Skip to main content

Thrombotic Disorders

  • Chapter
  • First Online:
Book cover Hematological Disorders in Children

Abstract

Thromboembolism occurs as a consequence of the genetic predisposition, underlying diseases, and triggers of dehydration, infection, and injury. Thrombotic events are much rarer in infants and children than in adults. Aging is a potent risk factor for the development of venous thrombosis and stroke. The genetic effects on the hypercoagulability in pediatric patients are thus more carefully considered than in adult patients. The genetic predisposition of thromboembolism depends on the racial background. Factor V Leiden (G1691A) and factor II variant (G20210A) are the common thrombophilias in Caucasians, but not found in Asian ancestries. The incidence of pediatric thrombosis is increasing because of the advances in neonatal intensive care, cardiovascular surgery, and imaging techniques. There is an increasing number of reports on the molecular epidemiology of constitutional thrombophilias also in Asian countries. On the other hand, the treatment and prophylaxis of pediatric thrombosis have not been established. The advent of direct oral anticoagulants (DOACs) has opened a new era of anticoagulation for adult patients with thrombosis, while the management of heritable thrombophilia is under investigation. This chapter briefly introduces the thrombotic disorders in neonates, infants, and children, with special reference to the high-risk-inherited thrombophilia of natural anticoagulant deficiency.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

APC:

Activated protein C

AT:

Antithrombin

CVST:

Cerebral venous sinus thrombosis

DVT:

Deep vein thrombosis

ICTH:

Intracranial thrombosis/hemorrhage

NETs:

Neutrophil extracellular traps

OR:

Odds ratio

PC:

Protein C

PIVKAII:

Protein induced by vitamin K absence or antagonists

PS:

Protein S

PT:

Prothrombin time

VTE:

Venous thromboembolism

References

  1. Spentzouris G, Scriven RJ, Lee TK, Labropoulos N. Pediatric venous thromboembolism in relation to adults. J Vasc Surg. 2012;55:1785–93.

    Article  PubMed  Google Scholar 

  2. Hagedorn I, Vögtle T, Nieswandt B. Arterial thrombus formation. Novel mechanisms and targets. Hamostaseologie. 2010;30:127–35.

    CAS  PubMed  Google Scholar 

  3. Kimball AS, Obi AT, Diaz JA, Henke PK. The emerging role of NETs in venous thrombosis and immunothrombosis. Front Immunol. 2016;7:236.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nowak-Göttl U, Janssen V, Manner D, Kenet G. Venous thromboembolism in neonates and children—update 2013. Thromb Res. 2013;131:S39–41.

    Article  PubMed  Google Scholar 

  5. Raffini L, Huang YS, Witmer C, et al. 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. Ishola T, Kirk SE, Guffey D, et al. Risk factors and co-morbidities in adolescent thromboembolism are different than those in younger children. Thromb Res. 2016;141:178–82.

    Article  CAS  PubMed  Google Scholar 

  7. Tolbert J, Carpenter SL. Common acquired causes of thrombosis in children. Curr Probl Pediatr Adolesc Health Care. 2013;43:169–77.

    Article  PubMed  Google Scholar 

  8. Caspers M, Pavlova A, Driesen J, et al. Deficiencies of antithrombin, protein C and protein S—practical experience in genetic analysis of a large patient cohort. Thromb Haemost. 2012;108:247–57.

    Article  CAS  PubMed  Google Scholar 

  9. Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol. 2009;146:369–83.

    Article  PubMed  Google Scholar 

  10. Goldenberg NA, Everett AD, Graham D, Bernard TJ, Nowak-Göttl U. Proteomic and other mass spectrometry based “omics” biomarker discovery and validation in pediatric venous thromboembolism and arterial ischemic stroke: current state, unmet needs, and future directions. Proteomics Clin Appl. 2014;8:828–36.

    Article  CAS  PubMed  Google Scholar 

  11. Sosothikul D, Kittikalayawong Y, Aungbamnet P, Buphachat C, Seksarn P. Reference values for thrombotic markers in children. Blood Coagul Fibrinolysis. 2012;23:208–11.

