Skip to main content

Advertisement

SpringerLink
Log in

Relationship between serum zinc level and sepsis-induced coagulopathy

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Background

We investigated whether a decrease in the serum zinc level (SZL) among patients with sepsis admitted to the intensive care unit (ICU) was related to sepsis-induced coagulopathy.

Methods

All patients (≥20 years) with a diagnosis of sepsis defined by Sepsis-3 criteria, presenting to the ICU between June 2016 and July 2017, were enrolled. Demographic characteristics and the Sequential Organ Failure Assessment (SOFA) and Japanese Association of Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) scores were recorded. Blood samples were collected upon admission and analyzed for SZL.

Results

One hundred patients with sepsis (median age, 70 years) were enrolled. Patients with SOFA scores ≥8 had a significantly lower SZL compared to those with SOFA scores <8 (p < 0.001). The SZL in the DIC group (JAAM DIC score ≥4) was significantly lower than that in the non-DIC group (JAAM DIC score <4) (p < 0.001). Analysis of receiver operating characteristic (ROC) curves for prediction of sepsis-induced DIC based on SZL in patients with sepsis showed a cut-off value of 25 µg/dL for zinc level and a sensitivity of 63% and a specificity of 72% with AUC of 0.7 (p = 0.0065).

Conclusion

We observed that SZL reflects organ failure, particularly coagulopathy, in patients with sepsis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and materials

The dataset generated and/or analyzed during the current study is not publicly available because of patient-related confidentiality, but is available from the corresponding author upon reasonable request.

Abbreviations

APACHE:

Acute physiology and chronic health evaluation

AUC:

area under the curve

BMI:

Body mass index

DIC:

Disseminated intravascular coagulation

ICU:

Intensive care unit

JAAM:

Japanese association of acute medicine

MODS:

Multiple-organ dysfunction syndrome

PAI:

Plasminogen activator inhibitor

PC:

Protein C

PT:

Prothrombin time

ROC:

Receiver operating characteristic

SOFA:

Sequential organ failure assessment

SIRS:

Systemic inflammatory response syndrome

TNF-α:

Tumor necrotic factor alpha

WBC:

White blood cell

References

  1. Walkey AJ, Lagu T, Lindenauer PK. Trends in sepsis and infection sources in the United States. A population-based study. Ann Am Thorac Soc. 2015;12:216–20.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–51.

    Article  CAS  PubMed  Google Scholar 

  3. Russell JA. Management of sepsis. N Engl J Med. 2006;355:1699–713.

    Article  CAS  PubMed  Google Scholar 

  4. Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. BMJ (Clinical research ed). 2007;335:879–83.

    Article  CAS  PubMed Central  Google Scholar 

  5. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.

    Article  CAS  PubMed  Google Scholar 

  6. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.

    Article  CAS  PubMed  Google Scholar 

  7. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614.

    Article  PubMed  Google Scholar 

  8. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149:38–44.

    Article  CAS  PubMed  Google Scholar 

  9. Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation. 2004;109:2698–704.

    Article  PubMed  Google Scholar 

  10. Alker W, Haase H. Zinc and sepsis. Nutrients. 2018;10:976.

    Article  PubMed Central  Google Scholar 

  11. Mertens K, Lowes DA, Webster NR, Talib J, Hall L, Davies MJ, et al. Low zinc and selenium concentrations in sepsis are associated with oxidative damage and inflammation. Br J Anaesth. 2015;114:990–9.

    Article  CAS  PubMed  Google Scholar 

  12. Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine C, et al. Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev. 2013;93:1247–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Davies MJ. The oxidative environment and protein damage. Biochim Biophys Acta. 2005;1703:93–109.

    Article  CAS  PubMed  Google Scholar 

  14. Prasad AS, Bao B, Beck FW, Kucuk O, Sarkar FH. Antioxidant effect of zinc in humans. Free Radic Biol Med. 2004;37:1182–90.

    Article  CAS  PubMed  Google Scholar 

  15. Koekkoek WA, van Zanten AR. Antioxidant vitamins and trace elements in critical illness. Nutr Clin Pract. 2016;31:457–74.

