Post thrombotic syndrome following deep vein thrombosis in paediatric patients

Abstract

Background

Although well characterised in adults, less is known about post-thrombotic syndrome in children. In this review, current knowledge regarding paediatric post-thrombotic syndrome is summarised, with particular emphasis on pathophysiology, aetiology, diagnosis and management.

Methods

A Medline literature review was performed using search terms ‘post thrombotic syndrome’, ‘post phlebitic syndrome’, paediatric and children. Relevant articles were identified and included for summation analysis.

Results

The incident of paediatric venous thromboembolism is rising. Deep vein thrombosis can cause venous hypertension through a combination of venous reflux, venous obstruction and impairment of the calf muscle pump, leading to development of post-thrombotic syndrome. In children, this is more likely to occur if deep vein thrombosis diagnosis and treatment are delayed, if a higher number of vessels are involved, and if factors such as D-dimer are elevated at diagnosis and throughout treatment. Post-thrombotic syndrome occurs in about 26% of paediatric deep vein thrombosis, though the results of individual studies vary widely. A number of tools exist to diagnose paediatric post-thrombotic syndrome, including the modified Villalta scale and Manco-Johnson instrument. Once post-thrombotic syndrome develops, the mainstay of treatment remains supportive, with little evidence of benefit from pharmacological measures.

Conclusion

Surgical or interventional treatment is not advised except in exceptional cirumstances, due to variable prognosis of PTS in paediatric populations with rising incidence of paediatric venous thromboembolism, it follows that the prevalence of post-thrombotic syndrome in children may also increase. Evidence-based venous thromboembolism prevention strategies need to be implemented for prevention of deep vein thrombosis, but when it does occur, deep vein thrombosis requires prompt and effective treatment to prevent post-thrombotic syndrome. Optimum treatment strategies for post-thrombotic syndrome require further investigation.

Keywords

Deep vein thrombosis post-thrombotic syndrome

Introduction

Post-thrombotic syndrome (PTS) is a chronic venous insufficiency syndrome secondary to deep vein thrombosis (DVT) presenting with symptoms and signs in the upper or lower limb due to residual deep venous obstruction, valvular reflux or a combination of the two. Clinical features include pain, swelling, pigmentation, development of collaterals and varicosities, venous claudication and ulceration of the affected limb.^1,2 Although the exact number is uncertain, the incidence of DVT in hospitalised children is rising.^3–5 Therefore, it follows that the prevalence of childhood PTS may also increase. Paediatric PTS is a poorly researched entity and little published information is currently available. This narrative provides an overview of paediatric PTS and draws on a Medline search using the terms ‘post thrombotic syndrome’, ‘post phlebitic syndrome’, ‘paediatrics’ and ‘children’, defining the paediatric population of patients aged 0–21. This age range has been selected to allow incorporation of trials from tertiary centres, where patients are classified as paediatric up to this age. This narrative encompasses PTS aetiology, pathophysiology, diagnosis, management, prevention and relevant areas for future research, summarising current published information.

Paediatric VTE: the prodrome of PTS

The incidence of DVT amongst children aged 1 month to 18 years has been reported at 1 per 100,000 in a Canadian registry.⁶ A United States national study, quoted a DVT prevalence of 4 per 1000 amongst 1- to 17-year-old children discharged from hospital following an admission of at least four days.⁵ The incidence of paediatric DVT in the under 17 year olds appears to be rising with reported incidence increasing from 3–4 per 100,000 hospital admissions in 1992–1994 to 9–280 per 100,000 in 2005–2009.^3–5 This likely reflects increased central venous catheter use, prolonged survival of critically ill children, improved imaging, alongside an increased index of suspicion and subsequent diagnosis.^3,4,7,8 Paediatric venous thromboembolism displays a bimodal age distribution, peaking in infants and adolescents,^6,8–10 with equal sex distribution.^6,11 Large national paediatric cohort studies in the USA have not shown consistent patterns in venous thromboembolism prevalence amongst different ethnic groups.^9,10 There is no direct evidence as to the effect of puberty on venous thromboembolism; however, the adolescent peak may represent a rise in incidence towards adult levels, possibly secondary to hormonal changes during puberty.¹²

Paediatric venous thromboemboli are mostly DVTs (87%), with the rest being pulmonary emboli or a combination of the two.¹³ Amongst the children with DVT, lower limbs appear to be more frequently affected than the upper limbs with rates of 56% and 44% respectively.¹⁴ Furthermore, lower limb DVT appears to be on the rise, while upper limb DVT incidence may be falling.⁴

