Inflammation, Sepsis, and the Coagulation System

Abstract

Sepsis has been a major health problem for centuries and it is still the leading cause of hospital deaths. Several studies in the past decades have identified numerous biochemical abnormalities in severe cases, and many of these studies provide evidence of the perturbation of the hemostatic system. This can result in complications, such as disseminated intravascular coagulation that can lead to multiorgan failure. Nevertheless, large clinical studies have demonstrated that the simple approach of inhibiting the coagulation processes by any means fails to provide significant improvement in the survival of septic patients. A cause of this failure could be the fact that in sepsis the major clinical problems result not primarily from the presence of the infective agent or enhanced coagulation but from the complex dysregulated systemic host response to pathogens. If this overt reaction is not fully deciphered, appropriate interference is highly unlikely and any improvement by conventional therapeutic interventions would be limited. Cellular activation in sepsis can be targeted by novel approaches like inhibition of the heterotypic cellular interactions of blood cells by targeting surface receptors or posttranscriptional control of the hemostatic system by noncoding ribonucleic acid (RNA) molecules. Stable RNA molecules can affect the expression of several proteins. Thus, it can be anticipated that modulation of microRNA production would result in a multitude of effects that may be beneficial in septic cases. Here, we highlight some of the recent diagnostic possibilities and potential novel routes of the dysregulated host response.

Keywords

sepsis - inflammation - biomarker - p-selectin - procoagulant platelets - microRNAs

Author Contributions

J.K. supervised a part of the study and wrote the manuscript. I.B.D. set up laboratory assays regarding thrombin generation and performed experiments. Z.F. performed microRNA measurements and other laboratory tests. B.N. Jr. provided ideas for experiments, supervised a part of the sepsis studies, and critically reviewed this manuscript.

