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Published in: Thrombosis Journal 1/2022

Open Access 01-12-2022 | Disseminated Intravascular Coagulation | Research

Prognostic value of plasma high mobility group box 1 protein and histone H3 levels in patients with disseminated intravascular coagulation: a multicenter prospective cohort study

Authors: Hirotaka Mori, Yuki Kataoka, Kayo Harada-Shirado, Noriaki Kawano, Mineji Hayakawa, Yoshinobu Seki, Toshimasa Uchiyama, Kazuma Yamakawa, Hiroyasu Ishikura, Yuhei Irie, Kenji Nishio, Noritaka Yada, Kohji Okamoto, Shingo Yamada, Takayuki Ikezoe

Published in: Thrombosis Journal | Issue 1/2022

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Abstract

Background

We compared the prognostic value of plasma high mobility group box 1 protein (HMGB1) and histone H3 levels with the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scores for 28-day in-hospital mortality in patients with DIC caused by various underlying diseases.

Methods

We conducted a multicenter prospective cohort study including two hematology departments, four emergency departments, and one general medicine department in Japan, between August 2017 and July 2021. We included patients diagnosed with DIC by the ISTH DIC scoring system.

Results

Overall, 104 patients were included: 50 with hematopoietic disorders, 41 with infections, and 13 with the other diseases. The 28-day in-hospital mortality rate was 21%. The receiver operator characteristic (ROC) curve showed that a DIC score of 6 points, plasma HMGB1 level of 8 ng/mL, and plasma histone H3 level of 2 ng/mL were the optimal cutoff points. The odds ratios of more than these optimal cutoff points of the DIC score, plasma HMGB1, and histone H3 levels were 1.58 (95% confidence interval [CI]: 0.60 to 4.17, p = 0.36), 5.47 (95% CI: 1.70 to 17.6, p = 0.004), and 9.07 (95% CI: 2.00 to 41.3, p = 0.004), respectively. The area under the ROC curve of HMGB1 (0.74, 95% CI: 0.63 to 0.85) was better than that of the ISTH DIC scores (0.55, 95% CI: 0.43 to 0.67, p = 0.03), whereas that of histone H3 was not (0.71, 95% CI: 0.60 to 0.82, p = 0.07). Calibration and net reclassification plots of HMGB1 identified some high-risk patients, whereas the ISTH DIC scores and histone H3 did not. The category-free net reclassification improvement of HMGB1 was 0.45 (95% CI: 0.01 to 0.90, p = 0.04) and that of histone H3 was 0.37 (95% CI: − 0.05 to 0.78, p = 0.08).

