Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76fb5796d-9pm4c Total loading time: 0 Render date: 2024-04-27T08:51:51.064Z Has data issue: false hasContentIssue false

Chapter 15 - New anticoagulants in children: A review of recent studies and a look to the future

from Section 2 - Special considerations in pediatric patients

Published online by Cambridge University Press:  18 December 2014

By
G. Young  and
Neil A. Goldenberg
Edited by
Neil A. Goldenberg  and
Marilyn J. Manco-Johnson
G. Young
Affiliation:
University of Southern California
Neil A. Goldenberg
Affiliation:
Johns Hopkins University School of Medicine
Neil A. Goldenberg
Affiliation:
The Johns Hopkins University School of Medicine
Marilyn J. Manco-Johnson
Affiliation:
Hemophilia and Thrombosis Center, University of Colorado, Denver
Get access

Summary

Introduction

The incidence of venous thromboembolism (VTE) in children is steadily rising [1,2]. While some of this increase may be due to increased recognition, it is likely that this represents a true increase in incidence. Much of the increase is due to the advancements in the management of critically ill children and particularly the widespread use of central venous catheters, which are the leading cause for the development of VTE. Treatment of VTE in children involves the use of anticoagulation and occasionally, thrombolytic agents. Treatment guidelines for the management of VTE in children have been published; however, these are largely based on low levels of evidence in the published literature, and relevant to this chapter, do not discuss the use of newer anticoagulants [3]. This chapter will provide a brief overview of the current (standard) anticoagulants in use in children (details can be found in other chapters), in particular discussing their limitations as they relate to the properties of the newer agents. This will be followed by a discussion of the data available regarding the use of new anticoagulants. Table 15.1 provides a historical context of anticoagulant clinical use and studies in children.

Standard anticoagulants

The so-called standard or conventional anticoagulants currently in widespread use in children include unfractionated heparin, low molecular weight heparins (LMWH), of which there are several available around the world, and vitamin K antagonists (VKA), of which warfarin is the most commonly available. Despite a long history of use in pediatrics (Table 15.1) and an accumulated clinical experience among practitioners, very few large (e.g., multicenter) prospective studies have been performed and none are sufficiently powered randomized studies to definitively compare safety and efficacy between/among agents. Nevertheless, it is recognized that treatment of such patients is required to help resolve the VTE as well as to prevent complications such as pulmonary embolism and post-thrombotic syndrome. A brief discussion of the properties of these agents is described below.

Type
Chapter
Information
Pediatric Thrombotic Disorders , pp. 200 - 206
Publisher: Cambridge University Press
Print publication year: 2015

