Abstract：Rivaroxaban, the first oral factor Xa inhibitor, is a safe and effective oral anticoagulant with definite pharmaceutical properties. It is the first-line treatment of various thromboembolic disease (TED) in adults. With the increasing demand for anticoagulants in children, rivaroxaban shows great potential in the field of pediatrics. This article collected the latest guidelines and literatures related to rivaroxaban in children aged 0-18, and summarized the epidemiological characteristics of TED, the characteristics of coagulation system, the research in pharmaceutical characteristics and clinical efficacy and safety, so as to provide a basis for the rational use of rivaroxaban in pediatrics.
BAUERSACHS R, BERKOWITZ S D, BRENNER B, et al. Oral rivaroxaban for symptomatic venous thromboembolism[J]. N Engl J Med, 2010, 363(26):2499-2510.
[2]
PATEL M R, MAHAFFEY K W, GARG J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J]. N Engl J Med, 2011,365(10):883-891.
[3]
BAYER A G. Xarelto® (rivaroxaban) Summary of Product Characteristics.[EB/OL]. European Medicines Agency,[2020-01-17]. https://www.ema.europa.eu/en/documents/product-information/xarelto-epar-product-information_en.pdf.
[4]
TUCKUVIENE R, CHRISTENSEN A L, HELGESTAD J, et al. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study[J]. J Pediatr, 2011, 159(4):663-669.
[5]
RAFFINI L, HUANG Y S, WITMER C, et al. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007[J]. Pediatrics, 2009, 124(4):1001-1008.
[6]
CARPENTER S L, RICHARDSON T, HALL M. Increasing rate of pulmonary embolism diagnosed in hospitalized children in the United States from 2001 to 2014[J]. Blood Adv, 2018, 2(12):1403-1408.
[7]
GUPTA T, DELHI KUMAR C G, RAMESH KUMAR R, et al. Pediatric thrombotic events: incidence, clinical risk factors and outcome[J]. Indian J Pediatr, 2019, 86(3):241-244.
[8]
TETSUHARA K, ISHIGURO A, MICHIHATA N, et al. Pediatric thromboembolism in Japan[J]. The Indian J Pediatr, 2016, 83(10):1077-1081.
[9]
MONAGLE P, CHAN A K, GOLDENBERG N A, 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[J]. Chest, 2012, 141 (2 suppl): e737S-e801S.
[10]
MONAGLE P, CUELLO C A, AUGUSTINE C, et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism[J]. Blood Adv, 2018, 2(22):3292-3316.
[11]
PENKOV D, TOMASI P, EICHLER I, et al. Pediatric medicine development: an overview and comparison of regulatory processes in the European Union and United States[J]. Ther Innov Regul Sci, 2017, 51(3):360-371.
ANDREW M, DAVID M, ADAMS M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE[J]. Blood, 1994, 83(5):1251-1257.
[14]
VAN OMMEN C H, HEIJBOER H, BULLER H R, et al. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands[J]. J Pediatr, 2001, 139(5):676-681.
[15]
SABAPATHY C A, DJOUONANG T N, KAHN S R, et al. Incidence trends and mortality from childhood venous thromboembolism: a population-based cohort study[J]. J Pediatr, 2016, 172:175-180.e1.
[16]
MONAGLE P, NEWALL F, BARNES C, et al. Arterial thromboembolic disease: a single-centre case series study[J]. J Paediatr Child Health, 2008, 44(1-2):28-32.
[17]
ANDREW M, PAES B, MILNER R, et al. Development of the human coagulation system in the full-term infant[J]. Blood, 1987, 70(1):165-172.
[18]
ANDREW M, VEGH P, JOHNSTON M, et al. Maturation of the hemostatic system during childhood[J]. Blood, 1992, 80(8):1998-2005.
[19]
APPEL I M, GRIMMINCK B, GEERTS J, et al. Age dependency of coagulation parameters during childhood and puberty[J]. J Thromb Haemost, 2012, 10(11):2254-2263.
[20]
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[J]. Thromb Haemost, 2016, 116(1):9-16.
[21]
LIPPI G, FRANCHINI M, MONTAGNANA M, et al. Coagulation testing in pediatric patients: the young are not just miniature adults[J]. Semin Thromb Hemost, 2007, 33(8):816-820.
[22]
WILLMANN S, BECKER C, BURGHAUS R, et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban[J]. Clin Pharmacokinet, 2014, 53(1):89-102.
[23]
WILLMANN S, THELEN K, KUBITZA D, et al. Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study[J]. Thromb J, 2018, 16:32. doi: 10.1186/s12959-018-0185-1. eCollection 2018.
[24]
ATTARD C, MONAGLE P, KUBITZA D, et al. The in vitro anticoagulant effect of rivaroxaban in children[J]. Thromb Res, 2012, 130(5):804-807.
[25]
ATTARD C, MONAGLE P, KUBITZA D, et al. The in-vitro anticoagulant effect of rivaroxaban in neonates[J]. Blood Coagul Fibrin, 2014, 25(3):237-240.
[26]
KUBITZA D, WILLMANN S, BECKA M, et al. Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study[J]. Thromb J, 2018, 16:31. doi: 10.1186/s12959-018-0186-0. eCollection 2018.
[27]
MONAGLE P, LENSING A W A, THELEN K, et al. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies[J]. Lancet Haematol, 2019, 6(10):e500-e509.
[28]
MARTINELLI I, BUCCIARELLI P, ARTONI A, et al. Anticoagulant treatment with rivaroxaban in severe protein S deficiency[J]. Pediatrics, 2013, 132(5):e1435-e1439.
[29]
TRIPODI A, MARTINELLI, CHANTARANGKUL V, et al.Thrombin generation and other coagulation parameters in a patient with homozygous congenital protein S deficiency on treatment with rivaroxaban[J]. Int J Hematol, 2016, 103(2):165-172.
[30]
MENON N, SARODE R, ZIA A. Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency and warfarin-induced skin necrosis[J]. Blood Adv, 2018, 2(2):142-145.
[31]
MARTI'NEZ-MARTI'NEZ I, NAVARRO-FERNA'NDEZ J, STERGAARD A, et al. Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism[J]. Blood, 2012, 120(4):900-904.
[32]
VAN BRUWAENE L, HUISMAN A, URBANUS R T, et al. Heparin-resistant thrombosis due to homozygous antithrombin deficiency treated with rivaroxaban[J]. J Pediatr Hematol/Oncol, 2016, 38(8):658-660.
[33]
SKRZYPCZYK P, MIZERSKA-WASIAK M, OFIARA A, et al. Pulmonary embolism in a girl with nephrotic syndrome and factor V Leiden-case report[J]. Pol Merkur Lekarski,2018,45(267):114-118.
[34]
SAVINO S, BREEN K, HUNT B J. Rivaroxaban use in patients with antiphospholipid syndrome and previous venous thromboembolism[J]. Blood Coagul Fibrinolysis, 2015, 26(4):476-477.
[35]
MACK J M, RICHTER G T, CRARY S E. Effectiveness and safety of treatment with direct oral anticoagulant rivaroxaban in patients with slow-flow vascular malformations: a case series[J]. Lymphat Res Biol, 2018, 16(3):278-281.
[36]
MA J Y, ZHANG X, LI X F, et al. Thrombotic storm in a 4-year-old boy with a thrombus in the right atriu[J]. Chin J Pediatr(中华儿科杂志), 2018, 56(8):633-634.
[37]
SHI Z M, ZHANG T Q, GUO W, et al. A case report of mycoplasma pneumonia-combined pulmonary thromboembolism in child[J]. Clin Focus(临床荟萃), 2019, 34(8):748-751.
[38]
MALE C, LENSING A W A, PALUMBO J S, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial[J]. Lancet Haematol, 2020, 7(1):e18-e27.
[39]
LANGWIESER N, BERNLOCHNER I, WUSTROW I, et al. Combination of factor Xa inhibition and antiplatelet therapy after stenting in patients with iliofemoral post-thrombotic venous obstruction[J]. Phlebology, 2016, 31(6):430-437.
[40]
IYENGAR A J, WINLAW D S, GALATI J C, et al. The Australia and New Zealand Fontan Registry: description and initial results from the first population-based Fontan registry[J]. Intern Med J, 2014, 44(2):148-155.
[41]
PINA L M, 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)[J]. Am Heart J, 2019, 213:97-104.
[42]
DU X M, ZHU M T, JIAN L Y. Investigation and analysis of clinical application of rivaroxaban[J]. Chin Pharm J(中国药学杂志), 2019, 54(6):489-493.
[43]
US Food and Drug Administration.2018 Biological License Application Approvals [EB/OL]. US Food and Drug Administration, [2019-01-13]. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/2018-biological-license-application-approvals.
[44]
GOLDENBERG N A, ABSHIRE T, BLATCHFORD P J, et al. Multicenter randomized controlled trial on duration of therapy for thrombosis in children and young adults (the kids-DOTT trial): pilot/feasibility phase findings[J]. J Thromb Haemost, 2015, 13(9):1597-1605.
2021, Vol. 56 
