Antithrombotic therapy in children with venous thromboembolism

Summary

Antithrombotic therapy has recently become more frequent for the treatment of venous thromboembolism (VTE) in the paediatric population. This can be explained by the increased awareness of morbidities and mortalities of VTE in children, as well as the improved survival rate of children with various kinds of serious illnesses. Considering the large number of years a child is expected to survive, associated morbidities such as postthrombotic syndrome and risk of recurrence can significantly impact on the quality of life in children. Therefore, timely diagnosis, evidence-based treatment and prophylaxis strategies are critical to avoid such complications.

This review summarizes the current literature about the antithrombotic treatment for VTE in infants and children. It guides the paediatric medical care provider for making a logical and justifiable decision.

Keywords

Anticoagulation - venous thromboembolism - paediatrics - neonates

• References

• 1 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: 1251-1257.
• 2 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96: 939-943.
• 3 Nowak-Göttl U, von Kries R, Göbel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed 1997; 73: F163-F167.
• 4 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: 676-681.
• 5 Massicotte MP, Dix D, Monagle P. et al. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133: 770-776.
• 6 Kuhle S, Massicotte P, Chan A, Mitchell L. A case series of 72 neonates with renal vein thrombosis. Data from the 1–800-NO-CLOTS Registry. Thromb Haemost 2004; 92: 729-733.
• 7 Monagle P, Chalmers E, Chan A. et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8^th ed). Chest 2008; 133: 887S-968S.
• 8 Paediatric Stroke Working Group, Royal College of Physicians.. Stroke in childhood. Clinical guidelines for diagnosis, management and rehabilitation. http://www.rcplondon.ac.uk/pubs/books/childstroke/childstroke_guidelines.pdf (Accessed Aug. 2008); 2004
• 9 Roach ES, Golomb MR, Adams R. et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 2008; 39: 2644-2691.
• 10 Gatt ME, Paltiel O, Bursztyn M. Is prolonged immobilization a risk factor for symptomatic venous thromboembolism in elderly bedridden patients? Results of a historical-cohort study. Thromb Haemost 2004; 91: 538-543.
• 11 Osborne NH, Wakefield TW, Henke PK. Venous thromboembolism in cancer patients undergoing major surgery. Ann Surg Oncol. 2008 [Epub ahead of print].
• 12 Lee AY. Cancer and venous thromboembolism: prevention, treatment and survival. J Thromb Thrombolysis 2008; 25: 33-36.
• 13 Nelson SM, Greer IA. Thrombophilia and the risk for venous thromboembolism during pregnancy, delivery, and puerperium. Obstet Gynecol Clin North Am 2006; 33: 413-427.
• 14 De Stefano V, Rossi E, Leone G. Inherited thrombo philia, pregnancy, and oral contraceptive use: clinical implications. Semin Vasc Med 2003; 3: 47-60.
• 15 Battaglioli T, Martinelli I. Hormone therapy and thromboembolic disease. Curr Opin Hematol 2007; 14: 488-493.
• 16 Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92: 1107-1114.
• 17 De Stefano V, Simioni P, Rossi E. et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica 2006; 91: 695-698.
• 18 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-172.
• 19 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72: 1651-1657.
• 20 Andrew M, Vegh P, Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
• 21 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12: 95-104.
• 22 Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr 2004; 145: 563-565.
• 23 Monagle P, Ignjatovic V, Furmedge J. et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362-372.
• 24 Chan AKC, Black L, Ing C. et al. Utility of aPTT in monitoring unfractionated heparin in children. Thromb Res 2008; 122: 135-136.