Publication History

Received: 30 October 2023

Accepted: 21 December 2023

Article published online:
14 February 2024

• References

• 1 Kaukonen K-M, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015; 372 (17) 1629-1638
• 2 Arora J, Mendelson AA, Fox-Robichaud A. Sepsis: network pathophysiology and implications for early diagnosis. Am J Physiol Regul Integr Comp Physiol 2023; 324 (05) R613-R624
• 3 Liu XL, Wang XZ, Liu XX. et al. Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: a prospective clinical study. Exp Ther Med 2014; 7 (03) 604-608
• 4 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124 (04) 783-801
• 5 Osuchowski MF, Welch K, Siddiqui J, Remick DG. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 2006; 177 (03) 1967-1974
• 6 Hotchkiss RS, Swanson PE, Freeman BD. et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27 (07) 1230-1251
• 7 Sharma A, Yang WL, Matsuo S, Wang P. Differential alterations of tissue T-cell subsets after sepsis. Immunol Lett 2015; 168 (01) 41-50
• 8 Martin MD, Badovinac VP, Griffith TS. CD4 T cell responses and the sepsis-induced immunoparalysis state. Front Immunol 2020; 11: 1364
• 9 Otto GP, Sossdorf M, Claus RA. et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit Care 2011; 15 (04) R183-R183
• 10 Singer M, Deutschman CS, Seymour CW. et al. The third international consensus definitions forsepsis and septic shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
• 11 Shen G, Li S, Shao Z. et al. Platelet indices in patients with acute appendicitis: a systematic review with meta-analysis. Updates Surg 2021; 73 (04) 1327-1341
• 12 Jiang SQ, Huang QF, Xie WM, Lv C, Quan XQ. The association between severe COVID-19 and low platelet count: evidence from 31 observational studies involving 7613 participants. Br J Haematol 2020; 190 (01) e29-e33
• 13 Leli C, Di Matteo L, Gotta F. et al. Clinical utility of platelet count for screening of malaria. New Microbiol 2020; 43 (02) 89-92
• 14 Levi M, de Jonge E, van der Poll T. Sepsis and disseminated intravascular coagulation. J Thromb Thrombolysis 2003; 16 (1-2): 43-47
• 15 Shimizu M, Konishi A, Nomura S. Examination of biomarker expressions in sepsis-related DIC patients. Int J Gen Med 2018; 11: 353-361
• 16 McEver RP, Martin MN. A monoclonal antibody to a membrane glycoprotein binds only to activated platelets. J Biol Chem 1984; 259 (15) 9799-9804
• 17 Kappelmayer J, Nagy Jr B, Miszti-Blasius K, Hevessy Z, Setiadi H. The emerging value of P-selectin as a disease marker. Clin Chem Lab Med 2004; 42 (05) 475-486
• 18 Zonneveld R, Martinelli R, Shapiro NI, Kuijpers TW, Plötz FB, Carman CV. Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults. Crit Care 2014; 18 (02) 204
• 19 McEver RP. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res 2015; 107 (03) 331-339
• 20 McEver RP, Beckstead JH, Moore KL, Marshall-Carlson L, Bainton DFJ. GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. J Clin Invest 1989; 84 (01) 92-99
• 21 Schrijver IT, Kemperman H, Roest M, Kesecioglu J, de Lange DW. Soluble P-selectin as a biomarker for infection and survival in patients with a systemic inflammatory response syndrome on the intensive care unit. Biomark Insights 2017; 12: 11 77271916684823
• 22 Frenette PS, Johnson RC, Hynes RO, Wagner DD. Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci U S A 1995; 92 (16) 7450-7454
• 23 Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002; 300 (03) 729-735
• 24 Osterud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 1983; 49 (01) 5-7
• 25 Rahman M, Roller J, Zhang S. et al. Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis. Inflamm Res 2012; 61 (06) 571-579
• 26 Stokes KY, Granger DN. Platelets: a critical link between inflammation and microvascular dysfunction. J Physiol 2012; 590 (05) 1023-1034
• 27 Zhang C, Shang X, Yuan Y, Li Y. Platelet–related parameters as potential biomarkers for the prognosis of sepsis. Exp Ther Med 2023; 25 (03) 133
• 28 Schwertz H, Tolley ND, Foulks JM. et al. Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med 2006; 203 (11) 2433-2440
• 29 Panes O, Matus V, Sáez CG, Quiroga T, Pereira J, Mezzano D. Human platelets synthesize and express functional tissue factor. Blood 2007; 109 (12) 5242-5250
• 30 Rondina MT, Schwertz H, Harris ES. et al. The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost 2011; 9 (04) 748-758
• 31 Polgar J, Matuskova J, Wagner DD. The P-selectin, tissue factor, coagulation triad. J Thromb Haemost 2005; 3 (08) 1590-1596
• 32 Michelson AD, Barnard MR, Krueger LA, Valeri CR, Furman MI. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104 (13) 1533-1537
• 33 Evangelista V, Smyth SS, Michelson A. Interactions between platelets, leukocytes, and endothelium. In: Platelets. 3rd ed. London:: Elsevier;; 2013: 295-312
• 34 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
• 35 Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin?. J Cell Biol 2012; 198 (05) 773-783
• 36 Abrams ST, Morton B, Alhamdi Y. et al. A novel assay for neutrophil extracellular trap formation independently predicts disseminated intravascular coagulation and mortality in critically ill patients. Am J Respir Crit Care Med 2019; 200 (07) 869-880
