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DOI: 10.1055/s-0034-1398376
Coagulation in Patients with Severe Sepsis
Publication History
Publication Date:
15 January 2015 (online)
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Abstract
In the majority of patients with severe sepsis, systemic activation of coagulation is present. Increasing evidence points to an extensive cross-talk between coagulation and inflammation that may play an important role in the pathogenesis of sepsis. Inflammation not only leads to activation of coagulation, but coagulation also considerably affects inflammatory activity. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Proinflammatory cytokines and other mediators are capable of activating the coagulation system and downregulating important physiological anticoagulant pathways. Activation of the coagulation system and ensuing thrombin generation is dependent on expression of tissue factor on activated mononuclear cells and endothelial cells, and is insufficiently counteracted by TFPI. Simultaneously, endothelial-bound anticoagulant mechanism, in particular the protein C system, is shutoff by proinflammatory cytokines. In addition, fibrin removal is severely inhibited, because of inactivation of the fibrinolytic system, caused by an upregulation of its main inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Increased fibrin formation and impaired removal lead to (micro)vascular thrombosis, which may result in tissue ischemia and subsequent organ damage. The cornerstone of the management of coagulation in sepsis is the specific and vigorous treatment of the underlying disorder. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. Heparin may be an effective anticoagulant approach and alternative strategies comprise restoration of physiological anticoagulant pathways.
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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, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270 (8) 975-979
- 5 Levi M. The coagulant response in sepsis. Clin Chest Med 2008; 29 (4) 627-642 , viii
- 6 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341 (8) 586-592
- 7 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
- 8 Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular coagulation. Thromb Haemost 1999; 82 (2) 695-705
- 9 Ratnoff OD, Nebehay WG. Multiple coagulative defects in a patient with the Waterhouse-Friderichsen syndrome. Ann Intern Med 1962; 56: 627-632
- 10 Levi M, de Jonge E, van der Poll T. Sepsis and disseminated intravascular coagulation. J Thromb Thrombolysis 2003; 16 (1-2) 43-47
- 11 Vanderschueren S, De Weerdt A, Malbrain M , et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med 2000; 28 (6) 1871-1876
- 12 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
- 13 Akca S, Haji-Michael P, de Mendonça A, Suter P, Levi M, Vincent JL. Time course of platelet counts in critically ill patients. Crit Care Med 2002; 30 (4) 753-756
- 14 Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 2000; 28 (2) 451-457
- 15 Folman CC, Linthorst GE, van Mourik J , et al. Platelets release thrombopoietin (Tpo) upon activation: another regulatory loop in thrombocytopoiesis?. Thromb Haemost 2000; 83 (6) 923-930
- 16 François B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med 1997; 103 (2) 114-120
- 17 Warkentin TE, Aird WC, Rand JH. Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 2003; 497-519
- 18 MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003; 55 (1) 39-44
- 19 Shorr AF, Thomas SJ, Alkins SA, Fitzpatrick TM, Ling GS. D-dimer correlates with proinflammatory cytokine levels and outcomes in critically ill patients. Chest 2002; 121 (4) 1262-1268
- 20 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
- 21 Gando S, Nanzaki S, Sasaki S, Kemmotsu O. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. Thromb Haemost 1998; 79 (6) 1111-1115
- 22 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. [Review] [56 refs] Eur J Clin Invest 1997; 27 (1) 3-9
- 23 Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109 (22) 2698-2704
- 24 Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 29 (7, Suppl): S28-S34 ; discussion S34–S35
- 25 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2, Suppl): S26-S34
- 26 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
- 27 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
- 28 Osterud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 1983; 49 (1) 5-7
- 29 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
- 30 Giesen PL, Rauch U, Bohrmann B , et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A 1999; 96 (5) 2311-2315
- 31 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
- 32 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
- 33 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
- 34 Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002; 300 (3) 729-735
- 35 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
- 36 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
- 37 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
- 38 Hinshaw LB, Tekamp-Olson P, Chang AC , et al. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock 1990; 30 (3) 279-292
