Sepsis and Thrombosis

Abstract

Activation of coagulation frequently occurs in severe infection and sepsis and may contribute to the development of thrombosis. Coagulation abnormalities in sepsis range from a small decrease in platelet count and subclinical prolongation of global clotting times to fulminant disseminated intravascular coagulation (DIC), characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites. Septic patients with severe forms of DIC may present with manifest thromboembolic disease or clinically less apparent microvascular fibrin deposition, which predominantly presents as multiple organ dysfunction. Thrombophilia is associated with a prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with thrombophilia may suffer from more severe coagulopathy in case of severe infection or sepsis, which may result in a more serious clinical course and an unfavorable outcome. On the basis of the knowledge of the pathogenesis of thrombosis in severe inflammation and sepsis, strategies aimed at the inhibition of coagulation activation have been developed and have been found favorable in experimental and clinical studies.

Keywords

sepsis - thrombosis - inflammation - thrombophilia - heparin

• References

• 1 Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999; 340 (3) 207-214
• 2 Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348 (16) 1546-1554
• 3 Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29 (7) 1303-1310
• 4 Levi M. The coagulant response in sepsis. Clin Chest Med 2008; 29 (4) 627-642 , viii
• 5 Levi M, van der Poll T, Schultz M. New insights into pathways that determine the link between infection and thrombosis. Neth J Med 2012; 70 (3) 114-120
• 6 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341 (8) 586-592
• 7 Colman RW, Robboy SJ, Minna JD. Disseminated intravascular coagulation: a reappraisal. Annu Rev Med 1979; 30: 359-374
• 8 Miller DL, Welty-Wolf K, Carraway MS , et al. Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. Am J Respir Cell Mol Biol 2002; 26 (6) 650-658
• 9 Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular coagulation. Thromb Haemost 1999; 82 (2) 695-705
• 10 Ratnoff OD, Nebehay WG. Multiple coagulative defects in a patient with the Waterhouse-Friderichsen syndrome. Ann Intern Med 1962; 56: 627-632
• 11 Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res 2003; 60 (1) 26-39
• 12 Robboy SJ, Major MC, Colman RW, Minna JD. Pathology of disseminated intravascular coagulation (DIC). Analysis of 26 cases. Hum Pathol 1972; 3 (3) 327-343
• 13 Shimamura K, Oka K, Nakazawa M, Kojima M. Distribution patterns of microthrombi in disseminated intravascular coagulation. Arch Pathol Lab Med 1983; 107 (10) 543-547
• 14 Coalson JJ. Pathology of sepsis, septic shock, and multiple organ failure. In: Perspective on Sepsis and Septic Shock. Fullerton, CA: Society of Critical Care Medicine; 1986: 27-59
• 15 Creasey AA, Chang AC, Feigen L, Wün TC, Taylor Jr FBJ, Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91 (6) 2850-2860
• 16 Kessler CM, Tang Z, Jacobs HM, Szymanski LM. The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity. Blood 1997; 89 (12) 4393-4401
• 17 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
• 18 Taylor Jr FBJ, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79 (3) 918-925
• 19 Welty-Wolf KE, Carraway MS, Miller DL , et al. Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons. Am J Respir Crit Care Med 2001; 164 (10, Pt 1) 1988-1996
• 20 Fourrier F, Chopin C, Goudemand J , et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101 (3) 816-823
• 21 Dhainaut JF, Yan SB, Joyce DE , et al. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2004; 2 (11) 1924-1933
• 22 Vanderschueren S, De Weerdt A, Malbrain M , et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med 2000; 28 (6) 1871-1876
• 23 Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C, Hahn EG. Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome. Crit Care Med 2002; 30 (8) 1765-1771
• 24 Oppenheim-Eden A, Glantz L, Eidelman LA, Sprung CL. Spontaneous intracerebral hemorrhage in critically ill patients: incidence over six years and associated factors. Intensive Care Med 1999; 25 (1) 63-67
• 25 Stéphan F, Hollande J, Richard O, Cheffi A, Maier-Redelsperger M, Flahault A. Thrombocytopenia in a surgical ICU. Chest 1999; 115 (5) 1363-1370
• 26 Akca S, Haji-Michael P, de Mendonça A, Suter PM, Levi M, Vincent JL. Time course of platelet counts in critically ill patients. Crit Care Med 2002; 30 (4) 753-756
• 27 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
