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Paediatric patients with VTE: Protecting the most challenging population

Paediatric patients with VTE – disease burden – risk factors

 

Learn about the challenges of treating children with VTE

Understanding the risk of VTE in paediatric patients

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is primarily regarded as a disease that affects adults.1 Although the incidence in adults is approximately 100 times higher than in children1-3, it has been increasingly recognized that paediatric VTE is also associated with substantial morbidity and mortality.4,5 While the overall incidence of paediatric VTE is estimated to be 0.07–0.14 per 10,000 children,2,3 the incidence of VTE in hospitalized children is around 100–1000 times higher, occurring in ≥58 cases per 10,000 hospital admissions (Figure 1).6,7 Thus, the children most commonly affected are those who are already hospitalized with other conditions, such as malignancy or heart disease,5,8,9 highlighting that this is a particularly vulnerable group of patients.

TA VTE paediatric diagram

Figure 1: Annual incidence of VTE in hospitalized children6

In contrast to VTE in adults, paediatric VTE is rarely idiopathic.5 More than 90% of paediatric VTE events are related to underlying medical or surgical factors,2,3 and are considered provoked.5 The presence of central venous catheters is the most common risk factor, contributing to >90% of all neonatal VTE and >50% of all cases of VTE in other age groups.2,3,9 In addition to central venous catheters, trauma, cancer and infections have also been reported as major risk factors for VTE in children (Table 1).8,9

TA VTE paediatric diagram

Table 1: Risk factors for paediatric VTE8

The majority of paediatric VTE events are reported during early infancy, followed by another peak during adolescence.5 In the past two decades, the incidence of paediatric VTE has increased due to medical advances and improved clinical outcomes in illnesses that previously caused mortality.4 One of the main reasons for this increase is the frequent use of central venous catheters in the treatment of neonates.4

 

Thus, the increasing incidence of paediatric VTE, associated with increased mortality and morbidity, especially in hospitalized children, highlights the need for effective prevention and treatment strategies in this group of patients. However, current treatment guidelines are based on very little evidence.10

 

Current management of VTE in paediatric patients

So far, there is only one anticoagulant, dalteparin, that was FDA-approved for the reduction of VTE recurrence in paediatric patients aged one month and older in May 2019.11 Current treatment guidelines are largely based on evidence obtained from adult studies, smaller dose-finding and observational studies in children, and expert opinion.12 Management of paediatric VTE usually includes unfractionated heparin, low molecular weight heparin and oral vitamin K antagonists (VKAs).13 The standard practice in paediatric VTE is to monitor anticoagulant therapy within target therapeutic ranges, extrapolated from studies in adults.14

 

However, VKAs and heparins have been associated with various disadvantages in children, including challenges with intravenous or subcutaneous injections, and frequent blood sampling for laboratory monitoring.12,15 In addition, major differences between adults and children in the epidemiology and pathophysiology of VTE, the physiology of the haemostatic system and the impact of this on the pharmacology of antithrombotic agents highlight the need for specific evidence-based guidelines for the prevention and treatment of VTE in children.7

 

Challenges of conducting clinical trials in children with VTE

The lack of evidence-based treatment guidelines in paediatric VTE is due to limited data obtained from clinical trials of anticoagulants in children with VTE. Planning and conducting clinical trials in this particular patient population is challenging because of the low incidence of paediatric VTE and the correspondingly low recruitment rate.7,12 In addition, the different underlying conditions in paediatric VTE may complicate studies due to significant variations in bleeding risk factors, vascular access and concurrent medication.7 Study variables such as diagnostic modalities and treatment outcomes are also affected by the heterogenous nature of VTE in children. Paediatric VTE includes a wide range of events in different age groups, with different underlying pathophysiology, natural history and complications. Another challenge is the developing physiology of haemostasis in children. Developmental, age-related changes of the haemostatic system affect the pharmacology of anticoagulant agents, thus impacting on dosing, monitoring and adverse event rates.

