, echocardiographic, and hemodynamic signs. Am Heart J 1994; 127 (4 Pt 1) 913-918
• 67 Fera G, Semeraro N, De Mitrio V, Schiraldi O. Disseminated intravascular coagulation associated with disseminated cryptococcosis in a patient with acquired immunodeficiency syndrome. Infection 1993; 21 (3) 171-173
• 68 Schröder S, Spyridopoulos I, König J, Jaschonek KG, Luft D, Seif FJ. Thrombotic thrombocytopenic purpura (TTP) associated with a Borrelia burgdorferi infection. Am J Hematol 1995; 50 (1) 72-73
• 69 Gärdlund B ; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet 1996; 347 (9012) 1357-1361
• 70 Laing RB, Brettle RP, Leen CL. Venous thrombosis in HIV infection. Int J STD AIDS 1996; 7 (2) 82-85
• 71 Jenkins RE, Peters BS, Pinching AJ. Thromboembolic disease in AIDS is associated with cytomegalovirus disease. AIDS 1991; 5 (12) 1540-1542
• 72 Drancourt M, George F, Brouqui P, Sampol J, Raoult D. Diagnosis of Mediterranean spotted fever by indirect immunofluorescence of Rickettsia conorii in circulating endothelial cells isolated with monoclonal antibody-coated immunomagnetic beads. J Infect Dis 1992; 166 (3) 660-663
• 73 Keller TT, van Wissen M, Mairuhu AT, van Doornum GJ, Brandjes DP. Acute respiratory tract infections in elderly patients increase systemic levels of hemostatic proteins. J Thromb Haemost 2007; 5 (7) 1567-1569
• 74 van Wissen M, Keller TT, Ronkes B , et al. Influenza infection and risk of acute pulmonary embolism. Thromb J 2007; 5: 16
• 75 Grau AJ, Urbanek C, Palm F. Common infections and the risk of stroke. Nat Rev Neurol 2010; 6 (12) 681-694
• 76. Zoller B, Li X, Sundquist J, Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. Lancet 2012; 379 (9812) 244-249
• 77 Hayes EB, Gubler DJ. Dengue and dengue hemorrhagic fever. Pediatr Infect Dis J 1992; 11 (4) 311-317
• 78 Sumarmo WH, Wulur H, Jahja E, Gubler DJ, Suharyono W, Sorensen K. Clinical observations on virologically confirmed fatal dengue infections in Jakarta, Indonesia. Bull World Health Organ 1983; 61 (4) 693-701
• 79 Kuberski T, Rosen L, Reed D, Mataika J. Clinical and laboratory observations on patients with primary and secondary dengue type 1 infections with hemorrhagic manifestations in Fiji. Am J Trop Med Hyg 1977; 26 (4) 775-783
• 80 Limbos MA, Lieberman JM. Disseminated intravascular coagulation associated with rotavirus gastroenteritis: report of two cases. [see comments] Clin Infect Dis 1996; 22 (5) 834-836
• 81 Anderson DR, Harrison L, Hirsh J. Evaluation of a portable prothrombin time monitor for home use by patients who require long-term oral anticoagulant therapy. Arch Intern Med 1993; 153 (12) 1441-1447
• 82 McKay DG, Margaretten W. Disseminated intravascular coagulation in virus diseases. Arch Intern Med 1967; 120 (2) 129-152
• 83 Linder M, Müller-Berghaus G, Lasch HG, Gagel C. Virus infection and blood coagulation. Thromb Diath Haemorrh 1970; 23 (1) 1-11
• 84 Anderson DR, Schwartz J, Hunter NJ, Cottrill C, Bisaccia E, Klainer AS. Varicella hepatitis: a fatal case in a previously healthy, immunocompetent adult. Report of a case, autopsy, and review of the literature. Arch Intern Med 1994; 154 (18) 2101-2106
• 85 Clemens R, Pramoolsinsap C, Lorenz R, Pukrittayakamee S, Bock HL, White NJ. Activation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway. Br J Haematol 1994; 87 (1) 100-105
• 86 Badesha PS, Saklayen MG. Hemolytic uremic syndrome as a presenting form of HIV infection. Nephron 1996; 72 (3) 472-475
• 87 Ackerman B, Chongchitnant N, Chanzee J, Guo Y , eds. Inflammatory diseases. Histologic diagnosis of inflammatory skin diseases. Baltimore: Williams and Wilkins; 1997: 170-186
• 88 Lie JT. Vasculitis associated with infectious agents. Curr Opin Rheumatol 1996; 8 (1) 26-29
• 89 Guillevin L, Lhote F, Ghérardi R. The spectrum and treatment of virus-associated vasculitides. Curr Opin Rheumatol 1997; 9 (1) 31-36
• 90 Golden MP, Hammer SM, Wanke CA, Albrecht MA. Cytomegalovirus vasculitis. Case reports and review of the literature. Medicine (Baltimore) 1994; 73 (5) 246-255
• 91 Ho DD, Rota TR, Andrews CA, Hirsch MS. Replication of human cytomegalovirus in endothelial cells. J Infect Dis 1984; 150 (6) 956-957
• 92 Goodman MD, Porter DD. Cytomegalovirus vasculitis with fatal colonic hemorrhage. Arch Pathol 1973; 96 (4) 281-284
