Anticoagulation therapy in neonates, children and adolescents
Introduction
Anticoagulation in neonates, children and adolescents is an important clinical area in light of the increasing incidence of thrombosis, and therefore potential complications arising from thrombosis in the pediatric setting [1]. Thrombosis in paediatrics is a rare, but serious event with an estimated incidence of 58 per 10,000 hospital admissions and clinical management remains challenging [1], [2]. Predisposing factors for the development of thrombosis include the presence of vascular access devices, congenital cardiac disease, cancer, renal disease, organ transplantation, infection, inflammation and prematurity [3]. Anticoagulants are administered for the treatment of thrombosis to assist resolution, decrease the risk of embolism, limit extension and prevent recurrence or for thrombosis prophylaxis in individuals at risk [4].
The American College of Chest Physicians (ACCP) regularly publish recommendations based on the available evidence to guide clinical practice of Antithrombotic therapy in neonates and children, for specific clinical situations and scenarios [5], [6], [7], [8], [9], [10]. Despite much research in the field, many of the recommendations are based on low-grade evidence because high quality safety and efficacy studies are hard to conduct in the pediatric setting and thus many of the recommendations are extrapolated from adult studies. The lack of data specific to paediatrics complicates evidence-based management of anticoagulant therapy.
This is in part because neonates, children and adolescents are unique in their physiology, clinical conditions and response to pharmacologic agents. Developmental haemostasis is a term used to describe the physiological age related changes in the coagulation system [11], [12]. Dynamic changes of the hematologic system are evident throughout childhood, in the premature infant through to adolescents rendering anticoagulation management of different age ranges complex. Pediatric anticoagulation is a specialised area and as such, the ACCP recommended that a paediatric haematologist is required to manage anticoagulation therapy or alternatively, a neonatologist or pediatrician in collaboration with an experienced adult haematologist [9].
There is a range of anticoagulant agents available for the treatment of thrombosis in paediatrics with heparin, LMWH and warfarin being the most commonly used in paediatrics [13]. These agents are compared in Table 1. Choice of anticoagulant depends on considerations such as the presenting condition, risk of adverse events, drug interactions, diet, compliance, duration of therapy and patient and family preference. This review aims to provide an overview of the anticoagulation agents currently used in the pediatric setting. This will include description of the mechanisms of action, therapeutic ranges, dosing regimens, monitoring requirements and adverse effects.
Section snippets
Unfractionated heparin
Unfractionated heparin is a heavily sulphated mucopolysaccharide. Heparin molecules range in molecular weight from 3000 to 30,000 kDa (mean 15,000), but only a third of the molecules have the pentasaccharide sequence required for the anticoagulant activity of UFH.
Conclusion
Pediatric anticoagulation is a very unique area where extrapolation from adult studies is suboptimal. The most commonly used anticoagulant drugs in use have some data specific to the pediatric setting, and newer agents are being studied in a more systematic manner. However, there are many more studies required on anticoagulation in paediatrics, as the majority of the recommendations currently in use are based on low levels of evidence [9]. Studies examining monitoring regimens, drug target
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of interest
Nil.
Contributors
MH, PM and AC wrote and reviewed the article. All authors have approved the final article.
References (82)
Venous thrombosis in children
J. Thromb. Haemost.
(2003)- et al.
Antithrombotic therapy in children
Chest
(1995) Antithrombotic therapy in children
Chest
(1998)Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition)
Chest
(2008)Antithrombotic therapy in children: the seventh ACCP conference on antithrombotic and thrombolytic therapy
Chest
(2004)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)Antithrombotic therapy in children
Chest
(2001)- et al.
Hemostasis in neonates and children: pitfalls and dilemmas
Blood Rev.
(2010) Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines
Chest
(2012)Maturation of the hemostatic system during childhood
Blood
(1992)
Monitoring Unfractionated Heparin (UFH) therapy: which Anti-factor Xa assay is appropriate?
Thromb. Res.
Age-related differences in heparin response
Thromb. Res.
Age-specific differences in binding of heparin to plasma proteins
J. Thromb. Haemost.
In vivo age dependency of unfractionated heparin in infants and children
Thromb. Res.
Accidental heparin toxicity in the newborn intensive care unit
J. Pediatr.
The use of low molecular weight heparin in pediatric patients: a prospective cohort study
J. Pediatr.
Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study
J. Thromb. Haemost.
Enoxaparin for neonatal thrombosis: a call for a higher dose for neonates
Thromb. Res.
Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study
J. Pediatr.
Heparin sensitivity and resistance in the neonate: an explanation
Thromb. Res.
Oral anticoagulation therapy in children
Thromb. Res.
Analysis of warfarin therapy in pediatric patients: a prospective cohort study of 319 patients
Blood
The content of phylloquinone (vitamin K1) in human milk, cows' milk and infant formula foods determined by high-performance liquid chromatography
J. Nutr.
Anticoagulation clinics for children achieve improved warfarin management
Thromb. Res.
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.
Newell F Oral anticoagulant therapy interruption in children: a single centre experience
Thromb. Res.
Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007
Pediatrics
A guide to the use of anticoagulant drugs in children
Paediatr. Drugs
Direct thrombin and factor Xa inhibitors in children: a quest for new anticoagulants for children
Wien. Med. Wochenschr.
Developmental haemostasis. Impact for clinical haemostasis laboratories
Thromb. Haemost.
Limitations of the laboratory monitoring of heparin therapy. Scientific and standardization committee communications: on behalf of the control of anticoagulation subcommittee of the scientific and standardization committee of the international society of thrombosis and haemostasis
Thromb. Haemost.
Structure of the antithrombin-binding site in heparin
Proc. Natl. Acad. Sci. U. S. A.
Correlation between structure and function of heparin
Proc. Natl. Acad. Sci. U. S. A.
Persistent activation of coagulation mechanism in unstable angina and myocardial infarction
Circulation
Heparin-induced thrombocytopenia in children
J. Paediatr. Child Health
Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin
Thromb. Haemost.
Thrombin regulation in children differs from adults in the absence and presence of heparin
Thromb. Haemost.
Therapeutic range for unfractionated heparin therapy: age-related differences in response in children
J. Thromb. Haemost.
Age-related plasma reference ranges for two heparin-binding proteins—vitronectin and platelet factor 4
Int. J. Lab. Hematol.
Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin
Thromb. Haemost.
Heparin
N. Engl. J. Med.
Cited by (19)
Is bivalirudin an alternative anticoagulant for extracorporeal membrane oxygenation (ECMO) patients? A systematic review and meta-analysis
2022, Thrombosis ResearchCitation Excerpt :The difference in hospital mortality and thrombosis events in the bivalirudin group were not statistically significant when compared with those in the heparin group. The separate phenomenon of the differences in pooled results between adult and pediatric patients may be caused by specific physiological and clinical conditions among adult and pediatric patients, especially in hematologic systems, which vary throughout childhood [33]. In addition, cannula size, underlying conditions, and indications for ECMO may also play roles here.
Potential value of circulating endothelial cells for the diagnosis and treatment of COVID-19
2021, International Journal of Infectious DiseasesInsights into neonatal thrombosis
2019, Thrombosis ResearchCitation Excerpt :This nonintervention recommendation is supported by the extremely low recurrence rate in neonatal arterial stroke [28,31]. A limited choice of anticoagulants is currently available for the treatment of thrombosis in pediatric patients, with unfractionated heparin (UFH), low molecular weight heparins (LMWH) and warfarin being the most commonly used [37]. Notably, LMWH has become the anticoagulant of choice in many pediatric patients for primary and secondary prophylaxis of VTE, and Enoxaparin is the most commonly used LMWH for children [11].
Clearance and nutrition in neonatal continuous kidney replacement therapy using the Carpediem™ system
2024, Pediatric Nephrology