    Article  CAS  PubMed  Google Scholar 

  12. Ichiyama M, Ohga S, Ochiai M, et al. Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency. Brain Dev. 2016;38:253–6.

    Article  PubMed  Google Scholar 

  13. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965;13:516–30.

    CAS  PubMed  Google Scholar 

  14. Hultin MB, McKay J, Abildgaard U. Antithrombin Oslo. Type Ib classification of the first reported antithrombin-deficient family, with a review of hereditary antithrombin variants. Thromb Haemost. 1988;59:468–73.

    CAS  PubMed  Google Scholar 

  15. Weingarz L, Schwonberg J, Schindewolf M, et al. Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry. Br J Haematol. 2013;163:655–65.

    Article  PubMed  Google Scholar 

  16. Di Minno MN, Ambrosino P, Ageno W, et al. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res. 2015;135:923–32.

    Article  PubMed  Google Scholar 

  17. Holzhauer S, Goldenberg NA, Junker R, et al. Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study. Blood. 2012;120:1510–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. van der Meer FJM, Koster T, Vandenbroucke JP, et al. The Leiden Thrombophilia Study (LETS). Thromb Haemost. 1997;78:631–5.

    PubMed  Google Scholar 

  19. Perry DJ, Carrell RW. Molecular genetics of human antithrombin deficiency. Hum Mutat. 1996;7:7–22.

    Article  CAS  PubMed  Google Scholar 

  20. Rosenberg RD. Actions and interactions of antithrombin and heparin. N Engl J Med. 1975;292:146–51.

    Article  CAS  PubMed  Google Scholar 

  21. Harper PL, Luddington RJ, Daly M, et al. The incidence of dysfunctional antithrombin variants: four cases in 210 patients with thromboembolic disease. Br J Haematol. 1991;77:360–4.

    Article  CAS  PubMed  Google Scholar 

  22. Ohga S, Ishiguro A, Takahashi Y, et al. Protein C deficiency as the major cause of thrombophilias in childhood. Pediatr Int. 2013;55:267–71.

    Article  CAS  PubMed  Google Scholar 

  23. Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C: biased for translation. Blood. 2015;125:2898–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–64.

    Article  CAS  PubMed  Google Scholar 

  25. Quinn LM, Drakeford C, O’Donnell JS, Preston RJ. Engineering activated protein C to maximize therapeutic efficacy. Biochem Soc Trans. 2015;43:691–5.

    Article  CAS  PubMed  Google Scholar 

  26. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981;68:1370–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Ichiyama M, Ohga S, Ochiai M, et al. Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism. Pediatr Res. 2016;79:81–6.

    Article  CAS  PubMed  Google Scholar 

  29. Ishiguro A, Ezinne CC, Michihata N, et al. Pediatric thromboembolism: a national survey in Japan. Int J Hematol. 2017;105:52–8.

    Article  PubMed  Google Scholar 

  30. Kinoshita S, Iida H, Inoue S, 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 

  31. Miyata T, Sato Y, Ishikawa J, 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 

  32. Takahashi Y, Yoshioka A. Hemostasis and its regulation system in childhood. Jpn J Pediatr Hematol. 1994;8:389–97.

    Google Scholar 

  33. Ishimura M, Saito M, Ohga S, et al. Fulminant sepsis/meningitis due to Haemophilus influenzae in a protein C-deficient heterozygote treated with activated protein C therapy. Eur J Pediatr. 2009;168:673–7.

    Article  CAS  PubMed  Google Scholar 

  34. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995;73:87–93.

    CAS  PubMed  Google Scholar 

  35. Bereczky Z, Kovács KB, Muszbek L. Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game. Clin Chem Lab Med. 2010;48:S53–66.

    Article  PubMed  Google Scholar 

  36. Tang L, Lu X, Yu JM, et al. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. J Thromb Haemost. 2012;10:2019–26.

    Article  CAS  PubMed  Google Scholar 

  37. Miyata T, Sakata T, Yasumuro Y, et al. Genetic analysis of protein C deficiency in nineteen Japanese families: five recurrent defects can explain half of the deficiencies. Thromb Res. 1998;92:181–7.