• 28 Levi M, van der Poll T, Buller HR. Bidirectional relationship between coagulation and inflammation. Circulation 2004; 109 (22) 2698-2704
• 29 Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 29 (7, Suppl): S28-S34 , discussion S34–S35
• 30 van Deventer SJ, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76 (12) 2520-2526
• 31 van der Poll T, Büller HR, 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
• 32 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
• 33 Biemond BJ, Levi M, ten Cate H , et al. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/VIIa. Thromb Haemost 1995; 73 (2) 223-230
• 34 Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 2002; 30 (5, Suppl): S294-S301
• 35 Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002; 300 (3) 729-735
• 36 Vary TC, Kimball SR. Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol 1992; 262 (2, Pt 1) C445-C452
• 37 Seitz R, Wolf M, Egbring R, Havemann K. The disturbance of hemostasis in septic shock: role of neutrophil elastase and thrombin, effects of antithrombin III and plasma substitution. Eur J Haematol 1989; 43 (1) 22-28
• 38 Opal SM, Kessler CM, Roemisch J, Knaub S. Antithrombin, heparin, and heparan sulfate. Crit Care Med 2002; 30 (5, Suppl): S325-S331
• 39 Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. [see comments] Blood 1996; 88 (3) 881-886
• 40 Esmon CT. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J Exp Med 2002; 196 (5) 561-564
• 41 Zushi M, Gomi K, Yamamoto S, Maruyama I, Hayashi T, Suzuki K. The last three consecutive epidermal growth factor-like structures of human thrombomodulin comprise the minimum functional domain for protein C-activating cofactor activity and anticoagulant activity. J Biol Chem 1989; 264 (18) 10351-10353
• 42 Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996; 271 (28) 16603-16608
• 43 Taylor Jr FB, Peer GT, Lockhart MS, Ferrell G, Esmon CT. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 2001; 97 (6) 1685-1688
• 44 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
• 45 Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163 (3) 740-745
• 46 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
• 47 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
• 48 Levi M, Dörffler-Melly J, Reitsma PH , et al. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. Blood 2003; 101 (12) 4823-4827
• 49 Broze Jr GJ, Girard TJ, Novotny WF. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 1990; 29 (33) 7539-7546
• 50 de Jonge E, Dekkers PE, Creasey AA , et al. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 2000; 95 (4) 1124-1129
• 51 Gando S, Kameue T, Morimoto Y, Matsuda N, Hayakawa M, Kemmotsu O. Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis. Crit Care Med 2002; 30 (8) 1729-1734
• 52 Levi M. The imbalance between tissue factor and tissue factor pathway inhibitor in sepsis. Crit Care Med 2002; 30 (8) 1914-1915
• 53 Schouten M, van 't Veer C, van der Poll T, Levi M. Effect of the factor V Leiden mutation on the incidence and outcome of severe infection and sepsis. Neth J Med 2012; 70 (7) 306-310
• 54 Middeldorp S, Levi M. Thrombophilia: an update. Semin Thromb Hemost 2007; 33 (6) 563-572
• 55 Inbal A, Kenet G, Zivelin A , et al. Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency. Thromb Haemost 1997; 77 (6) 1086-1089
• 56 Dogan Y, Aygun D, Yilmaz Y , et al. Severe protein S deficiency associated with heterozygous factor V Leiden mutation in a child with purpura fulminans. Pediatr Hematol Oncol 2003; 20 (1) 1-5
• 57 al-Ismail S, Collins P, Najib R, James-Ellison M, O'Hagan M. Postinfection purpura fulminans in a patient heterozygous for prothrombin G20210A and acquired protein S resistance. Pediatr Hematol Oncol 1999; 16 (6) 561-564
• 58 Woods CR, Johnson CA. Varicella purpura fulminans associated with heterozygosity for factor V Leiden and transient protein S deficiency. Pediatrics 1998; 102 (5) 1208-1210
• 59 Saçkesen C, Seçmeer G, Gürgey A , et al. Homozygous Factor V Leiden mutation in a child with meningococcal purpura fulminans. Pediatr Infect Dis J 1998; 17 (1) 87
• 60 Hofstra JJ, Schouten M, Levi M. Thrombophilia and outcome in severe infection and sepsis. Semin Thromb Hemost 2007; 33 (6) 604-609
• 61 Texereau J, Pene F, Chiche JD, Rousseau C, Mira JP. Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis. Crit Care Med 2004; 32 (5, Suppl): S313-S319
• 62 Lay AJ, Liang Z, Rosen ED, Castellino FJ. Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities. J Clin Invest 2005; 115 (6) 1552-1561
• 63 Jalbert LR, Rosen ED, Moons L , et al. Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest 1998; 102 (8) 1481-1488