Conclusions

Plasma HMGB1 levels have a prognostic value for mortality in patients with DIC. This finding may help physicians develop treatment strategies.
Appendix
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Literature
1.
go back to reference Taylor FB Jr, Toh CB, Hoots WK, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327–30.CrossRef Taylor FB Jr, Toh CB, Hoots WK, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327–30.CrossRef
2.
go back to reference Yamakawa K, Ohbe H, Taniguchi K, Matsui H, Fushimi K, Yasunaga H. Time trends of the outcomes and treatment options for disseminated intravascular coagulation: A nationwide observational study in Japan. JMA J. 2020;3:313–20.PubMedPubMedCentral Yamakawa K, Ohbe H, Taniguchi K, Matsui H, Fushimi K, Yasunaga H. Time trends of the outcomes and treatment options for disseminated intravascular coagulation: A nationwide observational study in Japan. JMA J. 2020;3:313–20.PubMedPubMedCentral
3.
go back to reference Saito S, Uchino S, Hayakawa M, Yamakawa K, Kudo D, Iizuka Y, et al. Epidemiology of disseminated intravascular coagulation in sepsis and validation of scoring systems. J Crit Care. 2019;50:23–30.CrossRef Saito S, Uchino S, Hayakawa M, Yamakawa K, Kudo D, Iizuka Y, et al. Epidemiology of disseminated intravascular coagulation in sepsis and validation of scoring systems. J Crit Care. 2019;50:23–30.CrossRef
4.
go back to reference Levi M, Scully M. How I treat disseminated intravascular coagulation. Blood. 2018;131:845–54.CrossRef Levi M, Scully M. How I treat disseminated intravascular coagulation. Blood. 2018;131:845–54.CrossRef
5.
go back to reference Cowley LE, Farewell DM, Maguire S, Kemp AM. Methodological standards for the development and evaluation of clinical prediction rules: A review of the literature. Diagn Progn Res. 2019;3:16.CrossRef Cowley LE, Farewell DM, Maguire S, Kemp AM. Methodological standards for the development and evaluation of clinical prediction rules: A review of the literature. Diagn Progn Res. 2019;3:16.CrossRef
6.
go back to reference Madoiwa S, Honda G, Kawano N, Uchiyama T, Kawasugi K, Takezako N, et al. An evaluation of the Japanese society on thrombosis and hemostasis criteria for disseminated intravascular coagulation as a predictor of prognosis in patients with infection. Int J Lab Hematol. 2021;43:1566–74.CrossRef Madoiwa S, Honda G, Kawano N, Uchiyama T, Kawasugi K, Takezako N, et al. An evaluation of the Japanese society on thrombosis and hemostasis criteria for disseminated intravascular coagulation as a predictor of prognosis in patients with infection. Int J Lab Hematol. 2021;43:1566–74.CrossRef
7.
go back to reference Yamakawa K, Umemura Y, Murao S, Hayakawa M, Fujimi S. Optimal timing and early intervention with anticoagulant therapy for sepsis-induced disseminated intravascular coagulation. Clin Appl Thromb Hemost. 2019;25:107602961983505.CrossRef Yamakawa K, Umemura Y, Murao S, Hayakawa M, Fujimi S. Optimal timing and early intervention with anticoagulant therapy for sepsis-induced disseminated intravascular coagulation. Clin Appl Thromb Hemost. 2019;25:107602961983505.CrossRef
8.
go back to reference Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev. 2016;30:257–61.CrossRef Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev. 2016;30:257–61.CrossRef
9.
go back to reference Cai J, Lin Z. Correlation of blood high mobility group box-1 protein with mortality of patients with sepsis: A meta-analysis. Heart Lung. 2021;50:885–92.CrossRef Cai J, Lin Z. Correlation of blood high mobility group box-1 protein with mortality of patients with sepsis: A meta-analysis. Heart Lung. 2021;50:885–92.CrossRef
10.
go back to reference Yokoyama Y, Ito T, Yasuda T, Furubeppu H, Kamikokuryo C, Yamada S, et al. Circulating histone H3 levels in septic patients are associated with coagulopathy, multiple organ failure, and death: A single-center observational study. Thromb J. 2019;17:1.CrossRef Yokoyama Y, Ito T, Yasuda T, Furubeppu H, Kamikokuryo C, Yamada S, et al. Circulating histone H3 levels in septic patients are associated with coagulopathy, multiple organ failure, and death: A single-center observational study. Thromb J. 2019;17:1.CrossRef
11.
go back to reference Wildhagen KC, Wiewel MA, Schultz MJ, Horn J, Schrijver R, Reutelingsperger CP, et al. Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients. Thromb Res. 2015;136:542–7.CrossRef Wildhagen KC, Wiewel MA, Schultz MJ, Horn J, Schrijver R, Reutelingsperger CP, et al. Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients. Thromb Res. 2015;136:542–7.CrossRef
12.
