Skip to main content

Advertisement

SpringerLink
Log in

Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia

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

Abstract

Intranuclear proteins, including high mobility group box 1 (HMGB1) and histone H3, released from inflammatory cells activate platelets and the coagulation systems, leading to development of disseminated intravascular coagulation (DIC) in individuals with sepsis. These observations prompted us to hypothesize that HMGB1 and histone H3 liberated from leukemia cells undergoing apoptosis after chemotherapy might play a role in development of DIC. To test this hypothesis, we prospectively measured plasma levels of coagulation markers and intranuclear proteins in patients with newly diagnosed acute leukemia (n = 17) before and after chemotherapy. Ten of 17 patients were diagnosed with DIC at the time of diagnosis of leukemia. Serum levels of HMGB1 and histone H3 were significantly higher in patients with DIC than in non-DIC patients. Of note, seven patients developed DIC or experienced exacerbation of coagulopathy after administration of anti-leukemic agents. Intriguingly, an increase in levels of HMGB1 and histone H3 were detected in five of seven patients. These findings suggest that intranuclear proteins spontaneously released from leukemia cells may play a role in development of leukemia-related DIC. Additionally, remission induction chemotherapy causes apoptosis of leukemia cells, leading to forced release of intranuclear proteins, which may exacerbate coagulopathy.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

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

    Article  Google Scholar 

  2. Chi S, Ikezoe T. Disseminated intravascular coagulation in non-Hodgkin lymphoma. Int J Hematol. 2015;102(4):413–9. https://doi.org/10.1007/s12185-015-1854-5.

    Article  CAS  PubMed  Google Scholar 

  3. Ikezoe T. Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin. Int J Hematol. 2014;100:27–37.

    Article  CAS  Google Scholar 

  4. Ikezoe T. Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation. J Intensive Care. 2015;3:1. https://doi.org/10.1186/s40560-014-0050-7.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Uchiumi H, Matsushima T, Yamane A, Doki N, Irisawa H, Saitoh T, et al. Prevalence and clinical characteristics of acute myeloid leukemia associated with disseminated intravascular coagulation. Int J Hematol. 2007;86:137–42.

    Article  Google Scholar 

  6. Okamoto K, Tamura T, Sawatsubashi Y. Sepsis and disseminated intravascular coagulation. J Intensive Care. 2016;4:23. https://doi.org/10.1186/s40560-016-0149-0.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248–51.

    Article  CAS  Google Scholar 

  9. Ito T, Kawahara K, Nakamura T, Yamada S, Nakamura T, Abeyama K, et al. High-mobility group box 1 protein promotes development of microvascular thrombosis in rats. J Thromb Haemost. 2007;5:109–16.

    Article  CAS  Google Scholar 

  10. Carestia A, Rivadeneyra L, Romaniuk MA, Fondevila C, Negrotto S, Schattner M. Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost. 2013;110:1035–45.

    Article  CAS  Google Scholar 

  11. Nakahara M, Ito T, Kawahara K, Yamamoto M, Nagasato T, Shrestha B, et al. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism. PLoS ONE. 2013;8:e75961.

    Article  CAS  Google Scholar 

  12. Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15:1318–21.

    Article  CAS  Google Scholar 

  13. Chi S, Ikezoe T. Disseminated intravascular coagulation in non-Hodgkin lymphoma. Int J Hematol. 2015;102:413–9.

    Article  CAS  Google Scholar 

  14. 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 (eCollection 2016).

  15. Sadamura-Takenaka Y, Ito T, Noma S, Oyama Y, Yamada S, Kawahara K, et al. HMGB1 promotes the development of pulmonary arterial hypertension in rats. PLoS ONE. 2014;9:e102482.

    Article  Google Scholar 

  16. 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. https://doi.org/10.1186/s40560-018-0348-y.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  Google Scholar 

  18. Lu B, Wang C, Wang M, Li W, Chen F, Tracey KJ, et al. Molecular mechanism and therapeutic modulation of high mobility group box 1 release and action: an updated review. Expert Rev Clin Immunol. 2014;10:713–27.

    Article  CAS  Google Scholar 

  19. Ito T, Kawahara K, Okamoto K, Yamada S, Yasuda M, Imaizumi H, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombin–thrombomodulin complexes. Arterioscler Thromb Vasc Biol. 2008;28:1825–30.

    Article  CAS  Google Scholar 

  20. Wang J, Weiss I, Svoboda K, Kwaan HC. Thrombogenic role of cells undergoing apoptosis. Br J Haematol. 2001;115:382–91.

    Article  CAS  Google Scholar 

  21. Boles JC, Williams JC, Hollingsworth RM, Wang JG, Glover SL, Owens AP 3rd, et al. Anthracycline treatment of the human monocytic leukemia cell line THP-1 increases phosphatidylserine exposure and tissue factor activity. Thromb Res. 2012 Feb;129:197–203.

    Article  CAS  Google Scholar 

  22. Zhang X, Zhou H, Wang J, Yang L, Hu Y, Shen G, et al. Arsenic trioxide, retinoic acid and Ara-c regulated the expression of annexin II on the surface of APL cells, a novel co-receptor for plasminogen/tissue plasminogen activator. Thromb Res. 2002 Apr 1;106(1):63–70.

    Article  CAS  Google Scholar 

  23. Ikezoe T, Yang J, Nishioka C, Honda G, Furihata M, Yokoyama A. Thrombomodulin protects endothelial cells from a calcineurin inhibitor-induced cytotoxicity by upregulation of extracellular signal-regulated kinase/myeloid leukemia cell-1 signaling. Arterioscler Thromb Vasc Biol. 2012;32:2259–70.

    Article  CAS  Google Scholar 

  24. Ikezoe T, Takeuchi A, Isaka M, Arakawa Y, Iwabu N, Kin T, et al. Recombinant human soluble thrombomodulin safely and effectively rescues acute promyelocytic leukemia patients from disseminated intravascular coagulation. Leuk Res. 2012;36:1398–402.

    Article  CAS  Google Scholar 

  25. Ikezoe T, Yang J, Nishioka C, Isaka M, Iwabu N, Sakai M, et al. Thrombomodulin enhances the antifibrinolytic and antileukemic effects of all-trans retinoic acid in acute promyelocytic leukemia cells. Exp Hematol. 2012;40:457–65.

    Article  CAS  Google Scholar 

  26. Mirrakhimov AE, Ali AM, Khan M, Barbaryan A. Tumor lysis syndrome in solid tumors: an up to date review of the literature. Rare Tumors. 2014;6:68–75.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by KAKENHI (18K07419 and 18H02844).

Author information

Authors and Affiliations

  1. Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima, Fukushima, 960-1295, Japan

    Kayo Harada-Shirado, Xintao Wang, Hirotaka Mori, Masahiko Fukatsu, Hiroshi Takahashi, Akiko Shichishima-Nakamura, Satoshi Kimura, Hiroshi Ohkawara & Takayuki Ikezoe

  2. Shino-Test Corporation, R&D Center, Sagamihara, Japan

    Shingo Yamada

  3. Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Takashi Ito

Authors
  1. Kayo Harada-Shirado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xintao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hirotaka Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masahiko Fukatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroshi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akiko Shichishima-Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satoshi Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroshi Ohkawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shingo Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takashi Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takayuki Ikezoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takayuki Ikezoe.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Harada-Shirado, K., Wang, X., Mori, H. et al. Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia. Int J Hematol 111, 378–387 (2020). https://doi.org/10.1007/s12185-019-02798-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-019-02798-5

Keywords

Search

Navigation