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Venous thrombosis and thromboembolism in children: Treatment, prevention, and outcome

Authors
Manuela Albisetti, MD
Anthony KC Chan, MBBS, FRCPC, FRCPath
Section Editor
Donald H Mahoney, Jr, MD
Deputy Editor
Carrie Armsby, MD, MPH

INTRODUCTION

Venous thromboembolism (VTE) is increasingly recognized in the pediatric population as a complication of contemporary health care. Timely diagnosis, treatment, and optimal prophylactic strategies for VTE in children are extremely important to avoid long-term complications.

The treatment, prevention, and outcome of noncerebral VTE in infants and children will be discussed here. Other aspects of VTE are discussed in separate topic reviews:

Risk factors, clinical manifestations, and diagnosis of VTE in infants and children (see "Venous thrombosis and thromboembolism in children: Risk factors, clinical manifestations, and diagnosis")

VTE in the newborn (see "Pathogenesis, clinical features, and diagnosis of thrombosis in the newborn" and "Management of thrombosis in the newborn")

VTE in children with cancer (see "Thromboembolism in children with cancer")

                            

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Literature review current through: Aug 2017. | This topic last updated: Sep 01, 2017.
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References
Top
  1. Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e737S.
  2. Tuckuviene R, Christensen AL, Helgestad J, et al. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr 2011; 159:663.
  3. Chalmers E, Ganesen V, Liesner R, et al. Guideline on the investigation, management and prevention of venous thrombosis in children. Br J Haematol 2011; 154:196.
  4. Andrew M, Monagle P, Brooker LA. Thromboembolic complications during infancy and childhood, B C Dekker Inc, Hamilton, Ontario 2000.
  5. Choi M, Massicotte MP, Marzinotto V, et al. The use of alteplase to restore patency of central venous lines in pediatric patients: a cohort study. J Pediatr 2001; 139:152.
  6. Blaney M, Shen V, Kerner JA, et al. Alteplase for the treatment of central venous catheter occlusion in children: results of a prospective, open-label, single-arm study (The Cathflo Activase Pediatric Study). J Vasc Interv Radiol 2006; 17:1745.
  7. Shen V, Li X, Murdock M, et al. Recombinant tissue plasminogen activator (alteplase) for restoration of function to occluded central venous catheters in pediatric patients. J Pediatr Hematol Oncol 2003; 25:38.
  8. Chesler L, Feusner JH. Use of tissue plasminogen activator (rt-PA) in young children with cancer and dysfunctional central venous catheters. J Pediatr Hematol Oncol 2002; 24:653.
  9. Terrill KR, Lemons RS, Goldsby RE. Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer. J Pediatr Hematol Oncol 2003; 25:864.
  10. Biss TT, Brandão LR, Kahr WH, et al. Clinical features and outcome of pulmonary embolism in children. Br J Haematol 2008; 142:808.
  11. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S.
  12. Albisetti M. Thrombolytic therapy in children. Thromb Res 2006; 118:95.
  13. Manco-Johnson MJ, Grabowski EF, Hellgreen M, et al. Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis. Thromb Haemost 2002; 88:157.
  14. Wang M, Hays T, Balasa V, et al. Low-dose tissue plasminogen activator thrombolysis in children. J Pediatr Hematol Oncol 2003; 25:379.
  15. Gupta AA, Leaker M, Andrew M, et al. Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children. J Pediatr 2001; 139:682.
  16. Goldenberg NA, Durham JD, Knapp-Clevenger R, Manco-Johnson MJ. A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children. Blood 2007; 110:45.
  17. Cavo M, Wang W, O'Brien SH. Use of low molecular weight heparin for thromboprophylaxis in a pediatric inpatient population: reasons for use and incidence of bleeding complications. Thromb Res 2010; 125:370.
  18. Branchford BR, Mourani P, Bajaj L, et al. Risk factors for in-hospital venous thromboembolism in children: a case-control study employing diagnostic validation. Haematologica 2012; 97:509.
  19. Sharathkumar AA, Mahajerin A, Heidt L, et al. Risk-prediction tool for identifying hospitalized children with a predisposition for development of venous thromboembolism: Peds-Clot clinical Decision Rule. J Thromb Haemost 2012; 10:1326.
