Skip to main content Skip to main navigation menu Skip to site footer

Changes in plasma levels of IL-6 and D-dimer in high-risk thrombosis cancer patients undergoing chemotherapy

  • Budi Setiawan ,
  • Amelia KW Manurung ,
  • Alif Adlan Zulizar ,
  • Widi Budianto ,
  • Tri Wahyu Sukarnowati ,
  • Eko Adhi Pangarsa ,
  • Damai Santosa ,
  • Rahajuningsih Dharma Setiabudy ,
  • Catharina Suharti ,

Abstract

Background: Cancer and chemotherapy are venous thromboembolism (VTE) risk factors. The immune system and inflammation are essential in cancer-associated thrombosis's pathogenesis. Chemotherapy can induce inflammatory conditions that trigger the nuclear factor kappa B (NF-κB) signaling pathway to produce proinflammatory cytokines. Interleukin 6 (IL-6) improves procoagulant status primarily by inducing tissue factor (TF) expression. Tissue factor expression triggers the coagulation system, characterized by increased levels of D-dimer. This study assessed the change in plasma levels of IL-6 and D-dimer changed in high-risk thrombosis cancer patients undergoing chemotherapy.

Methods:  This study was a prospective cohort study of 54 newly diagnosed high-risk thrombosis cancer patients undergoing chemotherapy in Dr. Kariadi General Hospital from January 2021 to September 2021 based on inclusion and exclusion criteria. IL-6 and D-dimer concentrations were collected a day before and after chemotherapy. IL-6 measured by ELISA method and D-dimer measured by the turbidimetry chromogenic immunoassay method. We did correlation test, compared mean, and subgroup analysis. The p-value<0.05 was significant.

 

Results: There was a positive correlation between plasma levels of IL-6 and D-dimer both pre- and post-chemotherapy (r=0.36; 95% CI (0.1-0.6); p=0.006 and r=0.45; 95% CI (0.2-0.6); p=<0.001, respectively). Post-chemotherapy plasma IL-6 (61.0±84.9 pg/mL) was significantly lower (p=0.022) than pre-chemotherapy (102.4±141.6 pg/mL). Subgroup analysis based on risks of thrombosis showed a significant decrease in plasma levels of IL-6 in the higher risk cancer group of thrombosis post-chemotherapy compared with the low risk cancer group (77.7±144.1 pg/mL vs -0.9±127.8 pg/mL; p=0.037). There was an increase in D-dimer plasma levels post-chemotherapy, but it was not statistically significant (2598.1±2487.8 µg/ml vs 3098.6±3547.4 µg/ml; p=0.512). The subgroup analysis based on blood type, tumor stage, chemotherapy regimen, and risk of thrombosis showed no significant differences in delta plasma IL-6 and D-Dimer levels pre- and post-chemotherapy.

Conclusion: In high-risk thrombosis cancer patients who underwent chemotherapy, there was a statistically significant decrease in plasma levels of IL-6 post-chemotherapy. There was an increase in D-dimer plasma levels post-chemotherapy, but it was not statistically significant.

