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Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy

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Abstract

Purpose

Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course.

Methods

One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score.

Results

Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis.

Conclusion

Endothelial-derived microparticles are relevant biomarkers of septic shock-induced DIC and could be used to evaluate early vascular injury.

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References

  1. Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365:63–78

    Article  PubMed  CAS  Google Scholar 

  2. Fourrier F (2012) Severe sepsis, coagulation, and fibrinolysis: dead end or one way? Crit Care Med 40:2704–2708

    Article  PubMed  Google Scholar 

  3. Levi M (2012) Coagulation and sepsis: a winding road ahead. Crit Care Med 40:2733–2734

    Article  PubMed  Google Scholar 

  4. Gando S (2010) Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med 38:S35–S42

    Article  PubMed  Google Scholar 

  5. Gando S, Wada H, Tachil J; The Scientific Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) (2013) Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost 11:826–835

    Article  Google Scholar 

  6. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86:1327–1330

    PubMed  CAS  Google Scholar 

  7. Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, Mayumi T, Murata A, Ikeda T, Ishikura H, Ueyama M, Ogura H, Kushimoto S, Saitoh D, Endo S, Shimazaki S (2006) A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med 34:625–631

    PubMed  Google Scholar 

  8. Bakhtiari K, Meijers JC, de Jonge E, Levi M (2004) Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med 32:2416–2421

    Article  PubMed  Google Scholar 

  9. Singh RK, Baronia AK, Sahoo JN, Sharma S, Naval R, Pandey CM, Poddar B, Azim A, Gurjar M (2012) Prospective comparison of new Japanese Association for Acute Medicine (JAAM) DIC and International Society of Thrombosis and Hemostasis (ISTH) DIC score in critically ill septic patients. Thromb Res 129:e119–e125

    Article  PubMed  CAS  Google Scholar 

  10. Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, Levi M, Toh CH; The Scientific Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (2013) Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 11:761–767

    Article  Google Scholar 

  11. Boisramé-Helms J, Kremer H, Schini-Kerth V, Meziani F (2013) Endothelial dysfunction in sepsis. Curr Vasc Pharmacol 11:150–160

    PubMed  Google Scholar 

  12. Meziani F, Tesse A, Andriantsitohaina R (2008) Microparticles are vectors of paradoxical information in vascular cells including the endothelium: role in health and diseases. Pharmacol Rep 60:75–84

    PubMed  CAS  Google Scholar 

  13. Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107:1047–1057

    Article  PubMed  CAS  Google Scholar 

  14. Meziani F, Delabranche X, Asfar P, Toti F (2010) Bench-to-bedside review: circulating microparticles a new player in sepsis? Crit Care 14:236

    Article  PubMed  Google Scholar 

  15. Delabranche X, Berger A, Boisramé-Helms J, Meziani F (2012) Microparticles and infectious diseases. Med Mal Infect 42:335–343

    Article  PubMed  CAS  Google Scholar 

  16. Schouten M, Wiersinga WJ, Levi M, van der Poll T (2008) Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 83:536–545

    Article  PubMed  CAS  Google Scholar 

  17. Joop K, Berckmans RJ, Nieuwland R, Berkhout J, Romijn FP, Hack CE, Sturk A (2001) Microparticles from patients with multiple organ dysfunction syndrome and sepsis support coagulation through multiple mechanisms. Thromb Haemost 85:810–820

    PubMed  CAS  Google Scholar 

  18. Perez-Casal M, Thompson V, Downey C, Welters I, Wyncoll D, Thachil J, Toh CH (2011) The clinical and functional relevance of microparticles induced by activated protein C treatment in sepsis. Crit Care 15:R195

    Article  PubMed  Google Scholar 

  19. Mortaza S, Martinez MC, Baron-Menguy C, Burban M, De la Bourdonnaye M, Fizanne L, Pierrot M, Cales P, Henrion D, Andriantsitohaina R, Mercat A, Asfar P, Meziani F (2009) Detrimental hemodynamic and inflammatory effects of microparticles originating from septic rats. Crit Care Med 37:2045–2050

