Skip to main content

Advertisement

SpringerLink
Log in

Potentially life-threatening coagulopathy associated with simultaneous reduction in coagulation and fibrinolytic function in pediatric acute leukemia after hematopoietic stem-cell transplantation

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

Abstract

The pathogenesis of sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) is poorly understood, and limited information is available on global hemostatic function in HSCT. We assessed changes in coagulation and fibrinolysis using a simultaneous thrombin and plasmin generation assay (T/P-GA) during HSCT. Measurements of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) using T/P-GA in six pediatric acute leukemia patients treated with HSCT were compared to normal plasma. In the SOS case, the ratios of T-EP and P-Peak to normal were simultaneously decreased at four weeks post-HSCT (Pre; ~1.1/1.1–1.4, Week+4; 0.14/0.0084, respectively). Similarly, in the TMA patient, both ratios were decreased at 3 weeks and recovered after 8 weeks (Pre; 1.2/~0.95, Week+3; 0.59/0.22, Week+8; 1.2/0.64–0.85). In the other patients, when SOS/TMA was not evident, the T/P-GA data remained within normal limits. These findings suggest that the simultaneous reduction of coagulation and fibrinolytic function in patients developing SOS/TMA can lead to a life-threatening coagulopathy. Further research is warranted to clarify global hemostatic function after HSCT to establish optimal supportive therapy for these critical clinical disorders of hemostasis.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120:1165–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lange BJ, Smith FO, Feusner J, Barnard DR, Dinndorf P, Feig S, et al. Outcomes in CCG-2961, a children’s oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children’s oncology group. Blood. 2008;111:1044–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Creutzig U, Zimmermann M, Lehrnbecher T, Graf N, Hermann J, Niemeyer CM, et al. Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol. 2006;24:4499–506.

    Article  CAS  PubMed  Google Scholar 

  4. Tsukimoto I, Tawa A, Horibe K, Tabuchi K, Kigasawa H, Tsuchida M, et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol. 2009;27:4007–13.

    Article  CAS  PubMed  Google Scholar 

  5. Gibson BE, Wheatley K, Hann IM, Stevens RF, Webb D, Hills RK, et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia. 2005;19:2130–8.

    Article  CAS  PubMed  Google Scholar 

  6. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116–22.

    Article  CAS  PubMed  Google Scholar 

  7. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–83.

    Article  CAS  PubMed  Google Scholar 

  8. Carreras E, Grañena A, Rozman C. Hepatic veno-occlusive disease after bone marrow transplant. Blood Rev. 1993;7:43–51.

    Article  CAS  PubMed  Google Scholar 

  9. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85:3005–20.

    CAS  PubMed  Google Scholar 

  10. Batts ED, Lazarus HM. Diagnosis and treatment of transplantation-associated thrombotic microangiopathy: real progress or are we still waiting? Bone Marrow Transplant. 2007;40:709–19.

    Article  CAS  PubMed  Google Scholar 

  11. Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011;118:1452–62.

    Article  CAS  PubMed  Google Scholar 

  12. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:571–5.

    Article  PubMed  Google Scholar 

  13. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, et al. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007;92:95–100.

    Article  PubMed  Google Scholar 

  14. Kaleelrahman M, Eaton JD, Leeming D, Bowyer K, Taberner D, Chang J, et al. Role of plasminogen activator inhibitor-1 (PAI-1) levels in the diagnosis of BMT-associated hepatic veno-occlusive disease and monitoring of subsequent therapy with defibrotide (DF). Hematology. 2003;8:91–5.

    Article  CAS  PubMed  Google Scholar 

  15. Sartori MT, Spiezia L, Cesaro S, Messina C, Paris M, Pillon M, et al. Role of fibrinolytic and clotting parameters in the diagnosis of liver veno-occlusive disease after hematopoietic stem cell transplantation in a pediatric population. Thromb Haemost. 2005;93:682–9.

    CAS  PubMed  Google Scholar 

  16. Eber SW, Gungor T, Veldman A, Sykora K, Scherer F, Fischer D, et al. Favorable response of pediatric stem cell recipients to human protein C concentrate substitution for veno-occlusive disease. Pediatr Transplant. 2007;11:49–57.

    Article  CAS  PubMed  Google Scholar 

  17. Pinomäki A, Volin L, Joutsi-Korhonen L, Virtanen JO, Lemponen M, Ruutu T, et al. Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD. Bone Marrow Transplant. 2010;45:730–7.

    Article  PubMed  Google Scholar 

  18. Matsumoto T, Nogami K, Shima M. Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis. Thromb Haemost. 2013;110:761–8.

    Article  CAS  PubMed  Google Scholar 

  19. Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014;2:20.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Ikezoe T, Yang J, Nishioka C, Pan B, Xu K, Furihata M, et al. The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model. Bone Marrow Transplant. 2017;52:73–9.

    Article  CAS  PubMed  Google Scholar 

  22. Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol. 2006;26:2445–53.

    Article  CAS  PubMed  Google Scholar 

  23. Fujiwara H, Maeda Y, Sando Y, Nakamura M, Tani K, Ishikawa T, et al. Treatment of thrombotic microangiopathy after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin. Transfusion. 2016;56:886–92.

    Article  CAS  PubMed  Google Scholar 

  24. Nomura S, Ozasa R, Nakanishi T, Fujita S, Miyaji M, Mori S, et al. Can recombinant thrombomodulin play a preventive role for veno-occlusive disease after haematopoietic stem cell transplantation? Thromb Haemost. 2011;105:1118–20.

    Article  CAS  PubMed  Google Scholar 

  25. Nomura S, Maeda Y, Ishii K, Katayama Y, Yagi H, Fujishima N, et al. Relationship between HMGB1 and PAI-1 after allogeneic hematopoietic stem cell transplantation. J Blood Med. 2016;7:1–4.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was partly supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to KN (Grant No. 15K09663).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan

    Takashi Ishihara, Keiji Nogami, Tomoko Matsumoto, Akitaka Nomura, Yasufumi Takeshita, Satoshi Ochi & Midori Shima

Authors
  1. Takashi Ishihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keiji Nogami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomoko Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akitaka Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasufumi Takeshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Ochi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Midori Shima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keiji Nogami.

Ethics declarations

Conflict of interest

The other authors have no direct and indirect conflicts of interest.

Additional information

T. Matsumoto belongs to course affiliation endowed by Baxalta Japan Co., Ltd. (Tokyo, Japan).

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ishihara, T., Nogami, K., Matsumoto, T. et al. Potentially life-threatening coagulopathy associated with simultaneous reduction in coagulation and fibrinolytic function in pediatric acute leukemia after hematopoietic stem-cell transplantation. Int J Hematol 106, 126–134 (2017). https://doi.org/10.1007/s12185-017-2213-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-017-2213-5

Keywords

Search

Navigation