Paediatric venous thromboemboli are usually provoked, with risk factors present in 76–98% of cases.^6,10,13,15 The most frequently reported provoking factors are listed in Table 1. A national registry found malignancy and cardiovascular disease to be the most commonly associated conditions with paediatric DVT and central venous catheter use was noted in a third of patients.⁶ Oral contraceptive use has also been shown to be a risk factor in the adolescent population.^16–18 Often, several risk factors co-exist, further increasing susceptibility.¹⁹ As the majority of venous thromboemboli in children are associated with transient provoking factors, thrombophilia screening is not generally recommended, but may be appropriate after idiopathic venous thromboembolism. ^3,6,7,14,20 This is consistent with adult guidelines, from the National Institute of Health and Care Excellence (NICE) as well as the British Society for Haematology.^21,22

Table 1.

DVT risk factors in children.

DVT risk factors in children	Frequency (%)
Anatomical risk factors	20¹⁴
Central venous catheter	32–33^6,14
Congenital heart disease	5–15^3,6,14
Congenital thrombophilia	18–33³
Hormone therapy/Oral contraceptive	5–28^3,6,14,16
Immobilisation	4–14^3,16
Infection	7–13^6,14
Malignancy	12–23^3,6,14
Obesity	3–12^6,16
Prior DVT	5–38^3,16
Surgery/trauma	5–15^3,6,14,16

A further group potentially at increased risk of DVT is that with anatomical risk factors such as May Thurner or Paget Schroetter syndromes.^14,17,18 This appears to be of more significance in the adolescent population, going into young adulthood.^14,17,18

Pathophysiology of PTS

Current understanding of PTS pathophysiology stems predominantly from adult studies. PTS develops through a combination of venous obstruction and reflux resulting in venous hypertension (Figure 1). Venous obstruction may arise from residual thrombi, inadequate recanalisation or venous tract scarring. Venous reflux results from valve and wall destruction both during acute DVT and during recanalisation, through inflammation and fibrosis. In adults, reduced mobility post-DVT also contributes to lower limb PTS via calf muscle pump impairment, further raising venous pressure,^2,23,24 although this may be of limited significance in the paediatric population.

Venous hypertension subsequently increases capillary filtration and inflammation, worsening leg swelling. This disturbs microcirculation, impairing dermal oxygen delivery, resulting in skin damage and poor wound healing. These processes explain the features of chronic venous insufficiency characteristic of PTS.²⁵

The above description applies largely to lower limb PTS pathophysiology. Upper limbs are relatively protected from PTS due to abundant collaterals, lack of reflux and a shorter hydrostatic column.²⁶ The lack of weight-bearing reduces physical symptom severity compared to lower limbs and limitations in activity can be seen without associated pain. The manifestations of upper limb PTS include increased limb circumference and upper body collateral formation as well as arm pain, particularly with aerobic exercise. Loss of venous access is also characteristic of upper limb PTS and poses particular problems in children requiring central venous catheters.^27–29

Incidence of PTS

Following DVT, reported paediatric PTS incidence from individual studies varies greatly with a meta-analysis calculating the weighted mean frequency at 26%,¹ but ranging between 0 and 77%.^30–46 This wide range of reported incidence may stem from application of different diagnostic tools, with results from a Canadian registry using a non-standardised PTS assessment tool reporting an incidence of 21%⁶ and a cross-sectional study finding an incidence of 63% using the modified Villalta scale.³⁵ Furthermore, the clinical significance of reported PTS should be taken into consideration. One study reported a 72% incidence of all PTS; however, the majority of this was mild disease (59%).¹⁴ Therefore, concurrent use of two widely used PTS diagnostic tools alongside a separate definition of clinically important PTS has been recommended to allow for standardised and reproducible studies in future.⁴⁷

Given the significance of central venous catheter use as a risk factor for DVT and their common siting in the upper limbs, it is important to consider the incidence of upper limb PTS.⁴⁸ One study found PTS in 49% of non-neonatal paediatric patients following upper limb DVT, again the majority were mild with only 2% developing moderate disease and no patients developing severe PTS.⁴⁹

Diagnosis of PTS

PTS is a clinical diagnosis, based on characteristic symptoms and signs in patients with a DVT history. As the acute pain and swelling associated with the initial DVT may take 3–6 months to resolve, it is recommended that PTS diagnosis be deferred until after this acute phase.^47,50

Many clinical tools exist to aid PTS diagnosis and measure its severity. Two that are widely used and validated in adults are the Villalta Scale⁵¹ and CEAP (Clinical, aEtiology, Anatomical, Pathophysiology) classification.⁵² The Villalta Scale has been modified for paediatric use (Table 2) and has been validated for use in 0–18-year-olds. Scoring a single point on this scale implies PTS diagnosis with score totals allowing severity grading. This enables both diagnosis and disease monitoring, incorporating clinical symptoms and signs.^35,47,53

Table 2.