• 25 Ginsberg JS, Kowalchuk G, Hirsh J. et al. Heparin effect on bone density. Thromb Haemost 1990; 64: 286-289.
• 26 Newall F, Barnes C, Ignjatovic V, Monagle P. Heparin-induced thrombocytopenia in children. J Paediatr Child Health 2003; 39: 289-292.
• 27 Schmugge M, Risch L, Huber AR. et al. Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics 2002; 109: E10.
• 28 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: 719-724.
• 29 Risch L, Huber AR, Schmugge M. Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children. Thromb Res 2006; 118: 123-135.
• 30 Hassell K. The management of patients with heparin-induced thrombocytopenia who require anticoagulant therapy. Chest 2005; 127: 1S-8S.
• 31 Andrew M, Ofosu F, Schmidt B. et al. Heparin clearance and ex vivo recovery in newborn piglets and adult pigs. Thromb Res 1988; 52: 517-527.
• 32 McDonald MM, Jacobson LJ, Hay Jr WW, Hathaway WE. Heparin clearance in the newborn. Pediatr Res 1981; 15: 1015-1018.
• 33 Andrew M, deVeber G. Pediatric thromboembolism and stroke protocols. 1^st ed. Hamilton: B.C. Decker Inc.; 1997
• 34 Raschke RA, Reilly BM, Guidry JR. et al. The weight-based heparin dosing nomogram compared with a „standard care“ nomogram. A randomized controlled trial. Ann Intern Med 1993; 119: 874-881.
• 35 Weitz JI. Low-molecular-weight heparins. N Eng J Med 1997; 337: 688-698.
• 36 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: 300-304.
• 37 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: 313-318.
• 38 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: 93-99.
• 39 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: S134-S139.
• 40 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: 1164-1171.
• 41 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: 439-445.
• 42 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: 85-92.
• 43 Van Ryn-McKenna J, Cai L, Ofosu FA. et al. Neutralization of enoxaparine-induced bleeding by protamine sulfate. Thromb Res 1990; 63: 271-274.
• 44 Massonnet-Castel S, Pelissier E, Bara L. et al. Partial reversal of low molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis 1986; 16: 139-146.
• 45 Malowany JI, Monagle P, Knoppert DC. et al. Enoxaparin for neonatal thrombosis: A call for a higher dose for neonates. Thromb Res 2008; 122: 826-830.
• 46 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: 3007-3014.
• 47 Newall F, Barnes C, Savoia H. et al. Warfarin therapy in children who require long-term total parenteral nutrition. Pediatrics 2003; 112: e386.
• 48 Andrew M, Marzinotto V, Brooker LA. et al. Oral anticoagulation therapy in pediatric patients: a prospective study. Thromb Haemost 1994; 71: 265-269.
• 49 Taybi H, Capitanio MA. Tracheobronchial calcification: an observation in three children after mitral valve replacement and warfarin sodium therapy. Radiology 1990; 176: 728-730.
• 50 Barnes C, Newall F, Ignjatovic V. et al. Reduced bone density in children on long-term warfarin. Pediatr Res 2005; 57: 578-581.
• 51 Massicotte P, Julian J, Webber C, Charpentier K. Osteoporosis: A potential complication of long term warfarin therapy. Thromb Haemost 1999; 80: 1333a.
• 52 Zigman A, Yazbeck S, Emil S, Nguyen L. Renal vein thrombosis: a 10-year review. J Pediatr Surg 2000; 35: 1540-1542.
• 53 Duncan BW, Adzick NS, Longaker MT. et al. In utero arterial embolism from renal vein thrombosis with successful postnatal thrombolytic therapy. J Pediatr Surg 1991; 26: 741-743.
• 54 Andrew M, Brooker LA. Hemostatic complications in renal disorders of the young. Pediatr Nephrol 1996; 10: 88-99.
• 55 Bökenkamp A, von Kries R, Nowak-Göttl U. et al. Neonatal renal venous thrombosis in Germany between 1992 and 1994: epidemiology, treatment and outcome. Eur J Pediatr 2000; 159: 44-48.
• 56 Lau KK, Stoffman JM, Williams S. et al. Neonatal renal vein thrombosis: review of the English-language literature between 1992 and 2006. Pediatrics 2007; 120: e1278-e1284.