    Article  CAS  PubMed  Google Scholar 

  16. Fischer Walker C, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr. 2004;24:255–75.

    Article  PubMed  Google Scholar 

  17. Prasad AS. Zinc in human health: effect of zinc on immune cells. Mol Med. 2008;14:353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hamon R, Homan CC, Tran HB, Mukaro VR, Lester SE, Roscioli E, et al. Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD. PLoS One. 2014;9:e110056.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Fernandes N, Mosnier LO, Tonnu L, Heeb MJ. Zn(2)(+)-containing protein S inhibits extrinsic factor X-activating complex independently of tissue factor pathway inhibitor. J Thromb Haemost. 2010;8:1976–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Henderson SJ, Stafford AR, Leslie BA, Kim PY, Vaezzadeh N, Ni R, et al. Zinc delays clot lysis by attenuating plasminogen activation and plasmin-mediated fibrin degradation. Thromb Haemost. 2015;113:1278–88.

    Article  PubMed  Google Scholar 

  21. Heeb MJ, Prashun D, Griffin JH, Bouma BN. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor. FASEB J. 2009;23:2244–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hopmeier P, Halbmayer M, Fischer M, Marx G. Zinc modulates thrombin adsorption to fibrin. Thromb Res. 1990;58:293–301.

    Article  CAS  PubMed  Google Scholar 

  23. Watson BR, White NA, Taylor KA, Howes JM, Malcor JD, Bihan D, et al. Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner. Metallomics. 2016;8:91–100.

    Article  CAS  PubMed  Google Scholar 

  24. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006;34:625–31.

    Article  PubMed  Google Scholar 

  26. Funk DJ, Parrillo JE, Kumar A. Sepsis and septic shock: a history. Crit Care Clin. 2009;25:83–101.

    Article  PubMed  Google Scholar 

  27. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, et al. Shock and tissue injury induced by recombinant human cachectin. Science. 1986;234:470–4.

    Article  CAS  PubMed  Google Scholar 

  28. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372:1629–38.

    Article  CAS  PubMed  Google Scholar 

  29. Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg. 1995;130:739–48.

    Article  CAS  PubMed  Google Scholar 

  30. Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38:S26-34.

    Article  CAS  PubMed  Google Scholar 

  31. Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci. 1982;389:39–48.

    Article  CAS  PubMed  Google Scholar 

  32. Brown KH. Effect of infections on plasma zinc concentration and implications for zinc status assessment in low-income countries. Am J Clin Nutr. 1998;68:425–9.

    Article  Google Scholar 

  33. Hasanzadeh Kiabi F, Alipour A, Darvishi-Khezri H, Aliasgharian A, Emami Zeydi A. Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: a secondary analysis of a prospective, observational study. Indian J Crit Care Med. 2017;21:34–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wang L, Song Y. Efficacy of zinc given as an adjunct to the treatment of severe pneumonia: a meta-analysis of randomized, double-blind and placebo-controlled trials. Clin Respir J. 2018;12:857–64.

    Article  PubMed  Google Scholar 

  35. Mohammad MK, Zhou Z, Cave M, Barve A, McClain CJ. Zinc and liver disease. Nutr Clin Prac. 2012;27:8–20.

    Article  Google Scholar 

  36. Fraker PJ, King LE. A distinct role for apoptosis in the changes in lymphopoiesis and myelopoiesis created by deficiencies in zinc. FASEB J. 2001;15:2572–8.

    Article  CAS  PubMed  Google Scholar 

  37. Mayer LS, Uciechowski P, Meyer S, Schwerdtle T, Rink L, Haase H. Differential impact of zinc deficiency on phagocytosis, oxidative burst, and production of pro-inflammatory cytokines by human monocytes. Metallomics. 2014;6:1288–95.

    Article  CAS  PubMed  Google Scholar 

  38. Moshage H. Cytokines and the hepatic acute phase response. J Pathol. 1997;181:257–66.

    Article  CAS  PubMed  Google Scholar 

  39. Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037.

    Article  PubMed  Google Scholar 

  40. Iba T, Levy JH. Inflammation and thrombosis: Roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost. 2018;16:231–41.

    Article  CAS  PubMed  Google Scholar 

  41. Iba T, Levy JH, Thachil J, Wada H, Levi M, Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis. The progression from coagulopathy to disseminated intravascular coagulation in representative underlying diseases. Thromb Res. 2019;179:11–4.