Modified Villalta scale.¹

Symptoms ^a
Pain or abnormal use	1
Swelling	1
Signs
Increase limb circumference^b	1
Change in skin colour	1
Pitting oedema	1
Venous collaterals on skin	1
Pigmentation of skin	1
Tenderness on palpations of deep veins	1
Varicosities	1 moderate; 2 severe
Head swelling	1 moderate; 2 severe
Ulceration	9
Mild post-thrombotic syndrome	1–3
Moderate post-thrombotic syndrome	4–8
Severe post-thrombotic syndrome	9 or more

Reported by patient, parent, caregiver or proxy.

More than 3% compared with contralateral side.

The CEAP classification has been used alone in children and alongside the Wong-Baker pain scale, becoming the Manco-Johnson instrument (Table 3). This has been validated for use in patients aged 1–21 years, with a score of ≥1 diagnostic of PTS. The Manco-Johnson instrument offers an advantage over the modified Villalta Scale through its ability to measure functional limitation.^47,54

Table 3.

Manco-Johnson instrument.¹

Signs
Oedema^a	1
Dilated superficial collateral veins	1
Venous stasis dermatitis	1
Venous stasis ulcers	1
Symptoms
Chronic lower extremity pain
- limiting aerobic activities	0–5
- limiting activities of daily living	0–5
- at rest	0–5
Post-thrombotic syndrome absent	0
Any post-thrombotic syndrome present	1 or more
Physically and functionally significant post thrombotic syndrome	Signs ≥1 and symptoms ≥1

Less than 1 cm increase in mid-calf or mid-thigh circumference in the affected extremity compared with the contralateral extremity.

There is good correlation between the modified Villalta Scale and the Manco-Johnson instrument in assessing paediatric PTS and the use of both is advocated.^47,55 However, when these were compared with the adult Villalta Scale in children aged 12–18, significant discrepancy was identified with 66% of children diagnosed as having PTS using the modified Villalta Scale, but only 11% when using the adult version.⁵⁵ This raises questions over when adult scales become appropriate in paediatric practice.

Diagnosis and monitoring of upper limb PTS is more challenging compared with lower limbs as the latter has been better studied. However, the Manco-Johnson instrument has been validated for use in upper limb PTS.²⁹

Risk factors for paediatric PTS

Following a diagnosis of DVT, multiple predictors of PTS have been reported. In adults, well-described risk factors include extensive ileofemoral DVT, persistent symptoms >1 month from DVT diagnosis, obesity and increasing age.^50,56 A rise in PTS incidence has been shown with higher numbers of vessels involved and failure of thrombus resolution in children under 18 years of age.^14,35 However, these results may be biased by the high PTS incidence quoted in these studies and were not replicated in other studies.⁵⁷ A raised BMI has also been suggested as a predisposing risk factor for PTS in this age group.¹⁴

Biomarkers of coagulation activity or inflammation have been shown to predict PTS development.¹ Elevated levels of Factor VIII and/or D-dimer either at presentation or after completion of anticoagulation are associated with an increased risk of PTS in patients aged 0–20 (OR 6.1: 95% CI 2.1–17.7 and 4.7: 95% CI 1.8–12.6).^1,41 Elevated Factor VIII in combination with elevated D-dimer at presentation increased the risk of adverse outcome from 50% to 86%.¹ A retrospective study found that elevated fibrinogen levels at the time of diagnosis were predictive of PTS in a population of paediatric cardiac surgery patients, where most studied children were under a year of age.⁵⁸ The presence of thrombophilia does not affect PTS risk.^14,57

Risk factors for PTS specific to central venous catheter use include radiologically confirmed central venous catheter-related DVT and increased number of catheters used. Central venous catheter occlusion without a definite diagnosis of DVT was also strongly predictive of future PTS development and it was felt that these occlusions likely represented asymptomatic DVTs. However, these data stem from a study including participants up to the age of 26 and may not be fully applicable to paediatric populations.⁵⁹ Cardiac catheterisation in under 18-year-olds through the femoral vein without a history of symptomatic DVT has also been associated with an increased risk of PTS with rates reported at 64.5%, although only 11.3% had functionally significant disease.⁶⁰

Studies with longer duration of follow-up tend to report a higher incidence of PTS, highlighting the potential long lag time between initial DVT and consequent PTS.^14,35 Due to this lag time, it would be necessary to develop studies with long-term follow-up into adulthood to truly calculate the incidence of PTS following paediatric DVT.