go back to reference Wang M, Mei H, Kou H, Deng J, Wang H, Guo T, et al. Role of plasma high mobility group box-1 in disseminated intravascular coagulation with leukemia. Thromb Res. 2015;136:422–6.CrossRef Wang M, Mei H, Kou H, Deng J, Wang H, Guo T, et al. Role of plasma high mobility group box-1 in disseminated intravascular coagulation with leukemia. Thromb Res. 2015;136:422–6.CrossRef
13.
go back to reference Hatada T, Wada H, Nobori T, Okabayashi K, Maruyama K, Abe Y, et al. Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost. 2005;94:975–9.CrossRef Hatada T, Wada H, Nobori T, Okabayashi K, Maruyama K, Abe Y, et al. Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost. 2005;94:975–9.CrossRef
14.
go back to reference Asakura H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on thrombosis and hemostasis. Thromb J. 2016;14:42.CrossRef Asakura H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on thrombosis and hemostasis. Thromb J. 2016;14:42.CrossRef
15.
go back to reference Mao JY, Zhang JH, Cheng W, Chen JW, Cui N. Effects of neutrophil extracellular traps in patients with septic coagulopathy and their interaction with autophagy. Front Immunol. 2021;12: 757041.CrossRef Mao JY, Zhang JH, Cheng W, Chen JW, Cui N. Effects of neutrophil extracellular traps in patients with septic coagulopathy and their interaction with autophagy. Front Immunol. 2021;12: 757041.CrossRef
16.
go back to reference Alba AC, Agoritsas T, Walsh M, Hanna S, Iorio A, Devereaux PJ, et al. Discrimination and calibration of clinical prediction models: Users’ guides to the medical literature. JAMA. 2017;318:1377–84.CrossRef Alba AC, Agoritsas T, Walsh M, Hanna S, Iorio A, Devereaux PJ, et al. Discrimination and calibration of clinical prediction models: Users’ guides to the medical literature. JAMA. 2017;318:1377–84.CrossRef
17.
go back to reference Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Standards for Reporting of Diagnostic Accuracy, The STARD statement for reporting studies of diagnostic accuracy: Explanation and elaboration. Ann Intern Med. 2003;138:W1-12.CrossRef Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Standards for Reporting of Diagnostic Accuracy, The STARD statement for reporting studies of diagnostic accuracy: Explanation and elaboration. Ann Intern Med. 2003;138:W1-12.CrossRef
18.
go back to reference Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, et al. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost. 2006;4:90–7.CrossRef Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, et al. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost. 2006;4:90–7.CrossRef
19.
go back to reference Ito T, Nakahara M, Masuda Y, Ono S, Yamada S, Ishikura H, et al. Circulating histone H3 levels are increased in septic mice in a neutrophil-dependent manner: Preclinical evaluation of a novel sandwich ELISA for histone H3. J Intensive Care. 2018;6:79.CrossRef Ito T, Nakahara M, Masuda Y, Ono S, Yamada S, Ishikura H, et al. Circulating histone H3 levels are increased in septic mice in a neutrophil-dependent manner: Preclinical evaluation of a novel sandwich ELISA for histone H3. J Intensive Care. 2018;6:79.CrossRef
20.
go back to reference Yamada S, Inoue K, Yakabe K, Imaizumi H, Maruyama I. High mobility group protein 1 (HMGB1) quantified by ELISA with a monoclonal antibody that does not cross-react with HMGB2. Clin Chem. 2003;49:1535–7.CrossRef Yamada S, Inoue K, Yakabe K, Imaizumi H, Maruyama I. High mobility group protein 1 (HMGB1) quantified by ELISA with a monoclonal antibody that does not cross-react with HMGB2. Clin Chem. 2003;49:1535–7.CrossRef
21.
go back to reference Pencina MJ, D’Agostino RB Sr, Steyerberg EW. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med. 2011;30:11–21.CrossRef Pencina MJ, D’Agostino RB Sr, Steyerberg EW. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med. 2011;30:11–21.CrossRef
22.
go back to reference Pencina MJ, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond. Stat Med. 2008;27::157--72 discussion 207–12. Pencina MJ, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond. Stat Med. 2008;27::157--72 discussion 207–12.
23.
go back to reference Umemura Y, Yamakawa K. Optimal patient selection for anticoagulant therapy in sepsis: An evidence-based proposal from Japan. J Thromb Hemost. 2018;16:462–4. Umemura Y, Yamakawa K. Optimal patient selection for anticoagulant therapy in sepsis: An evidence-based proposal from Japan. J Thromb Hemost. 2018;16:462–4.
24.
go back to reference Abrams ST, Su D, Sahraoui Y, Lin Z, Cheng Z, Nesbitt K, et al. Assembly of alternative prothrombinase by extracellular histones initiates and disseminates intravascular coagulation. Blood. 2021;137:103–14.CrossRef Abrams ST, Su D, Sahraoui Y, Lin Z, Cheng Z, Nesbitt K, et al. Assembly of alternative prothrombinase by extracellular histones initiates and disseminates intravascular coagulation. Blood. 2021;137:103–14.CrossRef