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Raffini, L, Huang, Y, Witmer, C, Feudtner, C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001–2007. Pediatrics 2009;124:1001–8.CrossRefGoogle Scholar
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;59:258–64.CrossRefGoogle ScholarPubMed
Monagle, P, Chan, AK, Goldenberg, NA, Ichord, RN, Journeycake, JM, Nowak-Gottl, U, Vesley SK. Antithrombotic therapy in neonates and children: Antithrombotic therapy and prevention of thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e737S–801S.CrossRefGoogle Scholar
Newall, F, Johnston, L, Ignjatovic, V, Monagle, P. Unfractionated heparin therapy in infants and children. Pediatrics 2009;123:e510–18.CrossRefGoogle ScholarPubMed
Sutor, AH, Massicotte, P, Leaker, M, Andrew, M. Heparin therapy in pediatric patients. Semin Thromb Hemost 1997;23:303–19.CrossRefGoogle ScholarPubMed
Avila, ML, Shah, V, Brandão, LR. Systematic review on heparin-induced thrombocytopenia in children: a call to action. J Thromb Haemost 2013;11:660–9.CrossRefGoogle ScholarPubMed
Kishimoto, TK, Viswanathan, K, Ganguly, T, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Eng J Med 2008;358:2457–67.CrossRefGoogle ScholarPubMed
Hirsh, J, Levine, MN. Low molecular weight heparin. Blood 1992;79:1–17.Google ScholarPubMed
Samama, MM, Gerotziafas, GT. Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost 2000;26(Suppl 1):S31–8.CrossRefGoogle ScholarPubMed
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;109:93–9.CrossRefGoogle Scholar
Massicotte, P, Adams, M, Marzinotto, V, Brooker, LA, Andrew, M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose-finding study. J Pediatr 1996;128:313–18.CrossRefGoogle ScholarPubMed
Punzalan, RC, Hillery, CA, Montgomery, RR, Scott, CA, Gill, JC. Low-molecular-weight heparin in thrombotic disease in children and adolescents. J Pediatr Hematol/Oncol 2000;22:137–42.CrossRefGoogle ScholarPubMed
Albisetti, M, Andrew, M. Low molecular weight heparin in children. Eur J Pediatr 2002;161:71–7.CrossRefGoogle ScholarPubMed
O’Brien, SH, Lee, H, Ritchey, AK. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study. J Thromb Haemost 2007;5:1985–7.CrossRefGoogle ScholarPubMed
Trame, MN, Mitchell, L, Krumpel, A, et al. Population pharmacokinetics of enoxaparin in infants, children, and adolescents during secondary thromboembolic prophylaxis: a cohort study. J Thromb Haemost 2010;8:195–8.CrossRefGoogle ScholarPubMed
Massicotte, MP. Low-molecular-weight heparin therapy in children. J Pediatr Hematol/Oncol 2000;22:98–9.CrossRefGoogle ScholarPubMed
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;109:93–9.CrossRefGoogle Scholar
Nohe, N, Flemmer, A, Rumler, R, Praun, M, Auberger, K. 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):S134–9.CrossRefGoogle ScholarPubMed
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;94:1164–71.Google ScholarPubMed
Rajgopal, R, Bear, MK, Shaugnessy, SG. The effects of heparin and low molecular weight heparin on bone. Thromb Res 2008;122:293–8.CrossRefGoogle ScholarPubMed
Andrew, M, Marzinotto, V, Brooker, LA, et. al. Oral anticoagulation therapy in pediatric patients: a prospective study. Thromb Haemost 1994;71:265–9.Google ScholarPubMed
Streif, W, Andrew, M, Marzinotto, V, et al. Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients. Blood 1999;94:3007–14.Google ScholarPubMed
Woods, A, Vargas, J, Berri, G, Kreutzer, G, Meschengieser, S, Lazzari, MA. Antithrombotic therapy in children and adolescents. Thromb Res 1986;42:289–301.CrossRefGoogle ScholarPubMed
Gunther, T, Mazzitelli, D, Schreiber, C, et. al. Mitral-valve replacement in children under 6 years of age. Eur J Cardiothorac Surg 2000;17:426–30.CrossRefGoogle Scholar
Wermes, C, Bergmann, F, Reller, B, Sykora, KW. Severe protein C deficiency and aseptic osteonecrosis of the hip joint: a case report. Eur J Pediatr 1999;158(Suppl 3):S159–61.CrossRefGoogle ScholarPubMed
Hirsh, J. Oral anticoagulant drugs. N Engl J Med 1991;324:1865–75.Google ScholarPubMed
Nowak-Gottl, U, Dietrich, K, Schaffranek, D, et al. In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. Blood 2010;116:6101–5.CrossRefGoogle ScholarPubMed
