Skip to main content
SpringerLink
Log in

Pediatric thromboembolism: a national survey in Japan

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

Abstract

Thromboembolism is being detected at increasing rates in pediatric tertiary care hospitals. The incidence of pediatric thrombophilia differs across countries, and is unknown in Japan. We sent a survey to 520 pediatric department heads and 629 specialists, requesting details on patients who developed symptomatic thromboembolism between 2006 and 2010. Of 280 eligible cases, congenital thrombophilia and other conditions were reported. Congenital thrombophilia (n = 54, 19.3 %) comprised defects in protein C (27), protein S (9), and antithrombin (7). None had mutations in factor V Leiden or prothrombin G20210A, both of which are frequent in Caucasians. Non-congenital causes of thrombophilia included congenital heart disease, the use of central venous catheters, nephrotic syndrome, antiphospholipid syndrome, and malignancy with or without use of L-asparaginase. Patients with congenital thrombophilia developed thromboembolism at a significantly younger age (median 1.0 vs. 5.0 years, p = 0.014), had a higher frequency of consanguinity (35.2 vs. 1.8 %, p < 0.001) and post-thrombotic syndromes (29.6 vs. 13.3 %, p = 0.007) than those who did not. Thromboembolism in children with congenital thrombophilia recurred more frequently (50.0 vs. 13.7 %, p < 0.001) and was associated with more sequelae (61.1 vs. 37.2 %, p = 0.009) than in children without congenital thrombophilia. This nationwide survey provides the first comprehensive study of Japanese children with symptomatic thromboembolism. Significant recurrence and sequelae require optimized standards.

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

Similar content being viewed by others

References

  1. Estepp JH, Smeltzer M, Reiss UM. The impact of quality and duration of enoxaparin therapy on recurrent venous thrombosis in children. Pediatr Blood Cancer. 2012;59:105–9.

    Article  PubMed  Google Scholar 

  2. Kim SJ, Sabharwal S. Risk factors for venous thromboembolism in hospitalized children and adolescents: a systemic review and pooled analysis. J Pediatr Orthop B. 2014;23:389–93.

    Article  PubMed  Google Scholar 

  3. Macartney CA, Chan AK. Thrombosis in children. Semin Thromb Hemost. 2011;37:763–71.

    Article  CAS  PubMed  Google Scholar 

  4. Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics. 1995;96:291–4.

    CAS  PubMed  Google Scholar 

  5. Raffini L, Huang Y-S, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics. 2009;124:1001–8.

    Article  PubMed  Google Scholar 

  6. Nowak-Gottl U, von Kries R, Gobel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed. 1997;76:F163–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics. 1995;96:939–43.

    CAS  PubMed  Google Scholar 

  8. Kerlin BA, Stephens JA, Hogan MJ, Smoyer WE, O’Brien SH. Development of a pediatric-specific clinical probability tool for diagnosis of venous thromboembolism: a feasibility study. Pediatr Res. 2015;77:463–71.

    Article  PubMed  Google Scholar 

  9. Parker RI. Thrombosis in the pediatric population. Crit Care Med. 2010;38:S71–5.

    Article  PubMed  Google Scholar 

  10. Young G, Albisetti M, Bonduel M, Brandao L, Chan A, Friedrichs F, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. 2008;118:1373–82.

    Article  PubMed  Google Scholar 

  11. Ehrenforth S, Junker R, Koch HG, Kreuz W, Munchow N, Scharrer I, et al. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group. Eur J Pediatr. 1999;158(Suppl 3):S97–104.

    Article  PubMed  Google Scholar 

  12. Monagle P, Adams M, Mahoney M, Ali K, Barnard D, Bernstein M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res. 2000;47:763–6.

    Article  CAS  PubMed  Google Scholar 

  13. van Ommen CH, Heijboer H, Buller HR, Hirasing RA, Heijmans HS, Peters M. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr. 2001;139:676–81.

    Article  PubMed  Google Scholar 

  14. Atasay B, Arsan S, Günlemez A, Kemahli S, Akar N. Factor V Leiden and prothrombin gene 20210A variant in neonatal thromboembolism and in healthy neonates and adults: a study in a single center. Pediatr Hematol Oncol. 2003;20:627–34.

    Article  CAS  PubMed  Google Scholar 

  15. Jang MJ, Bang SM, Oh D. Incidence of venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database. J Thromb Haemost. 2011;9:85–91.

    Article  CAS  PubMed  Google Scholar 

  16. Lee CH, Lin LJ, Cheng CL, Kao Yang YH, Chen JY, Tsai LM. Incidence and cumulative recurrence rates of venous thromboembolism in the Taiwanese population. J Thromb Haemost. 2010;8:1515–23.

    Article  PubMed  Google Scholar 

  17. Ozbek N, Alioglu B, Avci Z, Malbora B, Onay O, Ozyurek E, et al. Incidence of and risk factors for childhood thrombosis: a single-center experience in Ankara, Turkey. Pediatr Hematol Oncol. 2009;26:11–29.