• 64 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2, Suppl): S26-S34
• 65 Kondaveeti S, Hibberd ML, Booy R, Nadel S, Levin M. Effect of the Factor V Leiden mutation on the severity of meningococcal disease. Pediatr Infect Dis J 1999; 18 (10) 893-896
• 66 Kerlin BA, Yan SB, Isermann BH , et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 2003; 102 (9) 3085-3092
• 67 Schouten M, van't Veer C, Roelofs JJ, Levi M, van der Poll T. Impact of the factor V Leiden mutation on the outcome of pneumococcal pneumonia: a controlled laboratory study. Crit Care 2010; 14 (4) R145
• 68 Brüggemann LW, Schoenmakers SH, Groot AP, Reitsma PH, Spek CA. Role of the factor V Leiden mutation in septic peritonitis assessed in factor V Leiden transgenic mice. Crit Care Med 2006; 34 (8) 2201-2206
• 69 Schouten M, van der Sluijs KF, Roelofs JJ, Levi M, Van't Veer C, van der Poll T. Factor V Leiden mutation does not affect coagulopathy or outcome in lethal H1N1 influenza. Eur Respir J 2010; 36 (6) 1346-1354
• 70 Elmas E, Suvajac N, Jilma B, Weiler H, Borggrefe M, Dempfle CE. Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model. Blood 2010; 116 (5) 801-805
• 71 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 (10) 699-709
• 72 Bernard GR, Margolis BD, Shanies HM , et al; Extended Evaluation of Recombinant Human Activated Protein C United States Investigators. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004; 125 (6) 2206-2216
• 73 Yan SB, Nelson DR. Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Crit Care Med 2004; 32 (5, Suppl): S239-S246
• 74 Benfield TL, Dahl M, Nordestgaard BG, Tybjaerg-Hansen A. Influence of the factor V Leiden mutation on infectious disease susceptibility and outcome: a population-based study. J Infect Dis 2005; 192 (10) 1851-1857
• 75 Benfield T, Ejrnaes K, Juul K , et al. Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study. Crit Care 2010; 14 (2) R28
• 76 du Toit HJ, Coetzee AR, Chalton DO. Heparin treatment in thrombin-induced disseminated intravascular coagulation in the baboon. Crit Care Med 1991; 19 (9) 1195-1200
• 77 Feinstein DI. Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy. Blood 1982; 60 (2) 284-287
• 78 Dörffler-Melly J, de Jonge E, Pont AC , et al. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002; 359 (9309) 849-850
• 79 Vlasuk GP, Bergum PW, Bradbury AE, Loynds P, Mant TG, Rote WE. Clinical evaluation of rNAPc2, an inhibitor of the fVIIa/tissue factor coagulation complex. Am J Cardiol 1997; 80: 66S
• 80 Abraham E, Reinhart K, Svoboda P , et al. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med 2001; 29 (11) 2081-2089
• 81 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
• 82 Levi M, Lowenberg E, Meijers JC. Recombinant anticoagulant factors for adjunctive treatment of sepsis. Semin Thromb Hemost 2010; 36 (5) 550-557
• 83 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 (15) 1869-1878
• 84 Kienast J, Juers M, Wiedermann CJ , et al; KyberSept investigators. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2006; 4 (1) 90-97
• 85 Bernard GR, Ely EW, Wright TJ , et al. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med 2001; 29 (11) 2051-2059
• 86 Ranieri VM, Thompson BT, Barie PS , et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366 (22) 2055-2064
• 87 Saito H, Maruyama I, Shimazaki S , et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5 (1) 31-41
• 88 Aikawa N, Shimazaki S, Yamamoto Y , et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 2011; 35 (4) 349-354
• 89 Cook DJ, Crowther MA. Thromboprophylaxis in the intensive care unit: focus on medical-surgical patients. Crit Care Med 2010; 38 (2, Suppl): S76-S82
• 90 Dörffler-Melly J, de Jonge E, Pont AC , et al. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002; 359 (9309) 849-850
• 91 Priglinger U, Delle Karth G, Geppert A , et al. Prophylactic anticoagulation with enoxaparin: is the subcutaneous route appropriate in the critically ill?. Crit Care Med 2003; 31 (5) 1405-1409
• 92 Rommers MK, Van der Lely N, Egberts TC, van den Bemt PM. Anti-Xa activity after subcutaneous administration of dalteparin in ICU patients with and without subcutaneous oedema: a pilot study. Crit Care 2006; 10 (3) R93
• 93 Haas CE, Nelsen JL, Raghavendran K , et al. Pharmacokinetics and pharmacodynamics of enoxaparin in multiple trauma patients. J Trauma 2005; 59 (6) 1336-1343 , discussion 1343–1344
• 94 Cook D, Douketis J, Meade M , et al; Canadian Critical Care Trials Group. Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors. Crit Care 2008; 12 (2) R32
• 95 Cohen AT, Spiro TE, Büller HR , et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (6) 513-523