Goldenberg, NA, Crowther, MA. The “age” of understanding VKA dose. Blood 2010;116:5789–90.CrossRefGoogle ScholarPubMed
Young, G. New anticoagulants in children: A review of recent studies and a look to the future. Thromb Res 2010;127:70–4.CrossRefGoogle Scholar
Chan, VHT, Monagle, P, Massicotte, P, Chan, AKC. Novel paediatric anticoagulants: a review of the current literature. Blood Coag Fibrin 2010;21:144–51.CrossRefGoogle ScholarPubMed
Deitcher, SR, Topoulos, AP, Bartholomew, JR, Kichuk-Chrisant, MR. Lepirudin anticoagulation for heparin-induced thrombocytopenia. J Pediatr 2002;140:264–6.CrossRefGoogle ScholarPubMed
Cetta, F, Graham, LC, Wrona, LL, Arruda, MJ, Walenga, JM. Argatroban use during pediatric interventional cardiac catheterization. Catheter Cardiovasc Interv 2004;61:147–9.CrossRefGoogle ScholarPubMed
Kawada, T, Kitagawa, H, Hoson, M, Okada, Y, Shiomura, J. Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation. Hematol Oncol Clin North Am 2000;14:445–57.CrossRefGoogle ScholarPubMed
Severin, T, Zieger, B, Sutor, AH. Anticoagulation with recombinant hirudin and danaparoid sodium in pediatric patients. Semin Thromb Hemost 2002;28:447–54.CrossRefGoogle ScholarPubMed
Deitcher, SR, Topoulos, AP, Bartholomew, JR, Kichuk-Chrisant, MR. Lepirudin anticoagulation for heparin-induced thrombocytopenia. J Pediatr 2002;140:264–6.CrossRefGoogle ScholarPubMed
Young, G, Tarantino, MD, Wohrley, J, Weber, LC, Belvedere, M, Nugent, DJ. Pilot dose-finding and safety study of bivalirudin in infants < 6 months of age with thrombosis. J Thromb Haemost 2007;5:1654–9.CrossRefGoogle ScholarPubMed
Rayapudi, S, Torres, A, Deshpande, GG, et al. Bivalirudin for anticoagulation in children. Pediatr Blood Cancer 2008;51:798–801.CrossRefGoogle ScholarPubMed
O’Brien, SH, Yee, D, Lira, J, Goldenberg, NA, Young, G. Prospective open-label clinical trial of bivalirudin in children with venous thrombosis. Blood (abstract) 2012;120:1165.Google Scholar
Forbes, TJ, Hijazi, Z, Young, G, Ringewald, JM, Aquino, PM, Vincent, RN, et al. Pediatric catheterization laboratory anticoagulation with bivalirudin. Catheter and Cardiovasc Interv 2011;77:671–9.CrossRefGoogle ScholarPubMed
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;56:1103–9.CrossRefGoogle ScholarPubMed
Argatroban prescribing information. Available at (accessed May 27, 2010).
Lewis, BE, Wallis, DE, Leya, F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003;163:1849–56.CrossRefGoogle ScholarPubMed
Madabushi, R, Cox, DS, Hossain, M, et al. Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics. J Clin Pharm 2011;51:19–28.CrossRefGoogle Scholar
Young, G, Nugent, DJ. Use of argatroban and fondaparinux in a child with heparin-induced thrombocytopenia. Pediatr Blood Cancer (abstract) 2004;42:S542.Google Scholar
Boshkov, LK, Kirby, A, Shen, I, et al. Recognition and management of heparin-induced thrombocytopenia in pediatric cardiopulmonary bypass patients. Ann Thorac Surg 2006;81:S2355–9.CrossRefGoogle ScholarPubMed
Grabowski, EF, Bussell, JB. Pediatric experience with fondaparinux in deep vein thrombosis. Blood (abstract) 2006;108:916.Google Scholar
Sharatkumar, AA, Crandall, C, Lin, JJ, et al. Treatment of thrombosis with fondaparinux (Arixtra) in a patient with end-stage renal disease receiving hemodialysis therapy. J Pediatr Hematol/Oncol 2007;29:581–4.CrossRefGoogle Scholar
Young, G, Yee, DL, O’Brien, S, Khanna, R, Nugent, DJ. FondaKIDS: A prospective dose-finding, pharmacokinetic, and safety study of fondaparinux in children between 1–18 years of age. Pediatr Blood Cancer 2011;57:1049–54.CrossRefGoogle Scholar
Ko, RH, Michieli, C, Bernardini, L, Young, G. FondaKIDS II: Long-term follow up data of children receiving fondaparinux for treatment of venous thrombotic events. Blood (abstract) 2012;120:3415.Google Scholar
Manco-Johnson, MJ, Wang, M, Goldenberg, NA, Soep, J, Gibson, E, Knoll, CM, Mourani, PM. Treatment, survival, and thromboembolic outcomes of thrombotic storm in children. J Pediatr 2012;161:682–8.CrossRefGoogle ScholarPubMed
Garcia, D, Libby, E, Crowther, MA. The new oral anticoagulants. Blood 2010;115:15–20.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×