References

  1. National Institute for Clinical Excellence. Venous thromboembolism in adults: diagnosis and management. NICE Clinical Guideline. 2016.
  2. Streiff MB, Agnelli G, Connors JM, Crowther M, Eichinger S, Lopes R, et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis. 2016;41(1):32–67. Available from: https://pubmed.ncbi.nlm.nih.gov/26780738
  3. American Cancer Society. Global cancer facts and figures 4th edition. Vol. 1, Am Cancer Soc. 2018.
  4. Sutandyo N, Tobing D, Kardinah K. Risk Factors of Deep Vein Thrombosis in Cancer Patients. Iran J Blood Cancer. 2018;10(4):117–23.
  5. Kirwan CC, McCollum CN, McDowell G, Byrne GJ. Investigation of Proposed Mechanisms of Chemotherapy-Induced Venous Thromboembolism. Clin Appl Thromb. 2015;21(5):420–7. Available from: http://dx.doi.org/10.1177/1076029615575071
  6. Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer. 2012;119(3):648–55. Available from: http://dx.doi.org/10.1002/cncr.27772
  7. Elyamany G, Alzahrani AM, Bukhary E. Cancer-associated thrombosis: an overview. Clin Med Insights Oncol. 2014;8:129–37. Available from: https://pubmed.ncbi.nlm.nih.gov/25520567
  8. Kalayci A, Gibson C, Chi G, Yee M, Korjian S, Datta S, et al. Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial. Thromb Haemost. 2018;118(12):2046–52. Available from: http://dx.doi.org/10.1055/s-0038-1675606
  9. Leizorovicz A, Cohen A, Turpie A, Olsson C-G, Goldhaber S, Vaitkus P. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients. Thromb Haemost. 2005;93(01):76–9. Available from: http://dx.doi.org/10.1160/th04-05-0323
  10. Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Old and new risk factors for upper extremity deep venous thrombosis. J Thromb Haemost. 2005;3(11):2471–8. Available from: http://dx.doi.org/10.1111/j.1538-7836.2005.01625.x
  11. Key NS, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2020;38(5):496–520. Available from: http://dx.doi.org/10.1200/jco.19.01461
  12. Farge D, Frere C, Connors JM, Ay C, Khorana AA, Munoz A, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2019;20(10):e566–81.
  13. Budnik I, Brill A. Immune Factors in Deep Vein Thrombosis Initiation. Trends Immunol. 2018/05/16. 2018;39(8):610–23. Available from: https://pubmed.ncbi.nlm.nih.gov/29776849
  14. Boccaccio C, Comoglio P. Oncogenes, Cancer and Hemostasis [Internet]. Cancer-Associated Thrombosis. CRC Press; 2007. p. 1–15. Available from: http://dx.doi.org/10.3109/9781420048001-2
  15. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9(6):7204–18. Available from: https://pubmed.ncbi.nlm.nih.gov/29467962
  16. Branchford BR, Carpenter SL. The Role of Inflammation in Venous Thromboembolism. Front Pediatr. 2018;6:142. Available from: https://pubmed.ncbi.nlm.nih.gov/29876337
  17. van Gorp ECM, Suharti C, ten Cate H, Dolmans WMV, van der Meer JWM, ten Cate JW, et al. Review: Infectious Diseases and Coagulation Disorders. J Infect Dis. 1999;180(1):176–86. Available from: http://dx.doi.org/10.1086/314829
  18. Haddad TC, Greeno EW. Chemotherapy-induced thrombosis. Thromb Res. 2006;118(5):555–68. Available from: http://dx.doi.org/10.1016/j.thromres.2005.10.015
  19. Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol. 2018;9:754. Available from: https://pubmed.ncbi.nlm.nih.gov/29706967
  20. Cocoi AF, Pop D, Cocoi M, Serban AM, Vida-Simiti LA. Involvement of inflammatory markers in pathogenesis of venous thromboembolism. Rev Rom Med Lab. 2017;25(3):227–36. Available from: http://dx.doi.org/10.1515/rrlm-2017-0019
  21. Pabinger I, Thaler J, Ay C. Biomarkers for prediction of venous thromboembolism in cancer. Blood. 2013;122(12):2011–8. Available from: http://dx.doi.org/10.1182/blood-2013-04-460147
  22. Schaefer JK, Jacobs B, Wakefield TW, Sood SL. New biomarkers and imaging approaches for the diagnosis of deep venous thrombosis. Curr Opin Hematol. 2017;24(3):274–81. Available from: http://dx.doi.org/10.1097/moh.0000000000000339
  23. Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 2009;1(5):a000141–a000141. Available from: https://pubmed.ncbi.nlm.nih.gov/20066113
  24. Park MH, Hong JT. Roles of NF-κB in Cancer and Inflammatory Diseases and Their Therapeutic Approaches. Cells. 2016;5(2):15. Available from: https://pubmed.ncbi.nlm.nih.gov/27043634
  25. Weitz I, Howard AL. Chemotherapy-Induced Hemostatic Activation and Thrombosis in Cancer. In: Korana A, Charles WF, editors. Cancer-Associated Thrombosis. New York: Informa Healthcare USA, Inc; 2008. p. 65–75. Available from: http://dx.doi.org/10.3109/9781420048001-9
