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Correlation between Angiopoietin-2 and IL-6 as inflammation biomarkers on the severity of coagulopathy and mortality in vasodilated shock patients

  • Dini Septian ,
  • Christrijogo Soemartono W ,
  • Bambang Pujo Semedi ,
  • Prihatma Kriswidyatomo ,
  • Lucky Andriyanto ,
  • Budi Utomo ,

Abstract

Background: Sepsis and vasodilatory shock are serious medical conditions and cause high mortality rates worldwide. It is known that IL-6 and angiopoietin-2 levels have a role in the etiology of shock in ICU patients. Consequently, this research aims to examine the involvement of angiopoietin-2 and IL-6 in the severity of coagulation problems in patients with vasodilatory shock.

Methods: The study's design is observational analytic with a cross-sectional study design, and the data came from those treated in the ICU room and the Emergency Room at RSUD Dr. Soetomo Surabaya from February 2020 to March 2022. Data collected included age, respiratory rate, DIC score, APACHE II score, mortality, IL-6 levels, and angiopoietin-2 levels. The data was then analyzed using Easy R (EZR).

Result: 27 of the 44 patients (61.4% of the total) belonged to the DIC group. A correlation between IL-6 levels and DIC incidence and mortality at first ICU admission and after 24 hours in the ICU was shown to be significant (p<0.05). There was also a significant correlation between Angiopoietin-2 and both DIC incidence and mortality upon admission to the ICU and after 24 hours in the ICU (p<0.05). It was found that the test specificity and sensitivity of Angiopoetin-2 and IL-6 levels on the severity of coagulation disorders and mortality in patients with vasodilatation shock were 85.9% for Angiopoetin-2 and 71.6% for IL-6.

Conclusion: There is a correlation between the severity of coagulation disorders in vasodilated shock and increased IL-6 and angiopoietin-2. IL-6 and angiopoietin-2 were to be correlated with mortality and Angiopoietin-2 has higher specificity and sensitivity than IL-6. Multicenter prospective studies are needed to confirm study results.

