The Pathogenesis of Sepsis

Overview

Journal Annu Rev Pathol

Publisher Annual Reviews

Specialty Pathology

Date 2010 Oct 5

PMID 20887193

Citations 279

Authors

Deborah J Stearns-Kurosawa

Marcin F Osuchowski

Catherine Valentine

Shinichiro Kurosawa

Daniel G Remick

Affiliations

Soon will be listed here.

Abstract

Sepsis is a serious clinical condition that represents a patient's response to a severe infection and has a very high mortality rate. Normal immune and physiologic responses eradicate pathogens, and the pathophysiology of sepsis is due to the inappropriate regulation of these normal reactions. In an ideal scenario, the first pathogen contact with the inflammatory system should eliminate the microbe and quickly return the host to homeostasis. The septic response may accelerate due to continued activation of neutrophils and macrophages/monocytes. Upregulation of lymphocyte costimulatory molecules and rapid lymphocyte apoptosis, delayed apoptosis of neutrophils, and enhanced necrosis of cells/tissues also contribute to the pathogenesis of sepsis. The coagulation system is closely tied to the inflammatory response, with cross talk between the two systems driving the dysregulated response. Biomarkers may be used to help diagnose patients with sepsis, and they may also help to identify patients who would benefit from immunomodulatory therapies.

Citing Articles

Corticosteroids in Cardiogenic Shock: A Retrospective Analysis of the Medical Information Mart for Intensive Care-IV Database.

Haddad G, Maslove D, Mbuagbaw L, Belley-Cote E, Rochwerg B Crit Care Explor. 2025; 7(2):e1210.

PMID: 39888591 PMC: 11789865. DOI: 10.1097/CCE.0000000000001210.

Association between D-dimer to lymphocyte ratio and in hospital all-cause mortality in elderly patients with sepsis: a cohort of 1123 patients.

Long X, Hu Z, Song C, Zhang J Front Cell Infect Microbiol. 2025; 14:1507992.

PMID: 39877653 PMC: 11772276. DOI: 10.3389/fcimb.2024.1507992.

Intestinal microbiome metabolites control sepsis outcome.

Polonio C, Quintana F Nat Immunol. 2025; 26(2):155-156.

PMID: 39825093 DOI: 10.1038/s41590-024-02050-1.

Prevalence of pathogenic variants of inborn errors of immunity in critically ill children admitted to the pediatric intensive care unit for sepsis: A Moroccan cohort study.

Aissaoui O, Moundir A, Drissi Boughanbour A, El Bakkouri J, Benhsaien I, Ailal F Tunis Med. 2025; 103(1):93-97.

PMID: 39812200 PMC: 11906231. DOI: 10.62438/tunismed.v103i1.5182.

Systemic inflammatory response index improves prognostic predictive value in intensive care unit patients with sepsis.

Xu T, Song S, Zhu K, Yang Y, Wu C, Wang N Sci Rep. 2025; 15(1):1908.

PMID: 39809872 PMC: 11732978. DOI: 10.1038/s41598-024-81860-7.

References

Borensztajn K, Peppelenbosch M, Spek C . Factor Xa: at the crossroads between coagulation and signaling in physiology and disease. Trends Mol Med. 2008; 14(10):429-40. DOI: 10.1016/j.molmed.2008.08.001. View

Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer K . In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005; 3(3):514-21. DOI: 10.1111/j.1538-7836.2005.01166.x. View

Fisher Jr C, Agosti J, Opal S, Lowry S, Balk R, Sadoff J . Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996; 334(26):1697-702. DOI: 10.1056/NEJM199606273342603. View

Di Nisio M, Middeldorp S, Buller H . Direct thrombin inhibitors. N Engl J Med. 2005; 353(10):1028-40. DOI: 10.1056/NEJMra044440. View

de Jonge E, Dekkers P, Creasey A, Hack C, Paulson S, Karim A . Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood. 2000; 95(4):1124-9. View

Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B . Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2002; 345(19):1368-77. DOI: 10.1056/NEJMoa010307. View

Abraham E, Laterre P, Garg R, Levy H, Talwar D, Trzaskoma B . Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005; 353(13):1332-41. DOI: 10.1056/NEJMoa050935. View

Barber D, Wherry E, Masopust D, Zhu B, Allison J, Sharpe A . Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2005; 439(7077):682-7. DOI: 10.1038/nature04444. View

Bode W . The structure of thrombin: a janus-headed proteinase. Semin Thromb Hemost. 2006; 32 Suppl 1:16-31. DOI: 10.1055/s-2006-939551. View

10.

Suntharalingam G, Perry M, Ward S, Brett S, Castello-Cortes A, Brunner M . Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006; 355(10):1018-28. DOI: 10.1056/NEJMoa063842. View

11.

Marlar R, Kleiss A, Griffin J . Human protein C: inactivation of factors V and VIII in plasma by the activated molecule. Ann N Y Acad Sci. 1981; 370:303-10. DOI: 10.1111/j.1749-6632.1981.tb29743.x. View

12.

Bogdanov V, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y . Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med. 2003; 9(4):458-62. DOI: 10.1038/nm841. View

13.

Fischer D, Schloesser R, Nold-Petry C, Nold M, Veldman A . Protein C concentrate in preterm neonates with sepsis. Acta Paediatr. 2009; 98(9):1526-9. DOI: 10.1111/j.1651-2227.2009.01404.x. View

14.

Hotchkiss R, Chang K, Grayson M, Tinsley K, Dunne B, Davis C . Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proc Natl Acad Sci U S A. 2003; 100(11):6724-9. PMC: 164514. DOI: 10.1073/pnas.1031788100. View

15.

Lavrentieva A, Kontakiotis T, Lazaridis L, Tsotsolis N, Koumis J, Kyriazis G . Inflammatory markers in patients with severe burn injury. What is the best indicator of sepsis?. Burns. 2007; 33(2):189-94. DOI: 10.1016/j.burns.2006.07.001. View

16.

Ahamed J, Versteeg H, Kerver M, Chen V, Mueller B, Hogg P . Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci U S A. 2006; 103(38):13932-7. PMC: 1599891. DOI: 10.1073/pnas.0606411103. View

17.

Rey C, Arcos M, Concha A, Medina A, Prieto S, Martinez P . Procalcitonin and C-reactive protein as markers of systemic inflammatory response syndrome severity in critically ill children. Intensive Care Med. 2007; 33(3):477-84. DOI: 10.1007/s00134-006-0509-7. View

18.

Keel M, Ungethum U, Steckholzer U, Niederer E, Hartung T, Trentz O . Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. Blood. 1997; 90(9):3356-63. View

19.

Remick D . Cytokine therapeutics for the treatment of sepsis: why has nothing worked?. Curr Pharm Des. 2003; 9(1):75-82. DOI: 10.2174/1381612033392567. View

20.

de Kleijn E, de Groot R, Hack C, Mulder P, Engl W, Moritz B . Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study. Crit Care Med. 2003; 31(6):1839-47. DOI: 10.1097/01.CCM.0000072121.61120.D8. View