• 93 Foucar E, Mukai K, Foucar K, Sutherland DE, Van Buren CT. Colon ulceration in lethal cytomegalovirus infection. Am J Clin Pathol 1981; 76 (6) 788-801
• 94 Booss J, Dann PR, Winkler SR, Griffith BP, Kim JH. Mechanisms of injury to the central nervous system following experimental cytomegalovirus infection. Am J Otolaryngol 1990; 11 (5) 313-317
• 95 Koeppen AH, Lansing LS, Peng SK, Smith RS. Central nervous system vasculitis in cytomegalovirus infection. J Neurol Sci 1981; 51 (3) 395-410
• 96 Lin CS, Penha PD, Krishnan MN, Zak FG. Cytomegalic inclusion disease of the skin. Arch Dermatol 1981; 117 (5) 282-284
• 97 Libman BS, Quismorio Jr FPJ, Stimmler MM. Polyarteritis nodosa-like vasculitis in human immunodeficiency virus infection. J Rheumatol 1995; 22 (2) 351-355
• 98 Calabrese LH. Vasculitis and infection with the human immunodeficiency virus. Rheum Dis Clin North Am 1991; 17 (1) 131-147
• 99 Gherardi R, Belec L, Mhiri C , et al. The spectrum of vasculitis in human immunodeficiency virus-infected patients. A clinicopathologic evaluation. Arthritis Rheum 1993; 36 (8) 1164-1174
• 100 Sergent JS, Lockshin MD, Christian CL, Gocke DJ. Vasculitis with hepatitis B antigenemia: long-term observation in nine patients. Medicine (Baltimore) 1976; 55 (1) 1-18
• 101 Carson CW, Conn DL, Czaja AJ, Wright TL, Brecher ME. Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa. J Rheumatol 1993; 20 (2) 304-309
• 102 Leruez-Ville M, Laugé A, Morinet F, Guillevin L, Dény P. Polyarteritis nodosa and parvovirus B19. Lancet 1994; 344 (8917) 263-264
• 103 Nikkari S, Mertsola J, Korvenranta H, Vainionpää R, Toivanen P. Wegener's granulomatosis and parvovirus B19 infection. [see comments] Arthritis Rheum 1994; 37 (11) 1707-1708
• 104 Yoto Y, Kudoh T, Haseyama K, Suzuki N, Chiba S, Matsunaga Y. Human parvovirus B19 infection in Kawasaki disease. Lancet 1994; 344 (8914) 58-59
• 105 Minick CR, Fabricant CG, Fabricant J, Litrenta MM. Atheroarteriosclerosis induced by infection with a herpesvirus. Am J Pathol 1979; 96 (3) 673-706
• 106 Mehta JL, Li DY. Inflammation in ischemic heart disease: response to tissue injury or a pathogenetic villain?. Cardiovasc Res 1999; 43 (2) 291-299
• 107 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link?. Lancet 1997; 350 (9075) 430-436
• 108 Benitez RM. Atherosclerosis: an infectious disease?. [Review] [12 refs] Hosp Pract (Minneap) 1999; 34 (9) 79-82 , 85–86, 89–90
• 109 Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011; 106 (5) 858-867
• 110 Melnick JL, Hu C, Burek J, Adam E, DeBakey ME. Cytomegalovirus DNA in arterial walls of patients with atherosclerosis. J Med Virol 1994; 42 (2) 170-174
• 111 Keller TT, van der Meer JJ, Teeling P , et al. Selective expansion of influenza A virus-specific T cells in symptomatic human carotid artery atherosclerotic plaques. Stroke 2008; 39 (1) 174-179
• 112 Loscalzo J. The relation between atherosclerosis and thrombosis. Circulation 1992; 86 (6, Suppl) III95-III99
• 113 Bisoendial RJ, Levi M, Tak PP, Stroes ES. The prothrombotic state in rheumatoid arthritis: an additive risk factor for adverse cardiovascular events. Semin Thromb Hemost 2010; 36 (4) 452-457
• 114 Libby P. Inflammation in atherosclerosis. Nature 2002; 420 (6917) 868-874
• 115 Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001; 88 (8) 756-762
• 116 Flynn PD, Byrne CD, Baglin TP, Weissberg PL, Bennett MR. Thrombin generation by apoptotic vascular smooth muscle cells. Blood 1997; 89 (12) 4378-4384
• 117 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
• 118 Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol 2001; 158 (3) 1039-1051
• 119 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
• 120 Bisoendial RJ, Stroes ES, Tak PP. Where the immune response meets the vessel wall. Neth J Med 2009; 67 (8) 328-333
• 121 Bisoendial RJ, Kastelein JJ, Peters SL , et al. Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects. J Lipid Res 2007; 48 (4) 952-960
• 122 Levi MM, Eerenberg E, Löwenberg E, Kamphuisen PW. Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management. Neth J Med 2010; 68 (2) 68-76
• 123 Levi M, Levy M, Williams MD , et al; Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007; 176 (5) 483-490
• 124 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 (2) 238-247