References

  1. Angus, D. C., and van der Poll, T. 2013. ‘Severe sepsis and septic shock’. N Engl J Med, 369(9), 840-851. doi:10.1056/NEJMra1208623
  2. Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R. et al. 2016. ‘The third international consensus definitions for sepsis and septic shock (sepsis-3)’. JAMA, 315(8), 801-810. doi:10.1001/jama.2016.0287
  3. Hershey, T. B., and Kahn, J. M. 2017. ‘State sepsis mandates - a new era for regulation of hospital quality’. N Engl J Med, 376(24), 2311-2313. doi:10.1056/NEJMp1611928
  4. Vincent, J. L., and De Backer, D. 2013. ‘Circulatory shock’. N Engl J Med, 369(18), 1726-1734. doi:10.1056/NEJMra1208943
  5. Divatia, J. V., Amin, P. R., Ramakrishnan, N., Kapadia, F. N., Todi, S., Sahu, S., Govil, D. et al. 2016. ‘Intensive care in india: The indian intensive care case mix and practice patterns study’. Indian J Crit Care Med, 20(4), 216-225. doi:10.4103/0972-5229.180042
  6. Jenkins, C. R., Gomersall, C. D., Leung, P., and Joynt, G. M. 2009. ‘Outcome of patients receiving high dose vasopressor therapy: A retrospective cohort study’. Anaesthesia and Intensive Care, 37(2), 286-289. doi:10.1177/0310057x0903700212
  7. Hultström, M., Fromell, K., Larsson, A., Quaggin, S. E., Betsholtz, C., Frithiof, R., Lipcsey, M. et al. 2021. ‘Elevated angiopoietin-2 inhibits thrombomodulin-mediated anticoagulation in critically ill covid-19 patients’. medRxiv. doi:10.1101/2021.01.13.21249429
  8. Williams, G. W., Berg, N. K., Reskallah, A., Yuan, X., and Eltzschig, H. K. 2021. ‘Acute respiratory distress syndrome’. Anesthesiology, 134(2), 270-282. doi:10.1097/ALN.0000000000003571
  9. Bester, J., and Pretorius, E. 2016. ‘Effects of il-1beta, il-6 and il-8 on erythrocytes, platelets and clot viscoelasticity’. Sci Rep, 6, 32188. doi:10.1038/srep32188
  10. Statz, S., Sabal, G., Walborn, A., Williams, M., Hoppensteadt, D., Mosier, M., Rondina, M. et al. 2018. ‘Angiopoietin 2 levels in the risk stratification and mortality outcome prediction of sepsis-associated coagulopathy’. Clin Appl Thromb Hemost, 24(8), 1223-1233. doi:10.1177/1076029618786029
  11. Kumpers, P., David, S., Haubitz, M., Hellpap, J., Horn, R., Brocker, V., Schiffer, M. et al. 2009. ‘The tie2 receptor antagonist angiopoietin 2 facilitates vascular inflammation in systemic lupus erythematosus’. Ann Rheum Dis, 68(10), 1638-1643. doi:10.1136/ard.2008.094664
  12. Siner, J. M., Bhandari, V., Engle, K. M., Elias, J. A., and Siegel, M. D. 2009. ‘Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis’. Shock, 31(4), 348-353. doi:10.1097/SHK.0b013e318188bd06
  13. Ziegler, T., Horstkotte, J., Schwab, C., Pfetsch, V., Weinmann, K., Dietzel, S., Rohwedder, I. et al. 2013. ‘Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis’. J Clin Invest, 123(8), 3436-3445. doi:10.1172/JCI66549
  14. Cioara, A., Valeanu, M., Todor, N., Cristea, V., and Lupse, M. 2016. ‘Early sepsis biomarkers and their relation to mortality’. Rom J Anaesth Intensive Care, 23(2), 159-160. doi:10.21454/rjaic.7518/232.psi
  15. Gentile, L. F., Cuenca, A. G., Vanzant, E. L., Efron, P. A., McKinley, B., Moore, F., and Moldawer, L. L. 2013. ‘Is there value in plasma cytokine measurements in patients with severe trauma and sepsis?’. Methods, 61(1), 3-9. doi:10.1016/j.ymeth.2013.04.024
  16. Nainggolan, S. C., Aman, A. K., and Hanafie, A. 2019b. ‘The relationship between the level of interleukin-6 and procalcitonin in severe sepsis patients at the adam malik hospital’. Indonesian Journal of Clinical Pathology and Medical Laboratory, 25(1). doi:10.24293/ijcpml.v25i1.1488