• 57 Schwartz DS, Gettner PA, Konstantino MM. et al. Umbilical venous catheterization and the risk of portal vein thrombosis. J Pediatr 1997; 131: 760-762.
• 58 Morag I, Epelman M, Daneman A. et al. Portal vein thrombosis in the neonate: risk factors, course, and outcome. J Pediatr 2006; 148: 735-739.
• 59 Kim JH, Lee YS, Kim SH. et al. Does umbilical vein catheterization lead to portal venous thrombosis? Prospective US evaluation in 100 neonates. Radiology 2001; 219: 645-650.
• 60 Heller C, Heinecke A, Junker R. et al. Cerebral venous thrombosis in children: a multifactorial origin. Circulation 2003; 108: 1362-1367.
• 61 Wu YW, Miller SP, Chin K. et al. Multiple risk factors in neonatal sinovenous thrombosis. Neurology 2002; 59: 438-440.
• 62 DeVeber G, Andrew M, Adams C. et al. Cerebral sinovenous thrombosis in children. N Engl J Med 2001; 345: 417-423.
• 63 DeVeber G. Arterial ischemic strokes in infants and children: an overview of current approaches. Semin Thromb Hemost 2003; 29: 567-573.
• 64 Fitzgerald KC, Williams LS, Garg BP. et al. Cerebral sinovenous thrombosis in the neonate. Arch Dis Child 2006; 63: 405-409.
• 65 Wu YW, Hamrick SE, Miller SP. et al. Intraventricular hemorrhage in term neonates caused by sinovenous thrombosis. Ann Neurol 2003; 54: 123-126.
• 66 Moharir M, Shroff M, MacGregor D. et al. Clinical and radiographic features of thrombosis propagation in neonatal and childhood cerebral sinovenous thrombosis. Ann Neurol 2006; 60: S141.
• 67 Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics 1995; 96: 291-294.
• 68 Nowak-Göttl U, Junker R, Kreuz W. et al. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97: 858-862.
• 69 Kearon C, Gent M, Hirsh J. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Eng J Med 1999; 340: 901-907.
• 70 Athale UH, Chan AK. Thrombosis in children with acute lymphoblastic leukemia. Part II, Pathogenesis of thrombosis in children with acute lympho blastic leukemia: effects of the disease and therapy. Thromb Res 2003; 111: 199-212.
• 71 Nowak-Göttl U, Heinecke A, von Kries R. et al. Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res 2001; 103: 165-172.
• 72 Einhäupl KM, Villringer A, Meister W. et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338: 597-600.
• 73 De Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30: 484-488.
• 74 DeVeber G, Chan A, Monagle P. et al. Anticoagulation therapy in pediatric patients with sinovenous thrombosis: a cohort study. Arch Neurol 1998; 55: 1533-1537.
• 75 Sébire G, Tabarki B, Saunders DE. et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain 2005; 128: 477-489.
• 76 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: 763-766.
• 77 Mitchell L, Andrew M, Hanna K. et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost 2003; 90: 235-244.
• 78 Elhasid R, Lanir N, Sharon R. et al. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis 2001; 12: 367-370.
• 79 Nowak-Göttl U, Münchow N, Klippel U. et al. The course of fibrinolytic proteins in children with malignant bone tumours. Eur J Pediatr 1999; 158: S151-S153.
• 80 Monagle P, Karl TR. Thromboembolic problems after the Fontan operation. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002; 5: 36-47.
• 81 Monagle P, Cochrane A, McCrindle B. et al. Thromboembolic complications after fontan procedures--the role of prophylactic anticoagulation. J Thorac Cardiovasc Surg 1998; 115: 493-498.
• 82 Kaulitz R, Ziemer G, Rauch R. et al. Prophylaxis of thromboembolic complications after the Fontan operation (total cavopulmonary anastomosis). J Thorac Cardiovasc Surg 2005; 129: 569-575.
• 83 Seipelt RG, Franke A, Vazquez-Jimenez JF. et al. Thromboembolic complications after Fontan procedures: comparison of different therapeutic approaches. Ann Thorac Surg 2002; 74: 556-562.