Elsevier

Thrombosis Research

Volume 173, January 2019, Pages 186-190
Thrombosis Research

Full Length Article
Slow progress. How do we shift the paradigm of thinking in pediatric thrombosis and anticoagulation?

https://doi.org/10.1016/j.thromres.2018.07.016Get rights and content

Highlights

  • Almost 25 years after Maureen Andrew led a Canadian team that described paediatric VTE we have arguably made little progress.

  • Despite being “an epidemic of tertiary paediatrics”, VTE remains rare in children.

  • We should adopt a rare disease mindset, establishing registries with highly detailed comparisons of specific types of VTE in specific age groups.

  • We need to address the question of natural history of VTE in neonates, children and adolescents, as it may be different in each age group.

  • Alternative methodologies; cohort, cross sectional, long term follow up, will provide better diagnostic and treatment related information.

Abstract

Since Maureen Andrew began systematically describing thrombosis in children in 1994, there has been surprisingly slow process in advancing our knowledge in terms of diagnosis, prevention and treatment of thrombosis in children. There are a variety of reasons for this slow progress. Overwhelmingly the low incidence of thrombosis in children has been a major barrier. Second, the developmental, age related, changes in haemostasis mean that the physiology of haemostasis in children, and the interaction of the haemostatic system with anticoagulant drugs is constantly changing. This presents further challenges in identifying the risk benefit ratio of therapies. In addition, the failure to adequately understand the subtleties of pathogenesis of the variety of thrombotic syndromes, and the failure to know the natural history of many types of thrombosis are also significant problems. We continue to try and solve these problems by extrapolation, not just of adult based data, but of methodologies for research founded in the adult paradigm. If we are truly going to improve our understanding of thrombosis in children and improve our ability to prevent and adequately treat thrombosis in this population, then we need multiple paradigm shifts; First, in the way we think about thrombosis and anticoagulation in children. Second in the way we design and conduct research studies to provide evidence on which to base the care of children suffering from thrombosis in the future.

Introduction

In 1994, Maureen Andrew led a Canadian consortium that published the first major systematic description of venous thromboembolic disease (VTE) in children [1]. The paper heralded what would be known as the new epidemic of tertiary pediatrics [2]. Despite this, almost 25 years later, one could argue that we have made little progress. Certainly in terms of the levels of evidence for treatment guidelines, there has been little advance from the first American College of Chest Physicians (ACCP) guidelines for treatment of venous thromboembolism (VTE) in children published in 1995, progressing through to the most recent published in 2012 [[3], [4], [5], [6], [7], [8]]. Across that time there have been limited numbers of randomised clinical trials of anticoagulants in children, both for primary prophylaxis and treatment, and yet none of these trials have substantially increased the level of evidence for any guideline (See Table 1) [[9], [10], [11], [12], [13], [14]]. Of note, there are no completed RCTs of an anticoagulant treatment for VTE in children that have ever enrolled >200 children, and almost all completed RCTs closed early due to slow recruitment [10]. The Kidsdott study comparing duration of anticoagulation in children is ongoing and has enrolled over 300 children, but has been running for over 10 years [14]. There are a number of current trials of Direct Oral Anticoagulants (DOACS), but these shall be specifically discussed subsequently.

So why has this been so difficult? There are a number of reasons, and one could argue that each reason requires a paradigm shift to be overcome.

Section snippets

Incidence of VTE

The incidence of VTE in children at a population level is very low, reported to be 0.07–0.14 per 10,000 children [1,15,16]. However, in hospitalised children the rate is increased 100–1000 times to at least 58 per 10,000 admissions [17]. Thus, despite some exceptions, VTE should be considered a disease of sick children. The commonest age groups for VTE are neonates and teenagers, and this reflects the pattern of associated underlying diseases and interventions. Greater than 90% of pediatric VTE

Natural history of VTE

The natural history of VTE in children remains unclear in many circumstances. The reported VTE mortality from registry data is approximately 3%, in the context of approximately 16% of children dying from their underlying illness [1]. The recurrence risk is variably reported up to 10–15%. Reports of post thrombotic syndrome (PTS) vary from 10 to 60% depending on the tools used to assess for PTS, and there remains great controversy as to the clinical implications of PTS in many children [22].

In

Diagnosis of VTE

If we make the first two paradigm shifts, that is we consider each type of VTE in each different age group as a separate rare disease that needs individual consideration in terms of pathogenesis, potential outcomes and treatments, and we agree that we need to understand the natural history of symptomatic and asymptomatic VTE in that context, then clearly accurate diagnosis and classification of VTE becomes paramount. This is another area that therefore requires a paradigm shift. The ongoing use

Treatment of VTE

There are currently no anticoagulant drugs approved for use in children, with very little specific research in children. Much of the evidence for treatment is extrapolated from adult practice, despite the major differences between adults and children in the epidemiology and pathophysiology of thrombosis, the physiology of the coagulation system and the impact of this on the pharmacology of antithrombotic agents [8].

Developmental haemostasis, a concept which was again pioneered by the work of

Conflict of interest statement

I have no financial conflicts to declare. I am on steering committee of industry sponsored trials of Rivaroxaban and apixaban.

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