  17. Riedel, S., and Carroll, K. C. 2013. ‘Laboratory detection of sepsis: Biomarkers and molecular approaches’. Clin Lab Med, 33(3), 413-437. doi:10.1016/j.cll.2013.03.006
  18. Takahashi, W., Nakada, T. A., Yazaki, M., and Oda, S. 2016. ‘Interleukin-6 levels act as a diagnostic marker for infection and a prognostic marker in patients with organ dysfunction in intensive care units’. Shock, 46(3), 254-260. doi:10.1097/SHK.0000000000000616
  19. Song, J., Park, D. W., Moon, S., Cho, H. J., Park, J. H., Seok, H., and Choi, W. S. 2019. ‘Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: A prospective controlled study according to the sepsis-3 definitions’. BMC Infect Dis, 19(1), 968. doi:10.1186/s12879-019-4618-7
  20. Behnes, M., Bertsch, T., Lepiorz, D., Lang, S., Trinkmann, F., Brueckmann, M., Borggrefe, M. et al. 2014. ‘Diagnostic and prognostic utility of soluble cd 14 subtype (presepsin) for severe sepsis and septic shock during the first week of intensive care treatment’. Crit Care, 18(5), 507. doi:10.1186/s13054-014-0507-z
  21. Vivas, M. C., Villamarin Guerrero, H. F., Tascon, A. J., and Valderrama-Aguirre, A. 2021. ‘Plasma interleukin-6 levels correlate with survival in patients with bacterial sepsis and septic shock’. Interv Med Appl Sci, 11(4), 224-230. doi:10.1556/1646.2020.00006
  22. Cho, S. Y., and Choi, J. H. 2014. ‘Biomarkers of sepsis’. Infect Chemother, 46(1), 1-12. doi:10.3947/ic.2014.46.1.1
  23. Pierrakos, C., and Vincent, J. L. 2010. ‘Sepsis biomarkers: A review’. Crit Care, 14(1), R15. doi:10.1186/cc8872
  24. Mat-Nor, M. B., Md Ralib, A., Abdulah, N. Z., and Pickering, J. W. 2016. ‘The diagnostic ability of procalcitonin and interleukin-6 to differentiate infectious from noninfectious systemic inflammatory response syndrome and to predict mortality’. J Crit Care, 33, 245-251. doi:10.1016/j.jcrc.2016.01.002
  25. Song, J., Park, D. W., Moon, S., Cho, H. J., Park, J. H., Seok, H., and Choi, W. S. (2019). Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: A prospective controlled study according to the sepsis-3 definitions. In (Vol. 19).
  26. Ma, L., Zhang, H., Yin, Y. L., Guo, W. Z., Ma, Y. Q., Wang, Y. B., Shu, C. et al. 2016. ‘Role of interleukin-6 to differentiate sepsis from non-infectious systemic inflammatory response syndrome’. Cytokine, 88, 126-135. doi:10.1016/j.cyto.2016.08.033
  27. Spittler, A., Razenberger, M., Kupper, H., Kaul, M., Hackl, W., Boltz-Nitulescu, G., Fugger, R. et al. 2000. ‘Relationship between interleukin-6 plasma concentration in patients with sepsis, monocyte phenotype, monocyte phagocytic properties, and cytokine production’. Clin Infect Dis, 31(6), 1338-1342. doi:10.1086/317499
  28. Oleksowicz, L., Mrowiec, Z., Isaacs, R., Dutcher, J. P., and Puszkin, E. 1995. ‘Morphologic and ultrastructural evidence of interleukin-6 induced platelet activation’. Am J Hematol, 48(2), 92-99. doi:10.1002/ajh.2830480205
  29. Shimizu, M., Konishi, A., and Nomura, S. 2018. ‘Examination of biomarker expressions in sepsis-related dic patients’. Int J Gen Med, 11, 353-361. doi:10.2147/IJGM.S173684
  30. Bassi, E., Park, M., and Azevedo, L. C. 2013. ‘Therapeutic strategies for high-dose vasopressor-dependent shock’. Crit Care Res Pract, 2013, 654708. doi:10.1155/2013/654708
  31. Iba, T., and Levy, J. H. 2018. ‘Inflammation and thrombosis: Roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis’. J Thromb Haemost, 16(2), 231-241. doi:10.1111/jth.13911
