Abstract
Background:
The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation.
Methods:
We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis.
Results:
Reduced activities were determined in 122 patients (40%). Low PC patients were most frequently found in the lowest age group (0–2 y, 45%), while low PS or low AT patients were found in the highest age group (16–20 y; PS: 30% and AT: 20%). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0–2 y (75%), while six of eight patients with PS gene mutation were in 7–20 y. Two AT gene–mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene–mutated patient suffered from intracranial thromboembolism, while PS/AT gene–mutated patients mostly developed extracranial venous thromboembolism.
Conclusion:
Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Spentzouris G, Scriven RJ, Lee TK, Labropoulos N. Pediatric venous thromboembolism in relation to adults. J Vasc Surg 2012;55:1785–93.
Nowak-Göttl U, Janssen V, Manner D, Kenet G. Venous thromboembolism in neonates and children–update 2013. Thromb Res 2013;131:Suppl 1:S39–41.
Tolbert J, Carpenter SL. Common acquired causes of thrombosis in children. Curr Probl Pediatr Adolesc Health Care 2013;43:169–77.
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.
Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol 2009;146:369–83.
Shatla HM, Tomoum HY, Elsayed SM, et al. Inherited thrombophilia in pediatric ischemic stroke: an Egyptian study. Pediatr Neurol 2012;47:114–8.
Sirachainan N, Sasanakul W, Visudibhan A, Chuansumrit A, Wongwerawattanakoon P, Parapakpenjune S. Protein C deficiency in Thai children with thromboembolism: a report of clinical presentations and mutation analysis. Thromb Res 2010;125:200–2.
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.
Tang L, Jian XR, Hamasaki N, et al. Molecular basis of protein S deficiency in China. Am J Hematol 2013;88:899–905.
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.
Sosothikul D, Kittikalayawong Y, Aungbamnet P, Buphachat C, Seksarn P. Reference values for thrombotic markers in children. Blood Coagul Fibrinolysis 2012;23:208–11.
Sakata T, Okamoto A, Mannami T, Tomoike H, Miyata T. Prevalence of protein S deficiency in the Japanese general population: the Suita Study. J Thromb Haemost 2004;2:1012–3.
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.
Limperger V, Klostermeier UC, Kenet G, et al. Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study. Br J Haematol 2014;167:385–93.
Klostermeier UC, Limperger V, Kenet G, et al. Role of protein S deficiency in children with venous thromboembolism. An observational international cohort study. Thromb Haemost 2015;113:426–33.
Limperger V, Franke A, Kenet G, et al. Clinical and laboratory characteristics of paediatric and adolescent index cases with venous thromboembolism and antithrombin deficiency. An observational multicentre cohort study. Thromb Haemost 2014;112:478–85.
Price VE, Ledingham DL, Krümpel A, Chan AK. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med 2011;16:318–22.
Ignjatovic V, Mertyn E, Monagle P. The coagulation system in children: developmental and pathophysiological considerations. Semin Thromb Hemost 2011;37:723–9.
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:Suppl 1:S53–66.
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.
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.
Oudot-Mellakh T, Cohen W, Germain M, et al. Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project. Br J Haematol 2012;157:230–9.
Cooper PC, Goodeve AC, Beauchamp NJ. Quality in molecular biology testing for inherited thrombophilia disorders. Semin Thromb Hemost 2012;38:600–12.
Ohga S, Ishiguro A, Takahashi Y, et al.; Japan Childhood Thrombophilia Study Group. Protein C deficiency as the major cause of thrombophilias in childhood. Pediatr Int 2013;55:267–71.
Ohga S, Kang D, Kinjo T, et al. Paediatric presentation and outcome of congenital protein C deficiency in Japan. Haemophilia 2013;19:378–84.
Takahashi Y, Yoshioka A. Hemostasis and its regulation system in childhood. Jpn J Pediatr Hematol 1994;8:389–97.
Athanasiadis G, Buil A, Souto JC, et al. A genome-wide association study of the protein C anticoagulant pathway. PLoS One 2011;6:e29168.
Tang W, Basu S, Kong X, et al. Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study. Blood 2010;116:5032–6.
Brummel-Ziedins KE, Orfeo T, Callas PW, Gissel M, Mann KG, Bovill EG. The prothrombotic phenotypes in familial protein C deficiency are differentiated by computational modeling of thrombin generation. PLoS One 2012;7:e44378.
Matsunaga Y, Ohga S, Kinjo T, et al. Neonatal asphyxia and renal failure as the presentation of non-inherited protein C deficiency. J Perinatol 2013;33:239–41.
Ishii H, Salem HH, Bell CE, Laposata EA, Majerus PW. Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain. Blood 1986;67:362–5.
Wang Y, Zhao Z, Chow N, Ali T, Griffin JH, Zlokovic BV. Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1. Brain Res 2013;1507:97–104.
Tsuda H, Hattori S, Tanabe S, et al. Screening for aetiology of thrombophilia: a high prevalence of protein S abnormality. Ann Clin Biochem 1999;36 (Pt 4):423–32.
Acknowledgements
We thank Michiyo Urata, Takeshi Uchiumi (Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan), and Naotaka Hamasaki (Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki, Japan) for the establishment of system, and all the staffs of the Department of Pediatrics, Kyushu University Hospital, Fukuoka, Japan for the clinical managements.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Figure S1
(TIFF 312 kb)
Supplementary Table S1
(DOC 26 kb)
Rights and permissions
About this article
Cite this article
Ichiyama, M., Ohga, S., Ochiai, M. et al. Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism. Pediatr Res 79, 81–86 (2016). https://doi.org/10.1038/pr.2015.180
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2015.180
This article is cited by
-
Diagnostic challenge of the newborn patients with heritable protein C deficiency
Journal of Perinatology (2019)
-
Streptococcus pyogenes-purpura fulminans as an invasive form of group A streptococcal infection
Annals of Clinical Microbiology and Antimicrobials (2018)