  20. Meier KA, Clark E, Tarango C, et al. Venous thromboembolism in hospitalized adolescents: an approach to risk assessment and prophylaxis. Hosp Pediatr 2015; 5:44.
  21. Jackson PC, Morgan JM. Perioperative thromboprophylaxis in children: development of a guideline for management. Paediatr Anaesth 2008; 18:478.
  22. Multidisciplinary VTE Prophylaxis BESt Team, Cincinnati Children's Hospital Medical Center: Best Evidence Statement Venous Thromboembolism (VTE) Prophylaxis in Children and Adolescents, BESt 181, pages 1-14, Date 2/18/14. Available at: https://www.cincinnatichildrens.org/-/media/cincinnati%20childrens/home/service/j/anderson-center/evidence-based-care/recommendations/type/venous%20thromboembolism%20best%20181.
  23. Mahajerin A, Petty JK, Hanson SJ, et al. Prophylaxis against venous thromboembolism in pediatric trauma: A practice management guideline from the Eastern Association for the Surgery of Trauma and the Pediatric Trauma Society. J Trauma Acute Care Surg 2017; 82:627.
  24. Newall F, Barnes C, Savoia H, et al. Warfarin therapy in children who require long-term total parenteral nutrition. Pediatrics 2003; 112:e386.
  25. Vegting IL, Tabbers MM, Benninga MA, et al. Prophylactic anticoagulation decreases catheter-related thrombosis and occlusion in children with home parenteral nutrition. JPEN J Parenter Enteral Nutr 2012; 36:456.
  26. Paglialonga F, Artoni A, Braham S, et al. Vitamin K antagonists in children with central venous catheter on chronic haemodialysis: a pilot study. Pediatr Nephrol 2016; 31:827.
  27. Albisetti M, Andrew M. Low molecular weight heparin in children. Eur J Pediatr 2002; 161:71.
  28. Young E, Wells P, Holloway S, et al. Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 1994; 71:300.
  29. Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109:85.
  30. Massicotte P, Adams M, Marzinotto V, et al. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr 1996; 128:313.
  31. Massicotte P, Julian JA, Marzinotto V, et al. Dose-finding and pharmacokinetic profiles of prophylactic doses of a low molecular weight heparin (reviparin-sodium) in pediatric patients. Thromb Res 2003; 109:93.
  32. Nohe N, Flemmer A, Rümler R, et al. The low molecular weight heparin dalteparin for prophylaxis and therapy of thrombosis in childhood: a report on 48 cases. Eur J Pediatr 1999; 158 Suppl 3:S134.
  33. Revel-Vilk S, Chan AK. Anticoagulation therapy in children. Semin Thromb Hemost 2003; 29:425.
  34. Kuhle S, Massicotte P, Dinyari M, et al. Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events. Thromb Haemost 2005; 94:1164.
  35. Schloemer NJ, Abu-Sultaneh S, Hanson SJ, et al. Higher doses of low-molecular-weight heparin (enoxaparin) are needed to achieve target anti-Xa concentrations in critically ill children*. Pediatr Crit Care Med 2014; 15:e294.
  36. Bidlingmaier C, Kenet G, Kurnik K, et al. Safety and efficacy of low molecular weight heparins in children: a systematic review of the literature and meta-analysis of single-arm studies. Semin Thromb Hemost 2011; 37:814.
  37. Melissari E, Parker CJ, Wilson NV, et al. Use of low molecular weight heparin in pregnancy. Thromb Haemost 1992; 68:652.
  38. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330.
  39. Van Ryn-McKenna J, Cai L, Ofosu FA, et al. Neutralization of enoxaparine-induced bleeding by protamine sulfate. Thromb Haemost 1990; 63:271.
  40. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:141S.
  41. Ignjatovic V, Summerhayes R, Than J, et al. Therapeutic range for unfractionated heparin therapy: age-related differences in response in children. J Thromb Haemost 2006; 4:2280.
  42. Andrew M, Ofosu F, Schmidt B, et al. Heparin clearance and ex vivo recovery in newborn piglets and adult pigs. Thromb Res 1988; 52:517.
  43. McDonald MM, Jacobson LJ, Hay WW Jr, Hathaway WE. Heparin clearance in the newborn. Pediatr Res 1981; 15:1015.
  44. Taylor BN, Bork SJ, Kim S, et al. Evaluation of weight-based dosing of unfractionated heparin in obese children. J Pediatr 2013; 163:150.
  45. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:7S.
  46. Schechter T, Finkelstein Y, Ali M, et al. Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti-factor Xa levels. J Thromb Haemost 2012; 10:368.
  47. Hanslik A, Kitzmüller E, Tran US, et al. Monitoring unfractionated heparin in children: a parallel-cohort randomized controlled trial comparing 2 dose protocols. Blood 2015; 126:2091.
  48. Andrew M, Marzinotto V, Massicotte P, et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994; 35:78.
  49. Newall F, Johnston L, Ignjatovic V, Monagle P. Unfractionated heparin therapy in infants and children. Pediatrics 2009; 123:e510.
  50. Trucco M, Lehmann CU, Mollenkopf N, et al. Retrospective cohort study comparing activated partial thromboplastin time versus anti-factor Xa activity nomograms for therapeutic unfractionated heparin monitoring in pediatrics. J Thromb Haemost 2015; 13:788.
  51. Diaz R, Moffett BS, Karabinas S, et al. Antithrombin Concentrate Use in Children Receiving Unfractionated Heparin for Acute Thrombosis. J Pediatr 2015; 167:645.
  52. O'Reilly MS. Antiangiogenic antithrombin. Semin Thromb Hemost 2007; 33:660.
  53. Schmidt B, Gillie P, Mitchell L, et al. A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158:470.
  54. Kuhle S, Eulmesekian P, Kavanagh B, et al. A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study. Haematologica 2007; 92:244.
  55. Newall F, Barnes C, Ignjatovic V, Monagle P. Heparin-induced thrombocytopenia in children. J Paediatr Child Health 2003; 39:289.
  56. Schmugge M, Risch L, Huber AR, et al. Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics 2002; 109:E10.
  57. Severin T, Sutor AH. Heparin-induced thrombocytopenia in pediatrics. Semin Thromb Hemost 2001; 27:293.
  58. Klenner AF, Lubenow N, Raschke R, Greinacher A. Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thromb Haemost 2004; 91:719.
  59. Warkentin TE. Heparin-induced thrombocytopenia. Pathogenesis, frequency, avoidance and management. Drug Saf 1997; 17:325.
  60. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79:1.
  61. Kuter DJ, Konkle BA, Hamza TH, et al. Clinical outcomes in a cohort of patients with heparin-induced thrombocytopenia. Am J Hematol 2017; 92:730.
  62. Obeng EA, Harney KM, Moniz T, et al. Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system. J Pediatr 2015; 166:144.
  63. Wilhelm MJ, Schmid C, Kececioglu D, et al. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996; 61:920.
  64. Streif W, Andrew M, Marzinotto V, et al. Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients. Blood 1999; 94:3007.
  65. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S.
  66. Moffett BS, Kim S, Bomgaars LR. Readmissions for warfarin-related bleeding in pediatric patients after hospital discharge. Pediatr Blood Cancer 2013; 60:1503.
  67. Taybi H, Capitanio MA. Tracheobronchial calcification: an observation in three children after mitral valve replacement and warfarin sodium therapy. Radiology 1990; 176:728.
  68. Bolton-Maggs P, Brook L. The use of vitamin K for reversal of over-warfarinization in children. Br J Haematol 2002; 118:924.
  69. Young G, Tarantino MD, Wohrley J, et al. Pilot dose-finding and safety study of bivalirudin in infants <6 months of age with thrombosis. J Thromb Haemost 2007; 5:1654.
  70. Chan VH, Monagle P, Massicotte P, Chan AK. Novel paediatric anticoagulants: a review of the current literature. Blood Coagul Fibrinolysis 2010; 21:144.
  71. Young G, Boshkov LK, Sullivan JE, et al. Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study. Pediatr Blood Cancer 2011; 56:1103.
  72. Risch L, Huber AR, Schmugge M. Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children. Thromb Res 2006; 118:123.
  73. Forbes TJ, Hijazi ZM, Young G, et al. Pediatric catheterization laboratory anticoagulation with bivalirudin. Catheter Cardiovasc Interv 2011; 77:671.
  74. Young G, Yee DL, O'Brien SH, et al. FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer 2011; 57:1049.
  75. von Vajna E, Alam R, So TY. Current Clinical Trials on the Use of Direct Oral Anticoagulants in the Pediatric Population. Cardiol Ther 2016; 5:19.
  76. Hursting MJ, Dubb J, Verme-Gibboney CN. Argatroban anticoagulation in pediatric patients: a literature analysis. J Pediatr Hematol Oncol 2006; 28:4.
  77. O'Brien SH, Yee DL, Lira J, et al. UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis. J Thromb Haemost 2015; 13:1615.
  78. Ko RH, Michieli C, Lira JL, Young G. FondaKIDS II: long-term follow-up data of children receiving fondaparinux for treatment of venous thromboembolic events. Thromb Res 2014; 134:643.
  79. EINSTEIN Junior Phase III: Oral Rivaroxaban in Children With Venous Thrombosis (EINSTEIN Jr), Study Record Detail. Available at: https://clinicaltrials.gov/ct2/show/NCT02234843 (Accessed on March 07, 2017).
  80. Apixaban for the Acute Treatment of Venous Thromboembolism in Children, Study Record Detail. Available at: https://clinicaltrials.gov/ct2/show/NCT02464969 (Accessed on March 07, 2017).
  81. Open Label Study Comparing Efficacy and Safety of Dabigatran Etexilate to Standard of Care in Paediatric Patients With Venous Thromboembolism (VTE), Study Record Detail. Available at: https://clinicaltrials.gov/ct2/show/NCT01895777 (Accessed on March 07, 2017).
  82. 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.
  83. Nowak-Göttl U, Junker R, Kreuz W, et al. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97:858.
  84. Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83:1251.
  85. van Ommen CH, Heijboer H, Büller HR, et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001; 139:676.
  86. Goldenberg NA, Knapp-Clevenger R, Manco-Johnson MJ, Mountain States Regional Thrombophilia Group. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. N Engl J Med 2004; 351:1081.
  87. Prandoni P, Lensing AW, Prins MR. The natural history of deep-vein thrombosis. Semin Thromb Hemost 1997; 23:185.
  88. Thulesius O. [The pathophysiology of post-thrombotic syndrome]. Wien Med Wochenschr 1994; 144:196.
  89. Immelman EJ, Jeffery PC. The postphlebitic syndrome. Pathophysiology, prevention and management. Clin Chest Med 1984; 5:537.
  90. Goldenberg NA, Brandão L, Journeycake J, et al. Definition of post-thrombotic syndrome following lower extremity deep venous thrombosis and standardization of outcome measurement in pediatric clinical investigations. J Thromb Haemost 2012; 10:477.
  91. Revel-Vilk S, Brandão LR, Journeycake J, et al. Standardization of post-thrombotic syndrome definition and outcome assessment following upper venous system thrombosis in pediatric practice. J Thromb Haemost 2012; 10:2182.
  92. van Ommen CH, Heijboer H, van den Dool EJ, et al. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost 2003; 1:2516.
  93. Monagle P, Adams M, Mahoney M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000; 47:763.
  94. Kuhle S, Koloshuk B, Marzinotto V, et al. A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res 2003; 111:227.
  95. van Ommen CH, Ottenkamp J, Lam J, et al. The risk of postthrombotic syndrome in children with congenital heart disease. J Pediatr 2002; 141:582.
  96. Spentzouris G, Gasparis A, Scriven RJ, et al. Natural history of deep vein thrombosis in children. Phlebology 2015; 30:412.
  97. Avila ML, Pullenayegum E, Williams S, et al. Post-thrombotic syndrome and other outcomes of lower extremity deep vein thrombosis in children. Blood 2016.
  98. Goldenberg NA, Donadini MP, Kahn SR, et al. Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica 2010; 95:1952.
  99. Rajpurkar M, Sharathkumar A, Williams S, et al. Recommendations for the assessment of non-extremity venous thromboembolism outcomes: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13:477.
  100. Manco-Johnson M, Knapp-Clevenger R, Miller B, et al. Post-thrombotic syndrome (PTS) in children: Validation of a new pediatric outcome instrument and results in a comprehensive cohort of children with extremity deep vein thrombosis (DVT). Blood 2003; 102:553a.
  101. Goldenberg NA, Pounder E, Knapp-Clevenger R, Manco-Johnson MJ. Validation of upper extremity post-thrombotic syndrome outcome measurement in children. J Pediatr 2010; 157:852.
  102. Raffini L, Huang YS, 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.
  103. Setty BA, O'Brien SH, Kerlin BA. Pediatric venous thromboembolism in the United States: a tertiary care complication of chronic diseases. Pediatr Blood Cancer 2012; 59:258.
  104. Biss TT, Brandão LR, Kahr WH, et al. Clinical probability score and D-dimer estimation lack utility in the diagnosis of childhood pulmonary embolism. J Thromb Haemost 2009; 7:1633.
  105. Dijk FN, Curtin J, Lord D, Fitzgerald DA. Pulmonary embolism in children. Paediatr Respir Rev 2012; 13:112.