Impact of PTS on children

Children under 18 with significant PTS have a worsened quality of life compared to children with mild or no PTS, particularly in the psychosocial, social and physical domains of the Paediatric Quality of Life Inventory.⁶¹ Data on cost of childhood PTS is currently unavailable, but in adults per patient annual cost is estimated at US$ 3817 for severe PTS.⁶² In children, any cost analysis should account for the long timespan children with PTS are expected to live compared to adults. Furthermore, adult PTS cost is compounded by work absenteeism,⁶² which may translate to poor school attendance in children and will continue to have economic implications as the child reaches working age.

Preventative strategies against PTS in children

The deleterious impact of PTS on quality of life makes its prevention paramount. Clearly, the primary focus should be on prevention of initial thrombosis. In adults, risk assessment of both surgical and medical inpatients and subsequent thromboprophylaxis is strongly advocated.^21,63,64 Thromboprophylaxis of high-risk paediatric patients may reduce incidence of venous thromboembolism and subsequent PTS.¹³ Paediatric venous thromboembolism risk assessment tools have been developed and validated, allowing identification of high risk children but their utility as a basis for intervention remains to be fully studied.^13,65,66 Of note, mechanical thromboprophylaxis is available and is currently used in paediatric orthopaedics, particularly in adolescent patients, where use of sequential compression devices was frequently reported. However, no data as to its efficacy in children were found.⁶⁷ As many paediatric thromboses are associated with central venous catheters, paediatric American College of Chest Physicians (ACCP) guidelines 2012 recommend low-dose intravenous heparin infusion through central venous devices and umbilical arterial catheters in neonates to help maintain patency and reduce associated thromboses. Thromboprophylaxis with heparin or vitamin K analogues is also recommended in children in whom central venous cathers are used for haemodialysis or home total parenteral nutrition, but not for children with medium-to-long term catheters for other purposes.⁶⁸ Furthermore, central venous catheter site appears to determine venous thromboembolism risk, therefore preferentially siting venous catheters in brachial or jugular over subclavian and femoral veins may be protective.⁴⁸

If a child develops DVT, then early recognition with initiation of anticoagulation and consideration of thrombolysis may reduce PTS incidence. A paediatric retrospective single-centre study, looking at under 15 year olds, showed that delaying initiation of anticoagulation by over 48 h after DVT diagnosis increased PTS risk.⁵⁷ This could be due to prevention of thrombus extension with successful anticoagulation, allowing for high rates of clot resolution, which has been found to be protective against PTS in under 18-year-olds.^35,69 Thrombolysis appears superior to anticoagulation in preventing PTS in children at high risk, with PTS rates of 22% and 77%, respectively, although this was in a small and retrospective study including patients aged 12 months to 21 years, where the majority of thrombolysed patients received systemic thrombolytic therapy.³² A prospective paediatric cohort study including children up to the age of 19, evaluated catheter-directed thrombolysis, reporting successful thrombolysis in 94% with subsequent clinically significant PTS developing in 13%.⁷⁰ While the high clot resolution rates are promising,³⁵ the lack of control group and small sample size call for cautious interpretation.⁷⁰ However, any reduction in PTS must be balanced against the increased risk of bleeding from thrombolysis, estimates of which vary between studies.⁷¹ A study of thrombolysis in young children (majority under 1 year of age) following cardiac surgery, which did not differentiate between children receiving systemic and catheter-directed thrombolysis, demonstrated major bleeding complications in 40%.⁵⁸ Catheter-directed thrombolysis theoretically carries reduced risk of bleeding complications, and one study investigating catheter-directed thrombolysis in older children up to the age of 21 reported no instances of peri-procedural haemorrhage.⁷⁰