    Article  CAS  PubMed  Google Scholar 

  18. Sakata T, Kario K, Katayama Y, Matsuyama T, Kato H, Miyata T. Studies on congenital protein C deficiency in Japanese: prevalence, genetic analysis, and relevance to the onset of arterial occlusive diseases. Semin Thromb Hemost. 2000;26:11–6.

    Article  CAS  PubMed  Google Scholar 

  19. Molina JA, Jiang ZG, Heng BH, Ong BK. Venous thromboembolism at the National Healthcare Group, Singapore. Ann Acad Med Singap. 2009;38:470–8.

    PubMed  Google Scholar 

  20. van den Broek A, Williams VK, Revesz T, Suppiah R. Pediatric thrombotic events: a single-center study. J Pediatr Hematol Oncol. 2015;37:e210–4.

    Article  PubMed  Google Scholar 

  21. Kinoshita S, Iida H, Inoue S, Watanabe K, Kurihara M, Wada Y, et al. Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. Clin Biochem. 2005;38:908–15.

    Article  CAS  PubMed  Google Scholar 

  22. Miyata T, Sato Y, Ishikawa J, Okada H, Takeshita S, Sakata T, et al. Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis. Thromb Res. 2009;124:14–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ohga S, Kang D, Kinjo T, Ochiai M, Ishimura M, Kayamori Y, et al. Paediatric presentation and outcome of congenital protein C deficiency in Japan. Haemophilia. 2013;19:378–84.

    Article  CAS  PubMed  Google Scholar 

  24. Zakai N, McClure L. Racial differences in venous thromboembolism. J Thromb Haemost. 2011;9:1877–82.

    Article  CAS  PubMed  Google Scholar 

  25. Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med. 1998;128:1000–3.

    Article  CAS  PubMed  Google Scholar 

  26. Miyata T, Kimura R, Kokubo Y, Sakata T. Genetic risk factors for deep vein thrombosis among Japanese: importance of protein S K196E mutation. Int J Hematol. 2006;83:217–23.

    Article  CAS  PubMed  Google Scholar 

  27. Zivelin A, Rosenberg N, Faier S, Kornbrot N, Peretz H, Mannhalter C, et al. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood. 1998;92:1119–24.

    CAS  PubMed  Google Scholar 

  28. Roach REJ, Lijfering WM, Rosendaal FR, Cannegieter SC, le Cessie S. Sex difference in risk of second but not of first venous thrombosis: paradox explained. Circulation. 2014;129:51–6.

    Article  PubMed  Google Scholar 

  29. Revel-Vilk S, Chan A, Bauman M, Massicotte P. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost. 2003;1:915–21.

    Article  CAS  PubMed  Google Scholar 

  30. Garcia-Bolado A, Del Cura JL. CT venography vs ultrasound in the diagnosis of thromboembolic disease in patients with clinical suspicion of pulmonary embolism. Emerg Radiol. 2007;14:403–9.

    Article  PubMed  Google Scholar 

  31. Thomas SM, Goodacre SW, Sampson FC, van Beek EJ. Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis. Clin Radiol. 2008;63:299–304.

    Article  CAS  PubMed  Google Scholar 

  32. Tan M, van Rooden CJ, Westerbeek RE, Huisman MV. Diagnostic management of clinically suspected acute deep vein thrombosis. Br J Haematol. 2009;146:347–60.

    Article  PubMed  Google Scholar 

  33. Avcin T, Cimaz R, Silverman ED, Cervera R, Gattorno M, Garay S, et al. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry. Pediatrics. 2008;122:e1100–7.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

AI, MT, and MS contributed to the conception and design of this study; NM performed the statistical analyses; AI and CC drafted the manuscript; and HN and AM critically reviewed the manuscript and supervised the whole study process. All authors read and approved the final manuscript. This survey was supported by a grant from the NCCHD (22-3). Authors are grateful to the study participants and clinicians involved in this study. We thank Dr. Julian Tang in the Department of Education for Clinical Research, NCCHD for his editorial support.

Author information

Authors and Affiliations

  1. Division of Hematology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Akira Ishiguro & Hisaya Nakadate

  2. Department of Postgraduate Education and Training, National Center for Child Health and Development, Tokyo, Japan

    Akira Ishiguro & Nobuaki Michihata

  3. Department of Health Policy, National Center for Child Health and Development, Tokyo, Japan

    Chibueze Chioma Ezinne

  4. Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan

    Atsushi Manabe

  5. Department of Pediatrics, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan

    Masashi Taki

  6. Department of Pediatrics, Nara Medical University, Nara, Japan

    Midori Shima

Authors
  1. Akira Ishiguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chibueze Chioma Ezinne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobuaki Michihata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hisaya Nakadate
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Atsushi Manabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masashi Taki
    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 Akira Ishiguro.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ishiguro, A., Ezinne, C.C., Michihata, N. et al. Pediatric thromboembolism: a national survey in Japan. Int J Hematol 105, 52–58 (2017). https://doi.org/10.1007/s12185-016-2079-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-016-2079-y

Keywords

Search

Navigation