Skip to main content
SpringerLink
Log in

Recombinant soluble human thrombomodulin (thrombomodulin alfa) in the treatment of neonatal disseminated intravascular coagulation

  • Original Article
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

An Erratum to this article was published on 29 July 2014

Abstract

Recombinant soluble human thrombomodulin (TM-α) has been shown to be useful in the treatment of disseminated intravascular coagulation (DIC) in a heparin-controlled study and has been available for clinical use in Japan since 2008. However, data on its use for neonatal DIC have not been reported from any clinical studies, so efficacy and safety were analyzed in 60 neonatal DIC patients identified in post-marketing surveillance. The DIC resolution rate as of the day after last administration of TM-α was 47.1 %, and the survival rate at 28 days after last administration was 76.7 %. Hemostatic test result profiles revealed decreased levels of fibrin/fibrinogen degradation products and increased platelet counts and antithrombin activity. Incidences of adverse drug reactions, bleeding-related adverse drug reactions, and bleeding-related adverse events were 6.7, 6.7, and 16.7 %, respectively, with no significant differences between neonatal, pediatric (excluding neonates), and adult DIC patients. Conclusion: This surveillance provided real-world data on the safety and effectiveness of TM-alpha in the treatment of neonatal DIC in general practice settings.

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

Similar content being viewed by others

Abbreviations

ADRs:

Adverse drug reactions

AEs:

Adverse events

DIC:

Disseminated intravascular coagulation

FDP:

Fibrinogen/fibrin degradation products

JMHW:

Japanese Ministry of Health and Welfare

PMS:

Post-marketing surveillance

TM:

Thrombomodulin

References

  1. Andrew M, Paes B, Johnston M (1990) Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 12(1):95–104

    Article  CAS  PubMed  Google Scholar 

  2. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P (1988) Development of the human coagulation system in the healthy premature infant. Blood 72(5):1651–1657

    CAS  PubMed  Google Scholar 

  3. Bhat R, Monagle P (2012) The preterm infant with thrombosis. Arch Dis Child Fetal Neonatal Ed 97(6):F423–F428

    PubMed  Google Scholar 

  4. Bick RL (2002) Disseminated intravascular coagulation: a review of etiology, pathophysiology, diagnosis, and management: guidelines for care. Clin Appl Thromb Hemost 8(1):1–31

    Article  CAS  PubMed  Google Scholar 

  5. Dairaku M, Sueishi K, Tanaka K (1982) Disseminated intravascular coagulation in newborn infants. Prevalence in autopsies and significance as a cause of death. Pathol Res Pract 174(1–2):106–115

    Article  CAS  PubMed  Google Scholar 

  6. De Carolis MP (2010) Use of protein C concentrate in neonatal period. Minerva Pediatr 62(3 Suppl 1):29–30

    PubMed  Google Scholar 

  7. El Beshlawy A, Alaraby I, Abou Hussein H, Abou-Elew HH, Mohamed Abdel Kader MS (2010) Study of protein C, protein S, and antithrombin III in newborns with sepsis. Pediatr Crit Care Med 11(1):52–59

    Article  PubMed  Google Scholar 

  8. Esmon CT (2002) Protein C pathway in sepsis. Ann Med 34(7–8):598–605

    Article  CAS  PubMed  Google Scholar 

  9. Esmon NL, Owen WG, Esmon CT (1982) Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 257(2):859–864

    CAS  PubMed  Google Scholar 

  10. Fischer D, Schloesser RL, Nold-Petry CA, Nold MF, Veldman A (2009) Protein C concentrate in preterm neonates with sepsis. Acta Paediatr 98(9):1526–1529

    Article  CAS  PubMed  Google Scholar 

  11. Gobel U, von Voss H, Jurgens H, Petrich C, Pothmann R, Sprock I, Lemburg P (1980) Efficiency of heparin in the treatment of newborn infants with respiratory distress syndrome and disseminated intravascular coagulation. Eur J Pediatr 133(1):47–49

    Article  CAS  PubMed  Google Scholar 

  12. Gomi K, Zushi M, Honda G, Kawahara S, Matsuzaki O, Kanabayashi T, Yamamoto S, Maruyama I, Suzuki K (1990) Antithrombotic effect of recombinant human thrombomodulin on thrombin-induced thromboembolism in mice. Blood 75(7):1396–1399

    CAS  PubMed  Google Scholar 

  13. Hanesaka Y, Takahashi Y, Kawaguchi C, Morikawa H, Yasuhara H, Yoshida K, Yoshioka A (2004) Clinical effect of nafamostat mesilate for disseminated intravascular coagulation of neonate the comparison with gabexate mesilate. Jpn J Pediatr Hematol 18:23–28

    Google Scholar 

  14. Hudson IR, Gibson BE, Brownlie J, Holland BM, Turner TL, Webber RG (1990) Increased concentrations of D-dimers in newborn infants. Arch Dis Child 65(4 Spec No):383–384

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H (1983) 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 49(49):265–275

    PubMed  Google Scholar 

  16. Koh SC, Cheong YC, Arulkumaran S, Ratnam SS (1997) Coagulation activation, fibrinolysis and inhibitors in neonates. Ann Acad Med Singap 26(6):767–771

    CAS  PubMed  Google Scholar 

  17. Kusuda S, Fujimura M, Sakuma I, Aotani H, Kabe K, Itani Y, Ichiba H, Matsunami K, Nishida H, Neonatal Research Network J (2006) Morbidity and mortality of infants with very low birth weight in Japan: center variation. Pediatrics 118(4):e1130–e1138