  32. Levi, M., van der Poll, T., ten Cate, H., and van Deventer, S. J. 1997. ‘The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia’. Eur J Clin Invest, 27(1), 3-9. doi:10.1046/j.1365-2362.1997.570614.x
  33. Semeraro, N., Ammollo, C. T., Semeraro, F., and Colucci, M. 2015. ‘Coagulopathy of acute sepsis’. Semin Thromb Hemost, 41(6), 650-658. doi:10.1055/s-0035-1556730
  34. Iba, T., Nisio, M. D., Levy, J. H., Kitamura, N., and Thachil, J. 2017. ‘New criteria for sepsis-induced coagulopathy (sic) following the revised sepsis definition: A retrospective analysis of a nationwide survey’. BMJ Open, 7(9), e017046. doi:10.1136/bmjopen-2017-017046
  35. Feng, J., Wang, L., Feng, Y., Yu, G., Zhou, D., and Wang, J. 2022. ‘Serum levels of angiopoietin 2 mrna in the mortality outcome prediction of septic shock’. Exp Ther Med, 23(5), 362. doi:10.3892/etm.2022.11289
  36. Statz, S., Sabal, G., Walborn, A., Williams, M., Hoppensteadt, D., Mosier, M., Rondina, M. et al. 2018. ‘Angiopoietin 2 levels in the risk stratification and mortality outcome prediction of sepsis-associated coagulopathy’. Clin Appl Thromb Hemost, 24(8), 1223-1233. doi:10.1177/1076029618786029
  37. Thamm, K., and David, S. 2016. ‘Role of angiopoietin-2 in infection - a double-edged sword?’. Cytokine, 83, 61-63. doi:10.1016/j.cyto.2016.03.019
  38. Wada, T., Jesmin, S., Gando, S., Sultana, S. N., Zaedi, S., and Yokota, H. 2012. ‘Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma’. Crit Care, 16(2), R63. doi:10.1186/cc11309
  39. Liu, X., Yu, Y., and Zhu, S. 2018. ‘Inflammatory markers in postoperative delirium (pod) and cognitive dysfunction (pocd): A meta-analysis of observational studies’. PLoS ONE, 13(4), e0195659. doi:10.1371/journal.pone.0195659
  40. Szederjesi, J., Almasy, E., Lazar, A., Hutanu, A., and Georgescu, A. 2015. ‘The role of angiopoietine-2 in the diagnosis and prognosis of sepsis’. J Crit Care Med (Targu Mures), 1(1), 18-23. doi:10.1515/jccm-2015-0004
  41. van Meurs, M., Kumpers, P., Ligtenberg, J. J., Meertens, J. H., Molema, G., and Zijlstra, J. G. 2009. ‘Bench-to-bedside review: Angiopoietin signalling in critical illness - a future target?’. Crit Care, 13(2), 207. doi:10.1186/cc7153
  42. Maisonpierre, P. C., Suri, C., Jones, P. F., Bartunkova, S., Wiegand, S. J., Radziejewski, C., Compton, D. et al. 1997. ‘Angiopoietin-2, a natural antagonist for tie2 that disrupts in vivo angiogenesis’. Science, 277(5322), 55-60. doi:10.1126/science.277.5322.55
  43. Ganter, M. T., Cohen, M. J., Brohi, K., Chesebro, B. B., Staudenmayer, K. L., Rahn, P., Christiaans, S. C. et al. 2008. ‘Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma?’. Ann Surg, 247(2), 320-326. doi:10.1097/SLA.0b013e318162d616
  44. David, S., Mukherjee, A., Ghosh, C. C., Yano, M., Khankin, E. V., Wenger, J. B., Karumanchi, S. A. et al. 2012. ‘Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*’. Crit Care Med, 40(11), 3034-3041. doi:10.1097/CCM.0b013e31825fdc31
  45. Jesmin, S., Wada, T., Gando, S., Sultana, S. S., and Zaedi, S. 2013. ‘The dynamics of angiogenic factors and their soluble receptors in relation to organ dysfunction in disseminated intravascular coagulation associated with sepsis’. Inflammation, 36(1), 186-196. doi:10.1007/s10753-012-9534-6
  46. Giuliano, J. S., Jr., Lahni, P. M., Harmon, K., Wong, H. R., Doughty, L. A., Carcillo, J. A., Zingarelli, B. et al. 2007. ‘Admission angiopoietin levels in children with septic shock’. Shock, 28(6), 650-654. doi:10.1097/shk.0b013e318123867b