 

Only a limited number of randomized clinical trials (RCTs) have been conducted in children, none of which have substantially increased the level of evidence for guidelines.7 There are no completed RCTs that enrolled >200 children, three RCTs closed early due to slow recruitment, and one was not powered for efficacy (Table 2).

TA VTE paediatric diagram

Table 2: Failed/uncompleted randomized trials of anticoagulation in children with VTE7

Thus, it is important to consider the above-mentioned unique aspects of paediatric patients with VTE when designing and conducting clinical studies to provide evidence-based treatment guidelines for this specific patient population.

 

Summary

Although VTE is increasingly recognized in paediatric practice, management of VTE in children is mainly based on extrapolation from studies in adults. The differences in VTE between paediatric and adult patients, including differences in epidemiology, pathophysiology and the haemostatic system, highlight the need for specific evidence-based guidelines for the prevention and treatment of VTE in children. Therefore, it is essential to improve the design and conduct of clinical studies that address the pharmacokinetics/ pharmacodynamics, efficacy and safety of antithrombotic treatments, in this particularly vulnerable group of patients.

 

Adverse clinical outcomes following VTE in children

Paediatric VTE has been associated with a number of adverse clinical outcomes, including mortality, recurrent thrombosis and post-thrombotic syndrome.16 In a Canadian registry, mortality directly attributable to VTE occurred in 2.2% of children with VTE (Figure 2).16 All of the children who died as result of thrombosis had central-venous-catheter-associated VTE. Recurrent thrombosis and post-thrombotic syndrome were reported in 8.1% and 12.4% of patients, respectively.

TA VTE paediatric diagram

Figure 2: VTE-related morbidity and mortality in 405 children with VTE16

Limitations of heparin and VKAs in the treatment of paediatric VTE

Current standard of care in the management of VTE in children has been associated with several disadvantages (Figure 3).

 
TA VTE paediatric diagram

Figure 3: Limitations of heparins and vitamin K antagonists in the treatment of paediatric VTE12,15

References
  • Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016;41:3–14. Return to content
  • Andrew M, David M, Adams M et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83:1251–1257. Return to content
  • van Ommen CH, Heijboer H, Büller HR et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001;139:676–681. Return to content
  • Schneppenheim R, Greiner J. Thrombosis in infants and children. Hematology Am Soc Hematol Educ Program 2006: doi:10.1182/asheducation-2006.1.86:86–96. Return to content
  • Mahajerin A, Croteau SE. Epidemiology and risk assessment of pediatric venous thromboembolism. Front Pediatr 2017;5:68. Return to content
  • Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009;124:1001–1008. Return to content
  • Monagle P. Slow progress. How do we shift the paradigm of thinking in pediatric thrombosis and anticoagulation? Thromb Res 2019;173:186–190. Return to content
  • Radulescu VC. Management of venous thrombosis in the pediatric patient. Pediatric Health, Medicine and Therapeutics 2015;6:111–119. Return to content
  • Giordano P, Grassi M, Saracco P et al. Paediatric venous thromboembolism: a report from the Italian Registry of Thrombosis in Children (RITI). Blood Transfus 2018;16:363–370. Return to content
  • Monagle P, Cuello CA, Augustine C et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Advances 2018;2:3292–3316. Return to content
  • FDA. FDA approves first anticoagulant (blood thinner) for pediatric patients to treat potentially life-threatening blood clots. 2019. Return to content
  • Goldenberg NA, Takemoto CM, Yee DL et al. Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities. Blood 2015;126:2541–2547. Return to content
  • Chalmers E, Ganesen V, Liesner R et al. Guideline on the investigation, management and prevention of venous thrombosis in children. Br J Haematol 2011;154:196-207. Return to content
  • Malec L, Young G. Treatment of venous thromboembolism in pediatric patients. Front Pediatr 2017;5:26. Return to content
  • Newall F, Branchford B, Male C. Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues. J Thromb Haemost 2018;16:196–208. Return to content
  • Monagle P, Adams M, Mahoney M et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000;47:763–766. Return to content

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