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Diagnosis and treatment of venous thrombosis and thromboembolism in infants and children

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


Venous thromboembolism (VTE) is increasingly recognized as a major secondary complication of advanced tertiary care in infants and children. Similar to the situation in adults, episodes of VTE may end fatally or cause serious long-term morbidity, including the post-thrombotic syndrome. The long-term morbidities are particularly important for young patients. Some morbidities, such as leg size differences, can have a negative impact on the child's development into a normal healthy adult. Thus, early and proper diagnosis, as well as optimal prophylactic and treatment strategies for VTE in children, are extremely important to avoid such complications.

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

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

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: Sep 2016. | This topic last updated: May 11, 2016.
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  1. David M, Manco-Johnson M, Andrew M. Diagnosis and treatment of venous thromboembolism in children and adolescents. On behalf of the Subcommittee on Perinatal Haemostasis of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 74:791.
  2. Male C, Chait P, Ginsberg JS, et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase. Thromb Haemost 2002; 87:593.
  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. Kroencke TJ, Taupitz M, Arnold R, et al. Three-dimensional gadolinium-enhanced magnetic resonance venography in suspected thrombo-occlusive disease of the central chest veins. Chest 2001; 120:1570.
  5. Thornton MJ, Ryan R, Varghese JC, et al. A three-dimensional gadolinium-enhanced MR venography technique for imaging central veins. AJR Am J Roentgenol 1999; 173:999.
  6. Shinde TS, Lee VS, Rofsky NM, et al. Three-dimensional gadolinium-enhanced MR venographic evaluation of patency of central veins in the thorax: initial experience. Radiology 1999; 213:555.
  7. Laor T, Burrows PE, Hoffer FA. Magnetic resonance venography of congenital vascular malformations of the extremities. Pediatr Radiol 1996; 26:371.
  8. Revel-Vilk S, Sharathkumar A, Massicotte P, et al. Natural history of arterial and venous thrombosis in children treated with low molecular weight heparin: a longitudinal study by ultrasound. J Thromb Haemost 2004; 2:42.
  9. 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.
  10. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688.
  11. Albisetti M, Andrew M. Low molecular weight heparin in children. Eur J Pediatr 2002; 161:71.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Revel-Vilk S, Chan AK. Anticoagulation therapy in children. Semin Thromb Hemost 2003; 29:425.
  17. 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.
  18. Dix D, Andrew M, Marzinotto V, et al. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136:439.
  19. Punzalan RC, Hillery CA, Montgomery RR, et al. Low-molecular-weight heparin in thrombotic disease in children and adolescents. J Pediatr Hematol Oncol 2000; 22:137.
  20. Van Ryn-McKenna J, Cai L, Ofosu FA, et al. Neutralization of enoxaparine-induced bleeding by protamine sulfate. Thromb Haemost 1990; 63:271.
  21. 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.
  22. Melissari E, Parker CJ, Wilson NV, et al. Use of low molecular weight heparin in pregnancy. Thromb Haemost 1992; 68:652.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. McDonald MM, Jacobson LJ, Hay WW Jr, Hathaway WE. Heparin clearance in the newborn. Pediatr Res 1981; 15:1015.
  28. Taylor BN, Bork SJ, Kim S, et al. Evaluation of weight-based dosing of unfractionated heparin in obese children. J Pediatr 2013; 163:150.
  29. 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.
  30. 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.
  31. 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.
  32. Diaz R, Moffett BS, Karabinas S, et al. Antithrombin Concentrate Use in Children Receiving Unfractionated Heparin for Acute Thrombosis. J Pediatr 2015; 167:645.
  33. O'Reilly MS. Antiangiogenic antithrombin. Semin Thromb Hemost 2007; 33:660.
  34. 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.
  35. Andrew M, Marzinotto V, Massicotte P, et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994; 35:78.
  36. Newall F, Johnston L, Ignjatovic V, Monagle P. Unfractionated heparin therapy in infants and children. Pediatrics 2009; 123:e510.
  37. Newall F, Barnes C, Ignjatovic V, Monagle P. Heparin-induced thrombocytopenia in children. J Paediatr Child Health 2003; 39:289.
  38. Schmugge M, Risch L, Huber AR, et al. Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics 2002; 109:E10.
  39. Severin T, Sutor AH. Heparin-induced thrombocytopenia in pediatrics. Semin Thromb Hemost 2001; 27:293.
  40. 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.
  41. Warkentin TE. Heparin-induced thrombocytopenia. Pathogenesis, frequency, avoidance and management. Drug Saf 1997; 17:325.
  42. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79:1.
  43. 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.
  44. 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.
  45. 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.
  46. Newall F, Barnes C, Savoia H, et al. Warfarin therapy in children who require long-term total parenteral nutrition. Pediatrics 2003; 112:e386.
  47. Bolton-Maggs P, Brook L. The use of vitamin K for reversal of over-warfarinization in children. Br J Haematol 2002; 118:924.
  48. Erhardtsen E, Nony P, Dechavanne M, et al. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 1998; 9:741.
  49. Muleo G, Santoro R, Iannaccaro PG, et al. Small doses of recombinant factor VIIa in acquired deficiencies of vitamin K dependent factors. Blood Coagul Fibrinolysis 1999; 10:521.
  50. Taybi H, Capitanio MA. Tracheobronchial calcification: an observation in three children after mitral valve replacement and warfarin sodium therapy. Radiology 1990; 176:728.
  51. Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991; 78:3114.
  52. Albisetti M. Thrombolytic therapy in children. Thromb Res 2006; 118:95.
  53. 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.
  54. Wang M, Hays T, Balasa V, et al. Low-dose tissue plasminogen activator thrombolysis in children. J Pediatr Hematol Oncol 2003; 25:379.
  55. 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.
  56. 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.
  57. 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.
  58. 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.
  59. 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.
  60. 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.
  61. 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.
  62. Stump DC, Thienpont M, Collen D. Urokinase-related proteins in human urine. Isolation and characterization of single-chain urokinase (pro-urokinase) and urokinase-inhibitor complex. J Biol Chem 1986; 261:1267.
  63. Ichinose A, Fujikawa K, Suyama T. The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986; 261:3486.
  64. 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.
  65. Andrew M, Monagle P, Brooker LA. Thromboembolic complications during infancy and childhood, B C Dekker Inc, Hamilton, Ontario 2000.
  66. Biss TT, Brandão LR, Kahr WH, et al. Clinical features and outcome of pulmonary embolism in children. Br J Haematol 2008; 142:808.
  67. 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.
  68. Kroiss S, Albisetti M. Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency. Biologics 2010; 4:51.
  69. Kumar R, Chan AK, Dawson JE, et al. Clinical presentation and molecular basis of congenital antithrombin deficiency in children: a cohort study. Br J Haematol 2014; 166:130.
  70. 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.
  71. 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.
  72. 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.
  73. 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.