The 2012 ACCP paediatric venous thromboembolism (VTE) guidelines advise that thrombolysis therapy be used only for life- or limb-threatening thrombosis and that if it is used that either systemic thrombolysis or catheter-directed thrombolysis could be used depending on institutional experience and technical feasibility.⁶⁸ Since this guideline was written, more data around catheter-directed thrombolysis in adults have been reported and demonstrated a reduction in PTS with reduced bleeding risk compared to systemic thrombolysis.⁷² This resulted in NICE 2014 guideline considering catheter-directed thrombolysis (but not systemic thrombolysis) in adults with acute ileofemoral vein thrombosis, less than 14 days duration, with life expectancy of at least one year, good functional status and at low risk of bleeding.²¹ However, the recent adult ACCP guidelines 2016 state that because the risk–benefit of catheter-directed thrombolysis remains uncertain, anticoagulation alone (rather than catheter-directed thrombolysis) in these circumstances is still considered reasonable.⁷³ The difficulty of venous access and calibre of vessels may potentially increase the complications of catheter-directed thrombolysis in children and its feasibility will be determined by the expertise available.⁷⁴ Ultimately, clinical trials are required to explore the benefits and risks of catheter-directed thrombolysis for acute extensive ileofemoval DVT in children, and meanwhile, prompt discussion with a multidisciplinary team that includes a paediatric haematologist and a vascular surgeon is pertinent to allow assessment of suitability for thrombolysis.

Evidence regarding elastic compressions stocking use in PTS prevention in paediatric populations is currently lacking, and disputed in adults. A Cochrane review in 2004 concluded that use of elastic compressions stockings after DVT reduced the risk of any PTS (OR 0.31 ; 95% CI 0.20–0.48) and severe PTS (OR 0.39; 95% 0.20–0.76),⁷⁵ and ACCP guidelines then advised that patients with a symptomatic acute proximal DVT wear elastic compressions stockings (pressure gradient 30–40 mmHg) for at least two years.⁷⁶ However, a recent, large, multicentre, randomised, double-blind placebo controlled trial showed no difference between active and placebo stockings, worn for two years, in reducing the incidence of PTS after a first proximal DVT (hazard ratio 1.0 95% CI 0.81–1.24)⁷⁷ and neither NICE nor ACCP guidelines currently recommend elastic compression stocking use to prevent PTS following DVT in adults.^21,73

Management of paediatric PTS

Once PTS is established, treatment options are largely limited to supportive measures, of which compression is the mainstay.⁷ In adult PTS, elastic compressions stockings improve haemodynamic performance and symptoms.⁷⁸ Similarly, a case report of a child diagnosed with PTS at six years of age documents improved functional status with elastic compressions stocking use, highlighting the need for well-designed, larger studies to validate this paediatric treatment option.⁷⁹ Compliance with elastic compressions stockings is problematic due to aesthetic concerns, discomfort and difficulty putting them on.⁸⁰ This may represent particular difficulty in children who may be reluctant to show visible signs of illness, which may invite peer criticism, and for whom obtaining appropriately sized, growth-adjusted garments poses an additional compliance barrier.²⁶ In adult patients with severe PTS, intermittent pneumatic compression has been reported to further improve symptoms, but evidence for this within paediatrics is lacking.^81,82

Structured exercise can improve calf muscle pump function in adults.⁸³ A randomised controlled trial of 39 adults demonstrated that an exercise training programme improved PTS severity and quality of life.⁸⁴ This may suggest a useful treatment strategy which could be further explored in older children.

While pharmacological therapy with ‘venoactive’ agents has been trialled in adult PTS, there is limited evidence of benefit and safety, with paediatric data lacking.^85,86

In adults, endovascular and surgical interventions may be used to reduce valvular reflux.⁸⁶ Endovenous stenting to relieve chronic venous obstruction is a rapidly developing intervention in adults and may be of benefit in treating PTS symptoms.⁸⁷ Endovenous stenting of stenosed or occluded deep veins has been used safely and effectively in children with congenital heart disease as well as adolescents with acute DVT.^18,88 However, long-term data on safety and efficacy, as well applicability to PTS in children, are currently unavailable. We would not routinely recommend surgical intervention in paediatric patients, particularly due to fluctuating symptom severity in children, and the distinct possibility of improvement over time. Decisions should be made on a case-by-case basis.^57,89

In both adults and children, it is important to explain the chronicity of the condition, and the remitting and relapsing nature of symptoms, with around a third of paediatric patients experiencing fluctuating symptom severity over time.⁵⁷

Limitations

This narrative has several limitations. The limited amount of paediatric research currently available resulted in stringent quality assessment methods not being applied and strict inclusion/exclusion criteria were not clearly defined, allowing for a broader incorporation of available research. The limited amount of paediatric research has also necessitated extrapolations from adult studies. The evidence assessed stems only from literature published in English, therefore potentially introducing bias.

Unanswered questions and future research

Large population-based studies are required to assess the current true incidence of DVT in paediatric populations to enable for robust recommendations around prophylaxis. