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A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD

Part of: Surgery

Published online by Cambridge University Press:  06 January 2022

Elizabeth J. Thompson
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Henry P. Foote
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Jennifer S. Li
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
Alexandre T. Rotta
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Neil A. Goldenberg
Department of Pediatrics and Medicine, Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Institute for Clinical and Translational Research, Cancer and Blood Disorders Institute, and Heart Institute, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
Christoph P. Hornik*
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
Author for correspondence: C. Hornik, MD, PhD, MPH, Department of Pediatrics, Duke University School of Medicine, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715 USA. Tel: 919-357-8145; Fax: 919-681-9457. E-mail:



To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass.


We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0–18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria.


We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common.


There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

© The Author(s), 2022. Published by Cambridge University Press

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Pasquali, SK, Thibault, D, O'Brien, SM, et al. National variation in congenital heart surgery outcomes. Circulation 2020; 142: 13511360.10.1161/CIRCULATIONAHA.120.046962CrossRefGoogle ScholarPubMed
Kern, FH, Morana, NJ, Sears, JJ, Hickey, PR. Coagulation defects in neonates during cardiopulmonary bypass. Ann Thorac Surg 1992; 54: 541546.10.1016/0003-4975(92)90451-9CrossRefGoogle ScholarPubMed
Mammen, EF, Koets, MH, Washington, BC, et al. Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 1985; 11: 281292.10.1055/s-2007-1004382CrossRefGoogle ScholarPubMed
Williams, GD, Bratton, SL, Riley, EC, Ramamoorthy, C. Association between age and blood loss in children undergoing open heart operations. Ann Thorac Surg 1998; 66: 870875, discussion, 5-6.10.1016/S0003-4975(98)00600-6CrossRefGoogle ScholarPubMed
Guzzetta, NA, Allen, NN, Wilson, EC, Foster, GS, Ehrlich, AC, Miller, BE. Excessive postoperative bleeding and outcomes in neonates undergoing cardiopulmonary bypass. Anesth Analg 2015; 120: 405410.10.1213/ANE.0000000000000531CrossRefGoogle ScholarPubMed
Holst, KA, Said, SM, Nelson, TJ, Cannon, BC, Dearani, JA. Current interventional and surgical management of congenital heart disease: specific focus on valvular disease and cardiac arrhythmias. Circ Res 2017; 120: 10271044.10.1161/CIRCRESAHA.117.309186CrossRefGoogle ScholarPubMed
Manlhiot, C, Menjak, IB, Brandão, LR, et al. Risk, clinical features, and outcomes of thrombosis associated with pediatric cardiac surgery. Circulation 2011; 124: 15111519.10.1161/CIRCULATIONAHA.110.006304CrossRefGoogle ScholarPubMed
Giglia, TM, Massicotte, MP, Tweddell, JS, et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation 2013; 128: 26222703.10.1161/01.cir.0000436140.77832.7aCrossRefGoogle ScholarPubMed
Murphy, LD, Benneyworth, BD, Moser, EAS, Hege, KM, Valentine, KM, Mastropietro, CW. Analysis of patient characteristics and risk factors for thrombosis after surgery for congenital heart disease. Pediatr Crit Care Med 2018; 19: 11461152.10.1097/PCC.0000000000001743CrossRefGoogle ScholarPubMed
McCulloch, MA, Conaway, MR, Haizlip, JA, Buck, ML, Bovbjerg, VE, Hoke, TR. Postoperative chylothorax development is associated with increased incidence and risk profile for central venous thromboses. Pediatr Cardiol 2008; 29: 556561.10.1007/s00246-007-9140-9CrossRefGoogle ScholarPubMed
Bristol-Myers Squibb Company. Coumadin [package insert]. U.S. Food and Drug Administration website 2007. Retrieved November 30, 2021. Scholar
Hikma Pharmaceuticals USA Inc. Heparin Sodium [package insert]. U.S. Food and Drug Administration website 2019. Retrieved November 30, 2021. Scholar
New Haven Pharmaceuticals, Inc. Durlaza [package insert]. U.S. Food and Drug Administration website 2015. Retrieved November 30, 2021. Scholar
Torok, RD, Li, JS, Kannankeril, PJ, et al. Recommendations to enhance pediatric cardiovascular drug development: report of a multi-stakeholder think tank. J Am Heart Assoc 2018; 7: e007283.10.1161/JAHA.117.007283CrossRefGoogle ScholarPubMed
Zimmerman, K, Gonzalez, D, Swamy, GK, Cohen-Wolkowiez, M. Pharmacologic studies in vulnerable populations: using the pediatric experience. Semin Perinatol 2015; 39: 532536.10.1053/j.semperi.2015.08.007CrossRefGoogle ScholarPubMed
King, CE, Thompson, EJ, Foote, HP, et al. An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020. Cardiol Young 2020; 30: 17571771.10.1017/S1047951120004151CrossRefGoogle ScholarPubMed
Al-Metwali, BZ, Rivers, P, Goodyer, L, O'Hare, L, Young, S, Mulla, H. Personalised warfarin dosing in children post-cardiac surgery. Pediatr Cardiol 2019; 40: 17351744.10.1007/s00246-019-02215-yCrossRefGoogle ScholarPubMed
Lowry, AW, Moffett, BS, Moodie, D, Knudson, JD. Warfarin anticoagulation after congenital heart surgery at a large children’s hospital. Pediatr Cardiol 2012; 33: 13771382.10.1007/s00246-012-0351-3CrossRefGoogle Scholar
Masoumi, G, Mardani, D, Musavian, M, Bigdelian, H. Comparison of the effect of fibrinogen concentrate with fresh frozen plasma (FFP) in management of hypofibrinogenemic bleeding after congenital cardiac surgeries: a clinical trial study. ARYA Atherosclerosis 2018; 14: 248253.Google Scholar
Mir, A, Frank, S, Journeycake, J, et al. Aspirin resistance in single-ventricle physiology: aspirin prophylaxis is not adequate to inhibit platelets in the immediate postoperative period. Ann Thorac Surg 2015; 99: 21582164.10.1016/j.athoracsur.2015.02.026CrossRefGoogle Scholar
Schroeder, AR, Axelrod, DM, Silverman, NH, Rubesova, E, Merkel, E, Roth, SJ. A continuous heparin infusion does not prevent catheter-related thrombosis in infants after cardiac surgery. Pediatr Crit Care Med 2010; 11: 489495.Google Scholar
Truong, DT, Johnson, JT, Bailly, DK, et al. Platelet inhibition in shunted infants on aspirin at short and midterm follow-Up. Pediatr Cardiol 2017; 38: 401409.10.1007/s00246-016-1529-xCrossRefGoogle Scholar
Vorisek, CN, Sleeper, LA, Piekarski, B, et al. High-dose heparin is associated with higher bleeding and thrombosis rates in pediatric patients following cardiac surgery. J Thorac Cardiovasc Surg 2019; 158: 11991206.10.1016/j.jtcvs.2019.06.015CrossRefGoogle ScholarPubMed
Thomas, CA, Taylor, K, Schamberger, MS, Rotta, AT. Safety of warfarin dosing in the intensive care unit following the Fontan procedure. Congenit Heart Dis 2014; 9: 361365.10.1111/chd.12151CrossRefGoogle ScholarPubMed
Nair, AG, Oladunjoye, OO, Trenor, CC, et al. An anticoagulation protocol for use after congenital cardiac surgery. J Thorac Cardiovasc Surg 2018; 156: 343352.e4.10.1016/j.jtcvs.2018.02.106CrossRefGoogle ScholarPubMed
Emani, S, Trainor, B, Zurakowski, D, et al. Aspirin unresponsiveness predicts thrombosis in high-risk pediatric patients after cardiac surgery. J Thorac Cardiovasc Surg 2014; 148: 810814, discussion, 814-816.10.1016/j.jtcvs.2014.06.016CrossRefGoogle ScholarPubMed
Emani, S, Zurakowski, D, Mulone, M, DiNardo, JA, Trenor, CC, Emani, SM. Platelet testing to guide aspirin dose adjustment in pediatric patients after cardiac surgery. J Thorac Cardiovasc Surg 2017; 154: 17231730.10.1016/j.jtcvs.2017.06.031CrossRefGoogle ScholarPubMed
Radulescu, VC. Anticoagulation therapy in children. Semin Thromb Hemost 2017; 43: 877885.Google ScholarPubMed
Nowak-Göttl, 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: 61016105.10.1182/blood-2010-05-283861CrossRefGoogle ScholarPubMed
Nguyen, N, Anley, P, Yu, MY, Zhang, G, Thompson, AA, Jennings, LJ. Genetic and clinical determinants influencing warfarin dosing in children with heart disease. Pediatr Cardiol 2013; 34: 984990.10.1007/s00246-012-0592-1CrossRefGoogle ScholarPubMed
Boris, JR, Harris, MA. The use of anticoagulation in pediatric cardiac disease. Images Paediatr Cardiol 2003; 5: 135.Google ScholarPubMed
Lankiewicz, MW, Hays, J, Friedman, KD, Tinkoff, G, Blatt, PM. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost 2006; 4: 967970.10.1111/j.1538-7836.2006.01815.xCrossRefGoogle ScholarPubMed
Vear, SI, Stein, CM, Ho, RH. Warfarin pharmacogenomics in children. Pediatr Blood Cancer 2013; 60: 14021407.10.1002/pbc.24592CrossRefGoogle ScholarPubMed
Chan, AK, Leaker, M, Burrows, FA, et al. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost 1997; 77: 270277.Google ScholarPubMed
Toulon, P, Berruyer, M, Brionne-François, M, et al. Age dependency for coagulation parameters in paediatric populations. Results of a multicentre study aimed at defining the age-specific reference ranges. Thromb Haemost 2016; 116: 916.Google ScholarPubMed
Monagle, P, Chan, AKC, 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: e737Se801S.10.1378/chest.11-2308CrossRefGoogle ScholarPubMed
Hamberg, AK, Friberg, LE, Hanséus, K, et al. Warfarin dose prediction in children using pharmacometric bridging--comparison with published pharmacogenetic dosing algorithms. Eur J Clin Pharmacol 2013; 69: 12751283.10.1007/s00228-012-1466-4CrossRefGoogle ScholarPubMed
Björk, I, Lindahl, U. Mechanism of the anticoagulant action of heparin. Mol Cell Biochem 1982; 48: 161182.10.1007/BF00421226CrossRefGoogle ScholarPubMed
Mohanty, S, Vaidyanathan, B. Anti-platelet agents in pediatric cardiac practice. Ann Pediatr Cardiol 2013; 6: 5964.Google ScholarPubMed
Warner, TD, Nylander, S, Whatling, C. Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br J Clin Pharmacol 2011; 72: 619633.10.1111/j.1365-2125.2011.03943.xCrossRefGoogle ScholarPubMed
Mitchell, LG, Goldenberg, NA, Male, C, Kenet, G, Monagle, P, Nowak-Göttl, U. Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9: 18561858.10.1111/j.1538-7836.2011.04433.xCrossRefGoogle ScholarPubMed
Male, C, Lensing, AWA, Palumbo, JS, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol 2020; 7: e18e27.10.1016/S2352-3026(19)30219-4CrossRefGoogle ScholarPubMed
Pina, LM, Dong, X, Zhang, L, et al. Rivaroxaban, a direct Factor Xa inhibitor, versus acetylsalicylic acid as thromboprophylaxis in children post-Fontan procedure: rationale and design of a prospective, randomized trial (the UNIVERSE study). Am Heart J 2019; 213: 97104.10.1016/j.ahj.2019.04.009CrossRefGoogle Scholar
Li, JS, Yow, E, Berezny, KY, et al. Clinical outcomes of palliative surgery including a systemic-to-pulmonary artery shunt in infants with cyanotic congenital heart disease: does aspirin make a difference? Circulation 2007; 116: 293297.10.1161/CIRCULATIONAHA.106.652172CrossRefGoogle Scholar
Whitlock, RP, Sun, JC, Fremes, SE, Rubens, FD, Teoh, KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e576Se600S.CrossRefGoogle ScholarPubMed
Li, JS, Yow, E, Berezny, KY, et al. Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial. Circulation 2008; 117: 553559.10.1161/CIRCULATIONAHA.107.715821CrossRefGoogle ScholarPubMed
Wessel, DL, Berger, F, Li, JS, et al. Clopidogrel in infants with systemic-to-pulmonary-artery shunts. N Engl J Med 2013; 368: 23772384.10.1056/NEJMoa1114588CrossRefGoogle ScholarPubMed
Payne, RM, Burns, KM, Glatz, AC, et al. A multi-national trial of a direct oral anticoagulant in children with cardiac disease: design and rationale of the Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE) study. Am Heart J 2019; 217: 5263.10.1016/j.ahj.2019.08.002CrossRefGoogle ScholarPubMed
Bhatt, MD, Portman, MA, Berger, F, et al. ENNOBLE-ATE trial: an open-label, randomised, multi-centre, observational study of edoxaban for children with cardiac diseases at risk of thromboembolism. Cardiol Young 2021; 31: 12131219.10.1017/S1047951121002523CrossRefGoogle ScholarPubMed