    Article  CAS  PubMed  Google Scholar 

  42. Levy JH, Sniecinski RM, Welsby IJ, Levi M. Antithrombin: anti-inflammatory properties and clinical applications. Thromb Haemost. 2016;115:712–28.

    Article  PubMed  Google Scholar 

  43. Bajaj SP, Schmidt AE, Agah S, Bajaj MS, Padmanabhan K. High resolution structures of p-aminobenzamidine- and benzamidine-VIIa/soluble tissue factor: unpredicted conformation of the 192–193 peptide bond and mapping of Ca2+, Mg2+, Na+, and Zn2+ sites in factor VIIa. J Biol Chem. 2006;281:24873–88.

    Article  CAS  PubMed  Google Scholar 

  44. Esmon CT. The protein C pathway. Chest. 2003;124:26s–32s.

    Article  CAS  PubMed  Google Scholar 

  45. Burstyn-Cohen T, Heeb MJ, Lemke G. Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J Clin Invest. 2009;119:2942–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li B, Cui W, Tan Y, Luo P, Chen Q, Zhang C, et al. Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition. J Cell Mol Med. 2014;18:895–06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Prasad AS, Bao B, Beck FW, Sarkar FH. Zinc activates NF-kappaB in HUT-78 cells. J Lab Clin Med. 2001;138:250–6.

    Article  CAS  PubMed  Google Scholar 

  48. Liuzzi JP, Lichten LA, Rivera S, Blanchard RK, Aydemir TB, Knutson MD, et al. Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc Natl Acad Sci U S A. 2005;102:6843–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bahtouee M, Eghbali SS, Maleki N, Rastgou V, Motamed N. Acute physiology and chronic health evaluation II score for the assessment of mortality prediction in the intensive care unit: a single-centre study from Iran. Nurs Crit Care. 2019;24:375–80.

    Article  PubMed  Google Scholar 

  50. Cander B, Dundar ZD, Gul M, Girisgin S. Prognostic value of serum zinc levels in critically ill patients. J Crit Care. 2011;26:42–6.

    Article  CAS  PubMed  Google Scholar 

  51. Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T. Zinc homeostasis and signaling in health and diseases: Zinc signaling. J Biol Inorg Chem. 2011;16:1123–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sugiura T, Nakamura H. Metallothionein in platelets. Int Arch Allergy Immunol. 1994;103:341–8.

    Article  CAS  PubMed  Google Scholar 

  53. Taylor KA, Pugh N. The contribution of zinc to platelet behaviour during haemostasis and thrombosis. Metallomics. 2016;8:144–55.

    Article  CAS  PubMed  Google Scholar 

  54. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109–42.

    CAS  PubMed  Google Scholar 

  55. Jarosz M, Olbert M, Wyszogrodzka G, Młyniec K, Librowski T. Antioxidant and anti-inflammatory effects of zinc Zinc-dependent NF-κB signaling. Inflammopharmacology. 2017;25:11–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We appreciate the assistance of the nursing staff at the Emergency and Critical Care Center at Fukuoka University Hospital, Fukuoka, Japan. We thank Arshad Makhdum, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Author information

Authors and Affiliations

  1. Department of Emergency and Critical Care Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Yuhei Irie, Kota Hoshino, Yasumasa Kawano, Mariko Mizunuma, Ryo Hokama, Shinichi Morimoto, Yoshito Izutani & Hiroyasu Ishikura

Authors
  1. Yuhei Irie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kota Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasumasa Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariko Mizunuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryo Hokama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shinichi Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshito Izutani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroyasu Ishikura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuhei Irie.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Institutional Research Ethics Committee of Fukuoka University Hospital (No. 18-3-02). It complied with the principles of Helsinki Declaration.

Consent to participate

Informed consent was waived based on the study’s retrospective, observational design, which preserves the confidentiality of personal information.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Irie, Y., Hoshino, K., Kawano, Y. et al. Relationship between serum zinc level and sepsis-induced coagulopathy. Int J Hematol 115, 87–95 (2022). https://doi.org/10.1007/s12185-021-03225-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-021-03225-4

Keywords

Search

Navigation