Intravenous Direct Thrombin Inhibitors for Acute Venous Thromboembolism or Heparin-Induced Thrombocytopenia with Thrombosis in Children: A Systematic Review of the Literature

Abstract

Intravenous direct thrombin inhibitors (DTIs) are used for thromboembolic disorders. This systematic review aims to characterize intravenous DTI agents, dosing, monitoring strategies (or use), bleeding, and mortality, in pediatric patients with acute venous thromboembolism (VTE) or heparin-induced thrombocytopenia with thrombosis (HITT). MEDLINE, Embase, and Cochrane's CENTRAL were searched from inception through July 2023. Case series, retrospective studies, and prospective studies providing per-patient or summary data for patients < 18 years of age with VTE or HITT treated with an intravenous DTI were included. Selection and data extraction were conducted independently by two reviewers. Sixteen studies (7 case reports, 1 case series, 5 retrospective studies, 3 prospective studies) with 85 patients were included. Target conditions included acute VTE in 54 (64%) and HITT in 31 (36%) patients. Bivalirudin, argatroban, and lepirudin were used in 52 (61%), 27 (32%), and 6 (7%) patients, respectively. Fifty-two (61%) patients received a bolus dose, and weighted mean infusion rates for bivalirudin, argatroban, and lepirudin were 0.2 mg/kg/hr, 1.2 mcg/kg/min, and 0.15 mg/kg/hr, respectively. The activated partial thromboplastin time was utilized for monitoring in 82 (96%) patients. Complete or partial thrombus resolution was reported in 53 (62%) patients, mortality in 6 (7%) patients, and bleeding complications in 14 (16%) patients. In this systematic review involving 85 pediatric patients treated with an intravenous DTI for acute VTE or HITT, bivalirudin was the most commonly utilized agent, with a rate of resolution over 60% despite a high acuity in the population studied. Prospective collaborative studies are warranted to establish optimal dosing and further characterize VTE and bleeding outcomes.

Keywords

pediatrics - direct thrombin inhibitors - thromboembolism

Publication History

Article published online:
07 October 2024

• References

• 1 O'Brien SH, Stanek JR, Witmer CM, Raffini L. The continued rise of venous thromboembolism across US children's hospitals. Pediatrics 2022; 149 (03) e2021054649
• 2 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 (suppl2): e737S –801
• 3 Yee DL, O'Brien SH, Young G. Pharmacokinetics and pharmacodynamics of anticoagulants in paediatric patients. Clin Pharmacokinet 2013; 52 (11) 967-980
• 4 Chan AK, Black L, Ing C, Brandão LR, Williams S. Utility of aPTT in monitoring unfractionated heparin in children. Thromb Res 2008; 122 (01) 135-136
• 5 Ignjatovic V, Summerhayes R, Gan A. et al. Monitoring unfractionated heparin (UFH) therapy: which anti-factor Xa assay is appropriate?. Thromb Res 2007; 120 (03) 347-351
• 6 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 (03) 368-374
• 7 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 (09) 1985-1987
• 8 Trame MN, Mitchell L, Krümpel A, Male C, Hempel G, Nowak-Göttl U. Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study. J Thromb Haemost 2010; 8 (09) 1950-1958
• 9 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 (2-3): 93-99
• 10 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 (08) 1654-1659
• 11 O'Brien SH, Yee DL, Lira J, Goldenberg NA, Young G. UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis. J Thromb Haemost 2015; 13 (09) 1615-1622
• 12 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 (07) 1103-1109
• 13 Pollak U, Mishaly D, Kenet G, Vardi A. Heparin-induced thrombocytopenia complicating children after the Fontan procedure: single-center experience and review of the literature. Congenit Heart Dis 2018; 13 (01) 16-25
• 14 Deitcher SR, Topoulos AP, Bartholomew JR, Kichuk-Chrisant MR. Lepirudin anticoagulation for heparin-induced thrombocytopenia. J Pediatr 2002; 140 (02) 264-266
• 15 Bertamino M, Severino M, Parodi A. et al. Bivalirudin anticoagulation to overcome heparin resistance in a neonate with cerebral sinovenus thrombosis. Blood Coagul Fibrinolysis 2020; 31 (01) 97-100
• 16 Maurer SH, Wilimas JA, Wang WC, Reiss UM. Heparin induced thrombocytopenia and re-thrombosis associated with warfarin and fondaparinux in a child. Pediatr Blood Cancer 2009; 53 (03) 468-471
• 17 Rayapudi S, Torres Jr A, Deshpande GG. et al. Bivalirudin for anticoagulation in children. Pediatr Blood Cancer 2008; 51 (06) 798-801
• 18 Malloy KM, McCabe TA, Kuhn RJ. Bivalirudin use in an infant with persistent clotting on unfractionated heparin. J Pediatr Pharmacol Ther 2011; 16 (02) 108-112
• 19 Madabushi R, Cox DS, Hossain M. et al. Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics. J Clin Pharmacol 2011; 51 (01) 19-28
• 20 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 (04) 719-724
• 21 John TE, Hallisey Jr RK. Argatroban and lepirudin requirements in a 6-year-old patient with heparin-induced thrombocytopenia. Pharmacotherapy 2005; 25 (10) 1383-1388
• 22 Alsoufi B, Boshkov LK, Kirby A. et al. Heparin-induced thrombocytopenia (HIT) in pediatric cardiac surgery: an emerging cause of morbidity and mortality. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2004; 7: 155-171
• 23 Abdillah JN, Hu Q, Chen X. et al. Heparin-induced thrombocytopenia in infants after heart surgery. Thorac Cardiovasc Surg 2019; 67 (01) 21-27
• 24 Goldstein G, Maor J, Kleinbaum Y, Palumbo M, Sidi Y, Salomon O. Budd-Chiari syndrome in very young adult patients with polycythemia vera: report of case series with good outcome with direct thrombin inhibitor treatment. Blood Coagul Fibrinolysis 2013; 24 (08) 848-853
• 25 Walter KN, Erlacher M, Uhl M. et al. Lepirudin treatment in a girl with iliac vein thrombosis, severe pulmonary embolism and suspected heparin-induced thrombocytopenia (HIT) II. Klin Padiatr 2009; 221 (03) 174-175
• 26 Hasan RA, Pak J, Kirk CJ, Friedland-Little JM, Chandler WL. Monitoring direct thrombin inhibitors with calibrated diluted thrombin time vs activated partial thromboplastin time in pediatric patients. Am J Clin Pathol 2023; 159 (01) 60-68
• 27 Beyer JT, Lind SE, Fisher S, Trujillo TC, Wempe MF, Kiser TH. Evaluation of intravenous direct thrombin inhibitor monitoring tests: correlation with plasma concentrations and clinical outcomes in hospitalized patients. J Thromb Thrombolysis 2020; 49 (02) 259-267
• 28 Andrew M, Marzinotto V, Massicotte P. et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994; 35 (01) 78-83
• 29 Kuhle S, Eulmesekian P, Kavanagh B, Massicotte P, Vegh P, Mitchell LG. A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study. Haematologica 2007; 92 (02) 244-247