    Article  CAS  PubMed  Google Scholar 

  38. Iijima K, Nakamura A, Kurokawa H, Monobe S, Nakagawa M. A homozygous protein C deficiency (Lys 192 del) who developed venous thrombosis for the first time at adulthood. Thromb Res. 2010;125:100–1.

    Article  CAS  PubMed  Google Scholar 

  39. Yin T, Miyata T. Dysfunction of protein C anticoagulant system, main genetic risk factor for venous thromboembolism in northeast Asians. J Thromb Thrombolysis. 2014;37:56–65.

    Article  CAS  PubMed  Google Scholar 

  40. Sharma S, Anbazhagan J, Plakkal N. Neonatal purpura fulminans due to protein C deficiency. Arch Dis Child Fetal Neonatal Ed. 2015;100:F453.

    Article  PubMed  Google Scholar 

  41. Manco-Johnson MJ, Bomgaars L, Palascak J, et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency. Thromb Haemost. 2016;116:58–68.

    Article  PubMed  Google Scholar 

  42. Price VE, Ledingham DL, Krümpel A, Chan AK. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med. 2011;16:318–22.

    Article  CAS  PubMed  Google Scholar 

  43. Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Hemophilia. 2008;14:1214–21.

    Article  CAS  Google Scholar 

  44. Hamasaki N, Kuma H, Tsuda H. Activated protein C anticoagulant system dysfunction and thrombophilia in Asia. Ann Lab Med. 2013;33:8–13.

    Article  CAS  PubMed  Google Scholar 

  45. Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med. 1984;311:1525–8.

    Article  CAS  PubMed  Google Scholar 

  46. Kenet G, Liitkhoff LK, Albisetti M, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121:1838–47.

    Article  PubMed  Google Scholar 

  47. Marlar RA, Gausman JN. Protein S abnormalities: a diagnostic nightmare. Am J Hematol. 2011;86:418–21.

    Article  CAS  PubMed  Google Scholar 

  48. Alhenc-Gelas M, Plu-Bureau G, Horellou MH, Rauch A, Suchon P, GEHT Genetic Thrombophilia Group. PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency. Thromb Haemost. 2016;115:570–9.

    Article  PubMed  Google Scholar 

  49. Sirachainan N, Sasanakul W, Visudibhan A, et al. Protein C deficiency in Thai children with thromboembolism: a report of clinical presentations and mutation analysis. Thromb Res. 2010;125:200–2.

    Article  CAS  PubMed  Google Scholar 

  50. Shen MC, Lin JS, Tsay W. Protein C and protein S deficiencies are the most important risk factors associated with thrombosis in Chinese venous thrombophilic patients in Taiwan. Thromb Res. 2000;99:447–52.

    Article  CAS  PubMed  Google Scholar 

  51. Tang L, Jian XR, Hamasaki N, et al. Molecular basis of protein S deficiency in China. Am J Hematol. 2013;88:899–905.

    Article  CAS  PubMed  Google Scholar 

  52. Ikejiri M, Wada H, Sakamoto Y, et al. The association of protein S Tokushima-K196E with a risk of deep vein thrombosis. Int J Hematol. 2010;92:302–5.

    Article  CAS  PubMed  Google Scholar 

  53. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to previously unrecognized mechanism characterized by poor anti-coagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90:1004–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369(6475):64–7.

    Article  CAS  PubMed  Google Scholar 

  55. Middeldorp S, Meinardi JR, Koopman MM, et al. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med. 2001;135:322–7.

    Article  CAS  PubMed  Google Scholar 

  56. Nogami K, Shinozawa K, Ogiwara K, et al. Novel FV mutation (W1920R, FV Nara) associated with serious deep vein thrombosis and more potent APC resistance relative to FV Leiden. Blood. 2014;123:2420–8.

    Article  CAS  PubMed  Google Scholar 

  57. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–703.

    CAS  PubMed  Google Scholar 

  58. Miyawaki Y, Suzuki A, Fujita J, et al. Thrombosis from a prothrombin mutation conveying antithrombin resistance. N Engl J Med. 2012;366:2390–6.

