Semin Thromb Hemost 2011; 37(8): 955-960
DOI: 10.1055/s-0031-1297374
© Thieme Medical Publishers

Factor V Leiden Mutation in Severe Infection and Sepsis

Marcel Levi1 , Marcel Schouten1 , 2 , 3 , Cees van't Veer1 , 2 , 3 , Tom van der Poll1 , 2 , 3
  • 1Department of Medicine, Academic Medical Center, University of Amsterdam, The Netherlands
  • 2Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, The Netherlands
  • 3Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Further Information

Publication History

Publication Date:
23 December 2011 (online)

ABSTRACT

In severe infection and sepsis, activation of coagulation frequently occurs, which contributes to the development of multiple organ dysfunction. Factor V Leiden is a relatively common mutation resulting in a mild prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with factor V Leiden may suffer from more severe coagulopathy in cases of severe infection or sepsis. Aggravation of the procoagulant state in sepsis may subsequently result in more severe organ dysfunction and an increased risk of death. In this article we review the experimental and clinical evidence regarding the relationship between the presence of a factor V Leiden mutation and the incidence and outcome of sepsis.

REFERENCES

  • 1 Levi M. Current understanding of disseminated intravascular coagulation.  Br J Haematol. 2004;  124 (5) 567-576
  • 2 Levi M. Disseminated intravascular coagulation: a disease-specific approach.  Semin Thromb Hemost. 2010;  36 (4) 363-365
  • 3 Levi M, Ten Cate H. Disseminated intravascular coagulation.  N Engl J Med. 1999;  341 (8) 586-592
  • 4 Levi M, Schultz M, van der Poll T. Disseminated intravascular coagulation in infectious disease.  Semin Thromb Hemost. 2010;  36 (4) 367-377
  • 5 Levi M, Marder V J. Coagulation abnormalities in sepsis. In: Colman R W, Marder V J, Clowes A W, George J N, Goldhaber SZ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia: Lippincott William and Wilkins; 2006: 1601-1613
  • 6 Wheeler A P, Bernard G R. Treating patients with severe sepsis.  N Engl J Med. 1999;  340 (3) 207-214
  • 7 Levi M, de Jonge E, van der Poll T. Sepsis and disseminated intravascular coagulation.  J Thromb Thrombolysis. 2003;  16 (1-2) 43-47
  • 8 Levi M, Keller T T, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system.  Cardiovasc Res. 2003;  60 (1) 26-39
  • 9 Levi M, van der Poll T. Inflammation and coagulation.  Crit Care Med. 2010;  38 (2, Suppl) S26-S34
  • 10 Anas A A, Wiersinga W J, de Vos A F, van der Poll T. Recent insights into the pathogenesis of bacterial sepsis.  Neth J Med. 2010;  68 (4) 147-152
  • 11 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 (3) 327-343
  • 12 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
  • 13 Coalson J J. Pathology of sepsis, septic shock, and multiple organ failure. In: Sibbald WJ, ed. Perspective on Sepsis and Septic Shock. Fullerton, CA: Society of Critical Care Medicine; 1986: 27-59
  • 14 Levi M. The coagulant response in sepsis.  Clin Chest Med. 2008;  29 (4) 627-642 viii viii
  • 15 Creasey A A, Chang A C, Feigen L, Wün T C, Taylor Jr FBJ, Hinshaw L B. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.  J Clin Invest. 1993;  91 (6) 2850-2860
  • 16 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 (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 C T, D'Angelo A, Vigano-D'Angelo S, Blick K E. 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 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 (10 Pt 1) 1988-1996
  • 20 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 (6) 650-658
  • 21 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
  • 22 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 (11) 1924-1933
  • 23 Levi M, Löwenberg E C. Thrombocytopenia in critically ill patients.  Semin Thromb Hemost. 2008;  34 (5) 417-424
  • 24 Vanderschueren S, De Weerdt A, Malbrain M et al.. Thrombocytopenia and prognosis in intensive care.  Crit Care Med. 2000;  28 (6) 1871-1876
  • 25 Levi M M, Eerenberg E, Löwenberg E, Kamphuisen P W. Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management.  Neth J Med. 2010;  68 (2) 68-76
  • 26 Löwenberg E C, Meijers J C, Levi M. Platelet-vessel wall interaction in health and disease.  Neth J Med. 2010;  68 (6) 242-251
  • 27 Middeldorp S, Levi M. Thrombophilia: an update.  Semin Thromb Hemost. 2007;  33 (6) 563-572
  • 28 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
  • 29 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
  • 30 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
  • 31 Woods C R, Johnson C A. Varicella purpura fulminans associated with heterozygosity for factor V leiden and transient protein S deficiency.  Pediatrics. 1998;  102 (5) 1208-1210
  • 32 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
  • 33 Hofstra J J, Schouten M, Levi M. Thrombophilia and outcome in severe infection and sepsis.  Semin Thromb Hemost. 2007;  33 (6) 604-609
  • 34 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 (5, Suppl) S313-S319
  • 35 Mesters R M, Mannucci P M, 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
  • 36 Levi M, Schouten M, van der Poll T. Sepsis, coagulation, and antithrombin: old lessons and new insights.  Semin Thromb Hemost. 2008;  34 (8) 742-746
  • 37 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 (4) 1117-1123
  • 38 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 (7) 2455-2458
  • 39 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
  • 40 Bernard G R, Vincent J L, Laterre P F Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group et al. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 (10) 699-709
  • 41 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 (6) 1552-1561
  • 42 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 (8) 1481-1488
  • 43 Levi M, Dörffler-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 (12) 4823-4827
  • 44 Levi M, van der Poll T, Büller H R. Bidirectional relation between inflammation and coagulation.  Circulation. 2004;  109 (22) 2698-2704
  • 45 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 (5) 1984-1991
  • 46 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 (4) 1433-1446
  • 47 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 (10) 893-896
  • 48 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 (9) 3085-3092
  • 49 Schouten M, van't Veer C, Roelofs J J, 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
  • 50 Brüggemann 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 (8) 2201-2206
  • 51 Schouten M, van der Sluijs K F, Roelofs J J, 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
  • 52 Elmas E, Suvajac N, Jilma B, Weiler H, Borggrefe M, Dempfle C E. Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model.  Blood. 2010;  116 (5) 801-805
  • 53 Bernard G R, Margolis B D, Shanies H M Extended Evaluation of Recombinant Human Activated Protein C United States Investigators 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 (6) 2206-2216
  • 54 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 (5, Suppl) S239-S246
  • 55 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 (10) 1851-1857
  • 56 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
  • 57 Tsantes A E, Tsangaris I, Bonovas S et al.. The effect of four hemostatic gene polymorphisms on the outcome of septic critically ill patients.  Blood Coagul Fibrinolysis. 2010;  21 (2) 175-181
  • 58 Adamzik M, Frey U H, Riemann K et al.. Factor V Leiden mutation is associated with improved 30-day survival in patients with acute respiratory distress syndrome.  Crit Care Med. 2008;  36 (6) 1776-1779
  • 59 Weiler H, Kerlin B, Lytle M C. Factor V Leiden polymorphism modifies sepsis outcome: evidence from animal studies.  Crit Care Med. 2004;  32 (5, Suppl) S233-S238

Marcel LeviM.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

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