- 39 Abraham E, Wunderink R, Silverman H , et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995; 273 (12) 934-941
- 40 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
- 41 Stouthard JM, Levi M, Hack CE , et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76 (5) 738-742
- 42 Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg 1995; 130 (7) 739-748
- 43 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407 (6801) 258-264
- 44 Kaneider NC, Förster E, Mosheimer B, Sturn DH, Wiedermann CJ. Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. Thromb Haemost 2003; 90 (6) 1150-1157
- 45 Esmon CT. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J Exp Med 2002; 196 (5) 561-564
- 46 Yuksel M, Okajima K, Uchiba M, Horiuchi S, Okabe H. Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. Thromb Haemost 2002; 88 (2) 267-273
- 47 Murakami K, Okajima K, Uchiba M , et al. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 1996; 87 (2) 642-647
- 48 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
- 49 Levi M, Dörffler-Melly J, Reitsma P , et al. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. Blood 2003; 101 (12) 4823-4827
- 50 Baughman RP, Lower EE, Flessa HC, Tollerud DJ. Thrombocytopenia in the intensive care unit. Chest 1993; 104 (4) 1243-1247
- 51 Levi M, de Jonge E, Meijers J. The diagnosis of disseminated intravascular coagulation. Blood Rev 2002; 16 (4) 217-223
- 52 Levi M, Toh CH, Thachil J, Watson HG ; British Committee for Standards in Haematology. Guidelines for the diagnosis and management of disseminated intravascular coagulation. Br J Haematol 2009; 145 (1) 24-33
- 53 Dempfle CE, Pfitzner SA, Dollman M, Huck K, Stehle G, Heene DL. Comparison of immunological and functional assays for measurement of soluble fibrin. Thromb Haemost 1995; 74 (2) 673-679
- 54 McCarron BI, Marder VJ, Kanouse JJ, Francis CW. A soluble fibrin standard: comparable dose-response with immunologic and functional assays. Thromb Haemost 1999; 82 (1) 145-148
- 55 Dempfle CE. The use of soluble fibrin in evaluating the acute and chronic hypercoagulable state. Thromb Haemost 1999; 82 (2) 673-683
- 56 Horan JT, Francis CW. Fibrin degradation products, fibrin monomer and soluble fibrin in disseminated intravascular coagulation. Semin Thromb Hemost 2001; 27 (6) 657-666
- 57 Carr JM, McKinney M, McDonagh J. Diagnosis of disseminated intravascular coagulation. Role of D-dimer. Am J Clin Pathol 1989; 91 (3) 280-287
- 58 Prisco D, Paniccia R, Bonechi F, Francalanci I, Abbate R, Gensini GF. Evaluation of new methods for the selective measurement of fibrin and fibrinogen degradation products. Thromb Res 1989; 56 (4) 547-551
- 59 Shorr AF, Trotta RF, Alkins SA, Hanzel GS, Diehl LF. D-dimer assay predicts mortality in critically ill patients without disseminated intravascular coagulation or venous thromboembolic disease. Intensive Care Med 1999; 25 (2) 207-210
- 60 Bick RL. Disseminated intravascular coagulation: objective clinical and laboratory diagnosis, treatment, and assessment of therapeutic response. Semin Thromb Hemost 1996; 22 (1) 69-88
- 61 Levi M, Meijers JC. DIC: which laboratory tests are most useful. Blood Rev 2011; 25 (1) 33-37
- 62 Dempfle CE, Borggrefe M. Point of care coagulation tests in critically ill patients. Semin Thromb Hemost 2008; 34 (5) 445-450
- 63 Johansson PI, Stensballe J, Vindeløv N, Perner A, Espersen K. Hypocoagulability, as evaluated by thrombelastography, at admission to the ICU is associated with increased 30-day mortality. Blood Coagul Fibrinolysis 2010; 21 (2) 168-174
- 64 Park MS, Martini WZ, Dubick MA , et al. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time. J Trauma 2009; 67 (2) 266-275 , discussion 275–276
- 65 Collins PW, Macchiavello LI, Lewis SJ , et al. Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. Br J Haematol 2006; 135 (2) 220-227
- 66 Taylor Jr FBJ, Toh CH, Hoots WK, Wada H, Levi M ; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (5) 1327-1330
- 67 Bakhtiari K, Meijers JC, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med 2004; 32 (12) 2416-2421
- 68 Toh CH, Hoots WK ; SSC on Disseminated Intravascular Coagulation of the ISTH. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J Thromb Haemost 2007; 5 (3) 604-606
- 69 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
- 70 Levi M. Settling the score for disseminated intravascular coagulation. Crit Care Med 2005; 33 (10) 2417-2418
- 71 Alving BM, Spivak JL, DeLoughery TG. Consultative hematology: Hemostasis and transfusion issues in surgery and critical care medicine. In: McArthur JR, Schechter GP, Schrier SL, , eds. Hematology 1998. The American Society of Hematology Education Program Book; 1998: 320-341
- 72 de Jonge E, Levi M, Stoutenbeek CP, van Deventer SJ. Current drug treatment strategies for disseminated intravascular coagulation. Drugs 1998; 55 (6) 767-777
- 73 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
- 74 Feinstein DI. Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy. Blood 1982; 60 (2) 284-287
- 75 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
- 76 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