• 37 Ko YP, Flick MJ. Fibrinogen is at the interface of host defense and pathogen virulence in Staphylococcus aureus infection. Semin Thromb Hemost 2016; 42 (04) 408-421
• 38 Omiya K, Sato H, Sato T. et al. Albumin and fibrinogen kinetics in sepsis: a prospective observational study. Crit Care 2021; 25 (01) 436
• 39 Mori K, Tsujita Y, Yamane T, Eguchi Y. Decreasing plasma fibrinogen levels in the intensive care unit are associated with high mortality rates in patients with sepsis-induced coagulopathy. Clin Appl Thromb Hemost 2022; 28: 10 760296221101386
• 40 Yao C, Zhang G, Zhang N. et al. Fibrinogen is associated with prognosis of critically ill patients with sepsis: a study based on Cox regression and propensity score matching. Mediators Inflamm 2023; 2023: 7312822
• 41 Wang G, Liu J, Xu R, Liu X. Elevated plasma D-dimer levels are associated with the poor prognosis of critically ill children. Front Pediatr 2022; 10: 1001893
• 42 Li T, Hu WQ, Li X. et al. Prognostic value of PaO₂/FiO₂, SOFA and D-dimer in elderly patients with sepsis. Integr Med Res 2022; 50 (06) 1-10
• 43 Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P. Experimental models of sepsis and their clinical relevance. Shock 2008; 30 (Suppl. 01) 53-59
• 44 Roller J, Wang Y, Rahman M. et al. Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte-endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice. Inflamm Res 2013; 62 (03) 275-282
• 45 Tóth J, Debreceni IB, Berhés M. et al. Red blood cell and platelet parameters are sepsis predictors in an Escherichia coli induced lethal porcine model. Clin Hemorheol Microcirc 2017; 66 (03) 249-259
• 46 Yamakawa K, Ogura H, Koh T. et al. Platelet mitochondrial membrane potential correlates with severity in patients with systemic inflammatory response syndrome. J Trauma Acute Care Surg 2013; 74 (02) 411-417 , discussion 418
• 47 Dolmatova EV, Wang K, Mandavilli R, Griendling KK. The effects of sepsis on endothelium and clinical implications. Cardiovasc Res 2021; 117 (01) 60-73
• 48 van Horssen J, van Schaik P, Witte M. Inflammation and mitochondrial dysfunction: a vicious circle in neurodegenerative disorders?. Neurosci Lett 2019; 710: 132931
• 49 Tóth J, Debreceni IB, Deák Á. et al. Characteristics of thrombin generation in a fulminant porcine sepsis model. Thromb Res 2017; 158: 25-34 (b)
• 50 Wang Y, Braun OO, Zhang S, Luo L, Norström E, Thorlacius H. Dynamic changes in thrombin generation in abdominal sepsis in mice. Shock 2014; 42 (04) 343-349
• 51 Park J, Kang E, Kang S. et al. Mitochondrial gene mutations in pediatric septic shock. Pediatr Res 2021; 90 (05) 1016-1022
• 52 Umemura Y, Nishida T, Yamakawa K, Ogura H, Oda J, Fujimi S. Anticoagulant therapies against sepsis-induced disseminated intravascular coagulation. Acute Med Surg 2023; 10 (01) e884
• 53 Jaimes F, De La Rosa G, Morales C. et al. Unfractioned heparin for treatment of sepsis: a randomized clinical trial (The HETRASE Study). Crit Care Med 2009; 37 (04) 1185-1196
• 54 Liu V, Escobar GJ, Greene JD. et al. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA 2014; 312 (01) 90-92
• 55 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
• 56 Faust SN, Levin M, Harrison OB. et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345 (06) 408-416
• 57 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
• 58 Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004; 24 (08) 1374-1383
• 59 Vincent JL, Francois B, Zabolotskikh I. et al; SCARLET Trial Group. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical Trial. JAMA 2019; 321 (20) 1993-2002
• 60 Davenport EE, Burnham KL, Radhakrishnan J. et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 2016; 4 (04) 259-271
• 61 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116 (02) 281-297
• 62 Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V, Bansal P. MicroRNA therapeutics: discovering novel targets and developing specific therapy. Perspect Clin Res 2016; 7 (02) 68-74
• 63 Nilsen TW. Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet 2007; 23 (05) 243-249
• 64 Chen X, Liang H, Zhang J, Zen K, Zhang CY. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol 2012; 22 (03) 125-132
• 65 Águila S, Cuenca-Zamora E, Martínez C, Teruel-Montoya R. MicroRNAs in platelets: should I stay or should I go? In: Kerrigan SW, ed. Platelets. London:: IntechOpen; 2020
• 66 Szilágyi B, Fejes Z, Póliska S. et al. Reduced miR-26b expression in megakaryocytes and platelets contributes to elevated level of platelet activation status in sepsis. Int J Mol Sci 2020; 21 (03) 866
• 67 Elgheznawy A, Shi L, Hu J. et al. Dicer cleavage by calpain determines platelet microRNA levels and function in diabetes. Circ Res 2015; 117 (02) 157-165
• 68 Laffont B, Corduan A, Plé H. et al. Activated platelets can deliver mRNA regulatory Ago2•microRNA complexes to endothelial cells via microparticles. Blood 2013; 122 (02) 253-261
• 69 Laffont B, Corduan A, Rousseau M. et al. Platelet microparticles reprogram macrophage gene expression and function. Thromb Haemost 2016; 115 (02) 311-323
• 70 Maiese A, Scatena A, Costantino A. et al. Expression of MicroRNAs in sepsis-related organ dysfunction: a systematic review. Int J Mol Sci 2022; 23 (16) 9354