25.
go back to reference Justice AC, Covinsky KE, Berlin JA. Assessing the generalizability of prognostic information. Ann Intern Med. 1999;130:515–24.CrossRef Justice AC, Covinsky KE, Berlin JA. Assessing the generalizability of prognostic information. Ann Intern Med. 1999;130:515–24.CrossRef
26.
go back to reference Riley RD, Ensor J, Snell KIE, Harrell FE Jr, Martin GP, Reitsma JB, et al. Calculating the sample size required for developing a clinical prediction model. BMJ. 2020;368: m441.CrossRef Riley RD, Ensor J, Snell KIE, Harrell FE Jr, Martin GP, Reitsma JB, et al. Calculating the sample size required for developing a clinical prediction model. BMJ. 2020;368: m441.CrossRef
27.
go back to reference Cook NR, Paynter NP. Performance of reclassification statistics in comparing risk prediction models. Biom J. 2011;53:237–58.CrossRef Cook NR, Paynter NP. Performance of reclassification statistics in comparing risk prediction models. Biom J. 2011;53:237–58.CrossRef
28.
go back to reference Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014;6(2):20.CrossRef Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014;6(2):20.CrossRef
29.
go back to reference Rabinovich A, Abdul-Kadir R, Thachil J, Iba T, Othman M, Erez O. DIC in obstetrics: Diagnostic score, highlights in management, and international registry-communication from the DIC and Women’s Health SSCs of the International Society of Thrombosis and Haemostasis. Thromb Haemost. 2019;17:1562–6. Rabinovich A, Abdul-Kadir R, Thachil J, Iba T, Othman M, Erez O. DIC in obstetrics: Diagnostic score, highlights in management, and international registry-communication from the DIC and Women’s Health SSCs of the International Society of Thrombosis and Haemostasis. Thromb Haemost. 2019;17:1562–6.
30.
go back to reference Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the research committee on DIC in Japan. Bibl Haematol. 1983;49:265–75. Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the research committee on DIC in Japan. Bibl Haematol. 1983;49:265–75.
31.
go back to reference Gando S, Wada H, Asakura H, Iba T, Eguchi Y, Okamoto K, et al. Evaluation of new Japanese diagnostic criteria for disseminated intravascular coagulation in critically ill patients. Clin Appl Thromb Hemost. 2005;11:71–6.CrossRef Gando S, Wada H, Asakura H, Iba T, Eguchi Y, Okamoto K, et al. Evaluation of new Japanese diagnostic criteria for disseminated intravascular coagulation in critically ill patients. Clin Appl Thromb Hemost. 2005;11:71–6.CrossRef
32.
33.
go back to reference Moons KG, Altman DG, Reitsma JB, Ioannidis JP, Macaskill P, Steyerberg EW, et al. Transparent reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): Explanation and elaboration. Ann Intern Med. 2015;162:W1-73.CrossRef Moons KG, Altman DG, Reitsma JB, Ioannidis JP, Macaskill P, Steyerberg EW, et al. Transparent reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): Explanation and elaboration. Ann Intern Med. 2015;162:W1-73.CrossRef
34.
go back to reference Leening MJ, Vedder MM, Witteman JC, Pencina MJ, Steyerberg EW. Net reclassification improvement: Computation, interpretation, and controversies: A literature review and clinician’s guide. Ann Intern Med. 2014;160:122–31.CrossRef Leening MJ, Vedder MM, Witteman JC, Pencina MJ, Steyerberg EW. Net reclassification improvement: Computation, interpretation, and controversies: A literature review and clinician’s guide. Ann Intern Med. 2014;160:122–31.CrossRef
35.
go back to reference Van Calster B, Nieboer D, Vergouwe Y, De Cock B, Pencina MJ, Steyerberg EW. A calibration hierarchy for risk models was defined: From utopia to empirical data. J Clin Epidemiol. 2016;74:167–76.CrossRef Van Calster B, Nieboer D, Vergouwe Y, De Cock B, Pencina MJ, Steyerberg EW. A calibration hierarchy for risk models was defined: From utopia to empirical data. J Clin Epidemiol. 2016;74:167–76.CrossRef
Metadata
Title
Prognostic value of plasma high mobility group box 1 protein and histone H3 levels in patients with disseminated intravascular coagulation: a multicenter prospective cohort study
Authors
Hirotaka Mori
Yuki Kataoka
Kayo Harada-Shirado
Noriaki Kawano
Mineji Hayakawa
Yoshinobu Seki
Toshimasa Uchiyama
Kazuma Yamakawa
Hiroyasu Ishikura
Yuhei Irie
Kenji Nishio
Noritaka Yada
Kohji Okamoto
Shingo Yamada
Takayuki Ikezoe
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Thrombosis Journal / Issue 1/2022
Electronic ISSN: 1477-9560
DOI
https://doi.org/10.1186/s12959-022-00390-2

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