  26. Chen Y-M, Whang-Peng J, Liu J-M, Kuo BI-T, Wang S-Y, Tsai C-M, et al. Serum Cytokine Level Fluctuations in Chemotherapy-induced Myelosuppression. Jpn J Clin Oncol. 1996;26(1):18–23. Available from: http://dx.doi.org/10.1093/oxfordjournals.jjco.a023173
  27. Abdellateif MS, Salem SE, Badr DM, Shaarawy S, Hussein MM, Zekri A-RN, et al. The Prognostic Significance of 5-Fluorouracil Induced Inflammation and Immuno-Modulation in Colorectal Cancer Patients. J Inflamm Res. 2020;13:1245–59. Available from: https://pubmed.ncbi.nlm.nih.gov/33408498
  28. Tsavaris N, Kosmas C, Vadiaka M, Kanelopoulos P, Boulamatsis D. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br J Cancer. 2002;87(1):21–7. Available from: https://pubmed.ncbi.nlm.nih.gov/12085250
  29. Liu Y, Starr MD, Bulusu A, Pang H, Wong NS, Honeycutt W, et al. Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab. Cancer Med. 2013/03/06. 2013;2(2):234–42. Available from: https://pubmed.ncbi.nlm.nih.gov/23634291
  30. Jabeen S, Zucknick M, Nome M, Dannenfelser R, Fleischer T, Kumar S, et al. Serum cytokine levels in breast cancer patients during neoadjuvant treatment with bevacizumab. Oncoimmunology. 2018;7(11):e1457598–e1457598. Available from: https://pubmed.ncbi.nlm.nih.gov/30377556
  31. Gara E, Csikó KG, Ruzsa Z, Földes G, Merkely B. Anti-cancer drugs-induced arterial injury: risk stratification, prevention, and treatment. Med Oncol. 2019;36(8). Available from: http://dx.doi.org/10.1007/s12032-019-1295-8
  32. Lim SH, Woo S-Y, Kim S, Ko YH, Kim WS, Kim SJ. Cross-sectional Study of Patients with Diffuse Large B-Cell Lymphoma: Assessing the Effect of Host Status, Tumor Burden, and Inflammatory Activity on Venous Thromboembolism. Cancer Res Treat. 2015/03/02. 2016;48(1):312–21. Available from: https://pubmed.ncbi.nlm.nih.gov/25761485
  33. Mannucci PM, Franchini M. ABO blood group and thrombotic vascular disease. Thromb Haemost. 2014;112(12):1103–9. Available from: http://dx.doi.org/10.1160/th14-05-0457
  34. Zhou S, Welsby I. Is ABO blood group truly a risk factor for thrombosis and adverse outcomes? World J Cardiol. 2014;6(9):985–92. Available from: https://pubmed.ncbi.nlm.nih.gov/25276299
  35. Di Caro G, Carvello M, Pesce S, Erreni M, Marchesi F, Todoric J, et al. Correction: Circulating Inflammatory Mediators as Potential Prognostic Markers of Human Colorectal Cancer. PLoS One. 2016;11(5):e0156669–e0156669. Available from: https://pubmed.ncbi.nlm.nih.gov/27227770
  36. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218–28. Available from: http://dx.doi.org/10.1016/s1470-2045(12)70582-x
  37. Lippitz BE, Harris RA. Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis. Oncoimmunology. 2016;5(5):e1093722–e1093722. Available from: https://pubmed.ncbi.nlm.nih.gov/27467926
  38. Yu J, Li D, Lei D, Yuan F, Pei F, Zhang H, et al. Tumor-Specific D-Dimer Concentration Ranges and Influencing Factors: A Cross-Sectional Study. PLoS One. 2016;11(11):e0165390–e0165390. Available from: https://pubmed.ncbi.nlm.nih.gov/27835633
  39. Sutandyo N, Setiawan L. Perubahan Status Koagulasi Pasien Kanker Padat Pasca Kemoterapi di Indonesia: Sebuah Studi Prospektif. J Penyakit Dalam Indones. 2020;7(1):2. Available from: http://dx.doi.org/10.7454/jpdi.v7i1.387
  40. Seng S, Liu Z, Chiu SK, Proverbs-Singh T, Sonpavde G, Choueiri TK, et al. Risk of Venous Thromboembolism in Patients With Cancer Treated With Cisplatin: A Systematic Review and Meta-Analysis. J Clin Oncol. 2012;30(35):4416–26. Available from: http://dx.doi.org/10.1200/jco.2012.42.4358

How to Cite

Setiawan, B., Manurung, A. K., Zulizar, A. A., Budianto, W., Sukarnowati, T. W., Pangarsa, E. A., Santosa, D., Setiabudy, R. D., & Suharti, C. (2022). Changes in plasma levels of IL-6 and D-dimer in high-risk thrombosis cancer patients undergoing chemotherapy . Bali Medical Journal, 11(1), 520–527. https://doi.org/10.15562/bmj.v11i1.3162

HTML
15

Total
28

Share

Search Panel

Budi Setiawan
Google Scholar
Pubmed
BMJ Journal


Amelia KW Manurung
Google Scholar
Pubmed
BMJ Journal


Alif Adlan Zulizar
Google Scholar
Pubmed
BMJ Journal


Widi Budianto
Google Scholar
Pubmed
BMJ Journal


Tri Wahyu Sukarnowati
Google Scholar
Pubmed
BMJ Journal


Eko Adhi Pangarsa
Google Scholar
Pubmed
BMJ Journal


Damai Santosa
Google Scholar
Pubmed
BMJ Journal


Rahajuningsih Dharma Setiabudy
Google Scholar
Pubmed
BMJ Journal


Catharina Suharti
Google Scholar
Pubmed
BMJ Journal