    Article  CAS  PubMed  Google Scholar 

  59. Jenkins PV, Rawley O, Smith OP, O’Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol. 2012;157:653–63.

    Article  CAS  PubMed  Google Scholar 

  60. Goldenberg NA, Knapp-Clevenger R, Manco-Johnson MJ, et al. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. N Engl J Med. 2004;351:1081–8.

    Article  CAS  PubMed  Google Scholar 

  61. Moll S, Varga EA. Homocysteine and MTHFR mutations. Circulation. 2015;132:e6–9.

    Article  CAS  PubMed  Google Scholar 

  62. Bezemer ID, Doggen CJ, Vos HL, et al. No association between the common MTHFR677C―>T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med. 2007;167:497–501.

    Article  CAS  PubMed  Google Scholar 

  63. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death. The vitamin intervention for stroke prevention (VISP) randomized controlled trial. JAMA. 2004;291:565–75.

    Article  CAS  PubMed  Google Scholar 

  64. Glueck CJ, Smith D, Gandhi N, et al. Treatable high homocysteine alone or in concert with five other thrombophilias in 1014 patients with thrombotic events. Blood Coagul Fibrinolysis. 2015;26:736–42.

    CAS  PubMed  Google Scholar 

  65. Franchini M. Atypical hemolytic uremic syndrome: from diagnosis to treatment. Clin Chem Lab Med. 2015;53:1679–88.

    CAS  PubMed  Google Scholar 

  66. Fujimura Y, Matsumoto M, Isonishi A, et al. Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost. 2011;9(Suppl 1):283–301.

    Article  CAS  PubMed  Google Scholar 

  67. Sarker T, Roy S, Hollon W, Rajpurkar M. Lupus anticoagulant acquired hypoprothrombinemia syndrome in childhood: two distinct patterns and review of the literature. Haemophilia. 2015;21:754–60.

    Article  CAS  PubMed  Google Scholar 

  68. La Regina M, Orlandini F, Manna R. Autoinflammatory diseases: a possible cause of thrombosis? Thromb J. 2015;13:19.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Shah R, Ferreira P, Karmali S, Le D. Severe congenital protein C deficiency: practical aspects of management. Pediatr Blood Cancer. 2016;63:1488–90.

    Article  CAS  PubMed  Google Scholar 

  70. Tripodi A, Martinelli I, Chantarangkul V, et al. Thrombin generation and other coagulation parameters in a patient with homozygous congenital protein S deficiency on treatment with rivaroxaban. Int J Hematol. 2016;103:165–72.

    Article  PubMed  Google Scholar 

  71. Umemura Y, Yamakawa K, Ogura H, et al. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials. J Thromb Haemost. 2016;14:518–30.

    Article  CAS  PubMed  Google Scholar 

  72. Franchini M, Martinelli I, Mannucci PM. Uncertain thrombophilia markers. Thromb Haemost. 2016;115:25–30.

    Article  PubMed  Google Scholar 

  73. Dargaud Y, Jourdy Y, Le Quellec S, et al. Effect of five therapeutic strategies on the coagulation defect induced by the thrombomodulin c.1611C>A mutation. Br J Haematol. 2016;174:993–6.

    Article  CAS  PubMed  Google Scholar 

  74. Doi T, Ohga S, Ito N, et al. Limited renal prophylaxis in regular plasmatherapy for heritable ADAMTS13 deficiency. Pediatr Blood Cancer. 2013;60:1557–8.

    Article  PubMed  Google Scholar 

  75. Matsunami M, Ishiguro A, Fukuda A, et al. Successful living domino liver transplantation in a child with protein C deficiency. Pediatr Transplant. 2015;19:E70–4.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by a grant from the Kyushu University Clinical Research Network Project and a grant from the Ministry of Health, Labour and Welfare of Japan.

Conflict of Interest: The authors have no conflict of interests to disclose.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shouichi Ohga M.D., Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Ohga, S., Ishimura, M. (2017). Thrombotic Disorders. In: Ishii, E. (eds) Hematological Disorders in Children. Springer, Singapore. https://doi.org/10.1007/978-981-10-3886-0_10

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-3886-0_10

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-3885-3

  • Online ISBN: 978-981-10-3886-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics