Semin Thromb Hemost 2007; 33(6): 604-609
DOI: 10.1055/s-2007-985757
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Thrombophilia and Outcome in Severe Infection and Sepsis

Jorrit-Jan Hofstra1 , 2 , Marcel Schouten1 , 3 , 4 , Marcel Levi1
  • 1Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • 2Laboratory of Experimental Intensive Care and Anesthesiology
  • 3Center for Infection and Immunity Amsterdam (CINIMA)
  • 4Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Publikationsverlauf

Publikationsdatum:
04. September 2007 (online)

ABSTRACT

Thrombophilia is associated with a prohemostatic state and consequently with an increased tendency to develop thrombosis. In severe infection and sepsis, activation of coagulation frequently occurs, which contributes to the development of multiple organ dysfunction. Hypothetically, patients with thrombophilia may suffer from more severe coagulopathy in the presence of severe infection or sepsis, which may result in a more serious clinical course and an unfavorable outcome. This article reviews experimental and clinical evidence regarding such a relationship, with a particular focus on deficiencies of natural anticoagulant proteins (protein C and antithrombin), the factor V Leiden mutation, and genetic variation in the fibrinolytic system.

REFERENCES

  • 1 Wheeler A P, Bernard G R. Treating patients with severe sepsis.  N Engl J Med. 1999;  340 207-214
  • 2 Martin G S, Mannino D M, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000.  N Engl J Med. 2003;  348 1546-1554
  • 3 Levi M. Current understanding of disseminated intravascular coagulation.  Br J Haematol. 2004;  124 567-576
  • 4 Levi M, ten Cate H. Disseminated intravascular coagulation.  N Engl J Med. 1999;  341 586-592
  • 5 Colman R W, Robboy S J, Minna J D. Disseminated intravascular coagulation: a reappraisal.  Annu Rev Med. 1979;  30 359-374
  • 6 Marder V J, Feinstein D I, Colman R W, Levi M. Consumptive thrombohemorrhagic disorders. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA; J.B. Lippincott 2006: 1571-1600
  • 7 Levi M, van Gorp E, ten Cate H. Disseminated intravascular coagulation. In: Handin RI, Lux SE, Stossel TP Blood: Principles and Practice of Hematology. Philadelphia, PA; J.B. Lippincott 2002: 1275-1301
  • 8 Levi M, de Jonge E, van der Poll T. Sepsis and disseminated intravascular coagulation.  J Thromb Thrombolysis. 2003;  16 43-47
  • 9 Levi M, Keller T T, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system.  Cardiovasc Res. 2003;  60 26-39
  • 10 Robboy S J, Major M C, Colman R W, Minna J D. Pathology of disseminated intravascular coagulation (DIC). Analysis of 26 cases.  Hum Pathol. 1972;  3 327-343
  • 11 Shimamura K, Oka K, Nakazawa M, Kojima M. Distribution patterns of microthrombi in disseminated intravascular coagulation.  Arch Pathol Lab Med. 1983;  107 543-547
  • 12 Coalson J J. Pathology of Sepsis, Septic Shock, and Multiple Organ Failure. Perspective on Sepsis and Septic Shock. Fullerton, CA; Society of Critical Care Medicine 1986: 27-59
  • 13 Creasey A A, Chang A C, Feigen L et al.. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.  J Clin Invest. 1993;  91 2850-2856
  • 14 Kessler C M, Tang Z, Jacobs H M, Szymanski L M. 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 4393-4401
  • 15 Taylor F BJ, Chang A, Ruf W et al.. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody.  Circ Shock. 1991;  33 127-134
  • 16 Taylor F BJ, Chang A, Esmon C T et al.. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.  J Clin Invest. 1987;  79 918-925
  • 17 Welty-Wolf K E, Carraway M S, Miller D L et al.. Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons.  Am J Respir Crit Care Med. 2001;  164 1988-1996
  • 18 Miller D L, Welty-Wolf K, Carraway M S et al.. Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide.  Am J Respir Cell Mol Biol. 2002;  26 650-658
  • 19 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;  101 816-823
  • 20 Dhainaut J F, Yan S B, Joyce D E 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 1924-1933
  • 21 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 1086-1089
  • 22 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 1-5
  • 23 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;  16 561-564
  • 24 Woods C R, Johnson C A. Varicella purpura fulminans associated with heterozygosity for factor V Leiden and transient protein S deficiency.  Pediatrics. 1998;  102 1208-1210
  • 25 Sackesen C, Secmeer G, Gurgey A et al.. Homozygous factor V Leiden mutation in a child with meningococcal purpura fulminans.  Pediatr Infect Dis J. 1998;  17 87
  • 26 Texereau J, Pene F, Chiche J D, Rousseau C, Mira J P. Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis.  Crit Care Med. 2004;  32 S313-S319
  • 27 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 S90-S94
  • 28 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
  • 29 Lay A J, Liang Z, Rosen E D, Castellino F J. Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities.  J Clin Invest. 2005;  115 1552-1561
  • 30 Jalbert L R, Rosen E D, Moons L et al.. Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice.  J Clin Invest. 1998;  102 1481-1488
  • 31 Levi M, Dorffler-Melly J, Reitsma P H et al.. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein C deficient mice.  Blood. 2003;  101 4823-4827
  • 32 Levi M, van der Poll T, Buller H R. Bidirectional relation between inflammation and coagulation.  Circulation. 2004;  109 2698-2704
  • 33 Lay A J, Donahue D, Tsai M J, Castellino F J. Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency.  Blood. 2007;  109 1984-1991
  • 34 Ganopolsky J G, Castellino F J. A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model.  Am J Pathol. 2004;  165 1433-1446
  • 35 Mesters R M, Mannucci P M, Coppola R et al.. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients.  Blood. 1996;  88 881-886
  • 36 Minnema M C, Chang A C, Jansen P M et al.. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli .  Blood. 2000;  95 1117-1123
  • 37 Yanada M, Kojima T, Ishiguro K et al.. Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice.  Blood. 2002;  99 2455-2458
  • 38 Kondaveeti S, Hibberd M L, Booy R, Nadel S, Levin M. Effect of the factor V Leiden mutation on the severity of meningococcal disease.  Pediatr Infect Dis J. 1999;  18 893-896
  • 39 Kerlin B A, Yan S B, Isermann B H et al.. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia.  Blood. 2003;  102 3085-3092
  • 40 Bruggemann L W, Schoenmakers S H, Groot A P, Reitsma P H, Spek C A. Role of the factor V Leiden mutation in septic peritonitis assessed in factor V Leiden transgenic mice.  Crit Care Med. 2006;  34 2201-2206
  • 41 Bernard G R, Margolis B D, Shanies H M et al.. 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 2206-2216
  • 42 Yan S B, Nelson D R. Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C.  Crit Care Med. 2004;  32 S239-S246
  • 43 Benfield T L, Dahl M, Nordestgaard B G, 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 1851-1857
  • 44 Weiler H, Kerlin B, Lytle M C, Factor V. Leiden polymorphism modifies sepsis outcome: evidence from animal studies.  Crit Care Med. 2004;  32 S233-S238
  • 45 van der Poll T, Levi M, Buller H R et al.. Fibrinolytic response to tumor necrosis factor in healthy subjects.  J Exp Med. 1991;  174 729-732
  • 46 Biemond B J, Levi M, ten Cat 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. 1995;  88 587-594
  • 47 Yamamoto K, Loskutoff D J. 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 2440-2451
  • 48 Pinsky D J, Liao H, Lawson C A et al.. Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.  J Clin Invest. 1998;  102 919-928
  • 49 Haralambous E, Hibberd M L, Hermans P W et al.. Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children.  Crit Care Med. 2003;  31 2788-2793
  • 50 Hermans P W, Hibberd M L, Booy R et al.. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group.  Lancet. 1999;  354 556-560
  • 51 Westendorp R G, Hottenga J J, Slagboom P E. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock.  Lancet. 1999;  354 561-563
  • 52 Geishofer G, Binder A, Muller M et al.. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia.  Eur J Pediatr. 2005;  164 486-490

Marcel LeviM.D. Ph.D. 

Department of Medicine (F-4), Academic Medical Center, University of Amsterdam

Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

eMail: m.m.levi@amc.uva.nl