    Article  PubMed  CAS  Google Scholar 

  20. Zafrani L, Gerotziafas G, Byrnes C, Hu X, Perez J, Levi C, Placier S, Letavernier E, Leelahavanichkul A, Haymann JP, Elalamy I, Miller JL, Star RA, Yuen PS, Baud L (2012) Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release. Am J Respir Crit Care Med 185:744–755

    Article  PubMed  CAS  Google Scholar 

  21. Reid VL, Webster NR (2012) Role of microparticles in sepsis. Br J Anaesth 109:503–513

    Article  PubMed  CAS  Google Scholar 

  22. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med 29:530–538

    Article  PubMed  Google Scholar 

  23. Hugel B, Zobairi F, Freyssinet JM (2004) Measuring circulating cell-derived microparticles. J Thromb Haemost 2:1846–1847

    Article  CAS  Google Scholar 

  24. Bakouboula B, Morel O, Faure A, Zobairi F, Jesel L, Trinh A, Zupan M, Canuet M, Grunebaum L, Brunette A, Desprez D, Chabot F, Weitzenblum E, Freyssinet JM, Chaouat A, Toti F (2008) Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension. Am J Respir Crit Care Med 177:536–543

    Article  PubMed  CAS  Google Scholar 

  25. Shapiro NI, Schuetz P, Yano K, Sorasaki M, Parikh SM, Jones AE, Trzeciak S, Ngo L, Aird WC (2010) The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Crit Care 14:13

    Article  Google Scholar 

  26. Levi M, de Jonge E, van der Poll T (2003) Sepsis and disseminated intravascular coagulation. J Thromb Thrombolysis 16:43–47

    Article  PubMed  CAS  Google Scholar 

  27. Levi M (2010) The coagulant response in sepsis and inflammation. Hamostaseologie 30(10–12):14–16

    Google Scholar 

  28. Kushimoto S, Gando S, Saitoh D, Ogura H, Mayumi T, Koseki K, Ikeda T, Ishikura H, Iba T, Ueyama M, Eguchi Y, Otomo Y, Okamoto K, Endo S, Shimazaki S (2008) Clinical course and outcome of disseminated intravascular coagulation diagnosed by Japanese Association for Acute Medicine criteria. Comparison between sepsis and trauma. Thromb Haemost 100:1099–1105

    PubMed  CAS  Google Scholar 

  29. Takemitsu T, Wada H, Hatada T, Ohmori Y, Ishikura K, Takeda T, Sugiyama T, Yamada N, Maruyama K, Katayama N, Isaji S, Shimpo H, Kusunoki M, Nobori T (2011) Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation. Thromb Haemost 105:40–44

    Article  PubMed  CAS  Google Scholar 

  30. Okabayashi K, Wada H, Ohta S, Shiku H, Nobori T, Maruyama K (2004) Hemostatic markers and the sepsis-related organ failure assessment score in patients with disseminated intravascular coagulation in an intensive care unit. Am J Hematol 76:225–229

    Article  PubMed  Google Scholar 

  31. Nieuwland R, Berckmans RJ, McGregor S, Boing AN, Romijn FP, Westendorp RG, Hack CE, Sturk A (2000) Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 95:930–935

    PubMed  CAS  Google Scholar 

  32. Osterud B (2010) Tissue factor expression in blood cells. Thromb Res 125:S31–S34

    Article  PubMed  Google Scholar 

  33. Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renne T, ten Cate H, Spronk HM (2012) Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 10:1355–1362

    Article  Google Scholar 

  34. Heemskerk JW, Mattheij NJ, Cosemans JM (2013) Platelet-based coagulation: different populations, different functions. J Thromb Haemost 11:2–16

    Article  PubMed  CAS  Google Scholar 

  35. de Jong HK, van der Poll T, Wiersinga WJ (2010) The systemic pro-inflammatory response in sepsis. J Innate Immun 2:422–430

    Article  PubMed  Google Scholar 

  36. Ramma W, Ahmed A (2011) Is inflammation the cause of pre-eclampsia? Biochem Soc Trans 39:1619–1627

    Article  PubMed  CAS  Google Scholar 

  37. Dasgupta SK, Abdel-Monem H, Niravath P, Le A, Bellera RV, Langlois K, Nagata S, Rumbaut RE, Thiagarajan P (2009) Lactadherin and clearance of platelet-derived microvesicles. Blood 113:1332–1339

    Article  PubMed  CAS  Google Scholar 

  38. Mosnier LO, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109:3161–3172

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

XD, FT and FM had full access to all the study data and take responsibility for their integrity and the accuracy of the analysis. XD, FT, JMF and FM participated in the study design and obtained funding for the study. XD, PA, YM, JHB, AB and FM collected the data. XD, TL, FT and FM analysed the data; TL provided statistical expertise. XD, JHB, AB, LG, FL and FT performed biological analyses. XD, FT, FL and FM drafted the report, and the report was revised for important intellectual content by XD, PA, LG, CG, JMF, FT and FM. All authors read and approved the final manuscript.

We would like to thank Fatiha Zobairi for sample preparation and MP measurements, Jacqueline Picard for routine haemostasis tests, Sylvie Moog for sGPV analysis, François Lefebvre (MD) for complementary statistical analysis and Maleka Schenck-Dhif (MD) and Dominique Desprez (MD) for manuscript revision and Pierre Pothier for careful English proofreading of the manuscript.

This work was supported by grants from the French Ministry of Health (Projet Hospitalier de Recherche Clinique, Hôpitaux Universitaires de Strasbourg no. 4649), Laboratoire Français de Fractionnement et des Biotechnologies (LFB SA, Les Ullis, France), the Société de Réanimation de Langue Française (SRLF, Paris, France) and the Association pour le Développement et la Recherche en Réanimation (ADRER, Strasbourg, France).

Conflicts of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1, Place de l’Hôpital, 67091, Strasbourg Cedex, France

    Xavier Delabranche, Julie Boisramé-Helms, Asaël Berger & Ferhat Meziani

  2. EA 3072, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de Médecine, Université de Strasbourg, Strasbourg, France

    Xavier Delabranche, Julie Boisramé-Helms, Asaël Berger & Ferhat Meziani

  3. Service de Réanimation Médicale et Médecine Hyperbare, Centre Hospitalier Universitaire d’Angers, Angers, France

    Pierre Asfar

  4. Service de Réanimation Médicale, Centre Hospitalier de Mulhouse, Mulhouse, France

    Yoganaden Mootien

  5. EA 4438, Faculté de Médecine, Université de Strasbourg, Strasbourg, France

    Thierry Lavigne

  6. Laboratoire d’hématologie et Hémostase, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    Lélia Grunebaum

  7. UMR S949 INSERM, Université de Strasbourg et Établissement Français du Sang-Alsace, Strasbourg, France

    François Lanza & Christian Gachet

  8. U770 INSERM, Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, Orsay, France

    Jean-Marie Freyssinet

  9. UMR 7213 CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France

    Florence Toti

Authors
  1. Xavier Delabranche
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  2. Julie Boisramé-Helms
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  8. François Lanza
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  11. Florence Toti
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  12. Ferhat Meziani
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Corresponding author

Correspondence to Ferhat Meziani.

Additional information

Clinicaltrial.gov identifier NCT 01604551

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Delabranche, X., Boisramé-Helms, J., Asfar, P. et al. Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensive Care Med 39, 1695–1703 (2013). https://doi.org/10.1007/s00134-013-2993-x

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  • DOI: https://doi.org/10.1007/s00134-013-2993-x

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