    Article  PubMed  Google Scholar 

  18. Marlar RA, Kleiss AJ, Griffin JH (1982) Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 59(5):1067–1072

    CAS  PubMed  Google Scholar 

  19. McDonald MM, Johnson ML, Rumack CM, Koops BL, Guggenheim MA, Babb C, Hathaway WE (1984) Role of coagulopathy in newborn intracranial hemorrhage. Pediatrics 74(1):26–31

    CAS  PubMed  Google Scholar 

  20. Mimuro J, Takahashi H, Kitajima I, Tsuji H, Eguchi Y, Matsushita T, Kuroda T, Sakata Y (2013) Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation. Thromb Res 131(5):436–443

    Article  CAS  PubMed  Google Scholar 

  21. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, De Rosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Roy N, Rowlands S (2006) Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 95(2):362–372

    CAS  PubMed  Google Scholar 

  22. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B, REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE) study group (2007) Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 369:836–843

    Article  CAS  PubMed  Google Scholar 

  23. Nakamura T, Ariyoshi N, Asakura A, Shirahata A (1987) Effects of gabexate mesilate on DIC of infancy and childhood. Jpn J Pediatr Hematol 1:75–83

    Google Scholar 

  24. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, Hirayama A, Matsuda T, Asakura H, Nakashima M, Aoki N (2007) Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 5(1):31–41

    Article  CAS  PubMed  Google Scholar 

  25. Schmidt B, Gillie P, Mitchell L, Andrew M, Caco C, Roberts R (1998) A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 158(2):470–476

    CAS  PubMed  Google Scholar 

  26. Shirahata A, Shirakawa Y, Yoshida Y, Ichikawa K, Takahashi Y, Kajino Y, lguchi Y, Sato A, Ariyoshi N, Miyakawa T (1993) The usefulness of antithrombin III concentrate in disseminated intravascular coagulation of newborn infants. J Jpn Soc Perinat Neonatal Med 29:98–105

    Google Scholar 

  27. Tay SP, Cheong SK, Boo NY (2003) Circulating tissue factor, tissue factor pathway inhibitor and D-dimer in umbilical cord blood of normal term neonates and adult plasma. Blood Coagul Fibrinolysis 14(2):125–129

    Article  CAS  PubMed  Google Scholar 

  28. Veldman A, Fischer D, Nold MF, Wong FY (2010) Disseminated intravascular coagulation in term and preterm neonates. Semin Thromb Hemost 36(4):419–428

    Article  CAS  PubMed  Google Scholar 

  29. von Kries R, Stannigel H, Gobel U (1985) Anticoagulant therapy by continuous heparin-antithrombin III infusion in newborns with disseminated intravascular coagulation. Eur J Pediatr 144(2):191–194

    Article  Google Scholar 

  30. Williams MD, Chalmers EA, Gibson BE, Haemostasis, Thrombosis Task Force BCfSiH (2002) The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol 119(2):295–309

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study used the TM-α PMS database. We wish to thank all the participating physicians and registered patients who took part in this surveillance. We are also grateful to Katsuhito Nihashi for his support with statistical analyses. This surveillance was supported in part by the Japanese Society on Thrombosis and Hemostasis.

Conflict of interest

Masahiro Kajiki and Goichi Honda are employees of Asahi Kasei Pharma Corporation. The other authors have no competing financial interests to declare.

Author information

Authors and Affiliations

  1. University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan

    Akira Shirahata

  2. The Japanese Society on Thrombosis and Hemostasis Post Marketing Surveillance Committee for Thrombomodulin Alfa, Tokyo, Japan

    Jun Mimuro, Hoyu Takahashi, Isao Kitajima, Hajime Tsuji, Yutaka Eguchi, Tadashi Matsushita & Yoichi Sakata

  3. Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, School of Medicine, Tochigi, Japan

    Jun Mimuro & Yoichi Sakata

  4. Department of Internal Medicine, Niigata Prefectural Kamo Hospital, Niigata, Japan

    Hoyu Takahashi

  5. Department of Clinical Laboratory and Molecular Pathology, Graduate School of Medical and Pharmaceutical Science, University of Toyama, Toyama, Japan

    Isao Kitajima

  6. Department of Blood Transfusion, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Hajime Tsuji

  7. Critical and Intensive Care Medicine, Shiga University of Medical Science, Shiga, Japan

    Yutaka Eguchi

  8. Department of Transfusion Medicine, Nagoya University Hospital, Aichi, Japan

    Tadashi Matsushita

  9. Pharmaceuticals Sales Division, Asahi Kasei Pharma Corporation, Tokyo, Japan

    Masahiro Kajiki & Goichi Honda

  10. Kita-kyushu Yahata Higashi Hospital, 2-1-17 Nishi-honmachi, Yahata-higashi-ku, Kita-kyushu, Fukuoka, 805-0061, Japan

    Akira Shirahata

Authors
  1. Akira Shirahata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Mimuro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hoyu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isao Kitajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hajime Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yutaka Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tadashi Matsushita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masahiro Kajiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Goichi Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoichi Sakata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Shirahata.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shirahata, A., Mimuro, J., Takahashi, H. et al. Recombinant soluble human thrombomodulin (thrombomodulin alfa) in the treatment of neonatal disseminated intravascular coagulation. Eur J Pediatr 173, 303–311 (2014). https://doi.org/10.1007/s00431-013-2155-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-013-2155-8

Keywords

Search

Navigation