  47. Mankhambo, L. A., Banda, D. L., Group, I. P. D. S., Jeffers, G., White, S. A., Balmer, P., Nkhoma, S. et al. 2010. ‘The role of angiogenic factors in predicting clinical outcome in severe bacterial infection in malawian children’. Crit Care, 14(3), R91. doi:10.1186/cc9025
  48. Orfanos, S. E., Kotanidou, A., Glynos, C., Athanasiou, C., Tsigkos, S., Dimopoulou, I., Sotiropoulou, C. et al. 2007. ‘Angiopoietin-2 is increased in severe sepsis: Correlation with inflammatory mediators’. Crit Care Med, 35(1), 199-206. doi:10.1097/01.CCM.0000251640.77679.D7
  49. Ricciuto, D. R., dos Santos, C. C., Hawkes, M., Toltl, L. J., Conroy, A. L., Rajwans, N., Lafferty, E. I. et al. 2011. ‘Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis’. Crit Care Med, 39(4), 702-710. doi:10.1097/CCM.0b013e318206d285
  50. Fiedler, U., and Augustin, H. G. 2006. ‘Angiopoietins: A link between angiogenesis and inflammation’. Trends Immunol, 27(12), 552-558. doi:10.1016/j.it.2006.10.004
  51. Parikh, S. M., Mammoto, T., Schultz, A., Yuan, H. T., Christiani, D., Karumanchi, S. A., and Sukhatme, V. P. 2006. ‘Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans’. PLoS Med, 3(3), e46. doi:10.1371/journal.pmed.0030046
  52. van der Heijden, M., van Nieuw Amerongen, G. P., Koolwijk, P., van Hinsbergh, V. W., and Groeneveld, A. B. 2008. ‘Angiopoietin-2, permeability oedema, occurrence and severity of ali/ards in septic and non-septic critically ill patients’. Thorax, 63(10), 903-909. doi:10.1136/thx.2007.0873van der Poll, T., Levi, M., Hack, C. E., ten Cate, H., van Deventer, S. J., Eerenberg, A. J., de Groot, E. R. et al. 1994. ‘Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees’. J Exp Med, 179(4), 1253-1259. doi:10.1084/jem.179.4.1253
  53. Minanti BR, Soelistijo SA, Pranoto A. Characteristic profiles of patients with diabetes mellitus and COVID-19 during the second epidemic wave in East Java, Indonesia: a retrospective study. Bali Med J. [Internet]. 2023 Apr. 5 [cited 2023 Aug. 15];12(1):1120-6. Available from: https://www.balimedicaljournal.org/index.php/bmj/article/view/4208
  54. Pangarsa EA, Setiawan B, Santosa D, Naibaho RM, Rizky D, - S, Tobing ML, Suharti C. Position paper from the Indonesian Society of Thrombosis and Hemostasis (InaSTH), Semarang chapter: Management of coagulopathy in COVID-19. Bali Med J. [Internet]. 2020 Jul. 14 [cited 2023 Aug. 15];9(2):482-8. Available from: https://www.balimedicaljournal.org/index.php/bmj/article/view/1841
  55. Retnaningsih R, Tugasworo D, Andhitara Y, Ardhini R, Kurnianto A, Bunyamin J, Utami FS, Sogata IA, Hairuzaman H. Hemorrhagic transformation in SARS-CoV-2 infected patients: case reports from Indonesia. Bali Med J. [Internet]. 2021 Dec. 27 [cited 2023 Aug. 15];10(3):992-5. Available from: https://www.balimedicaljournal.org/index.php/bmj/article/view/2254.

How to Cite

Dini Septian, Christrijogo Soemartono W, Semedi, B. P., Prihatma Kriswidyatomo, Lucky Andriyanto, & Budi Utomo. (2023). Correlation between Angiopoietin-2 and IL-6 as inflammation biomarkers on the severity of coagulopathy and mortality in vasodilated shock patients. Bali Medical Journal, 12(3), 2582–2587. https://doi.org/10.15562/bmj.v12i3.4716

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Dini Septian
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Bambang Pujo Semedi
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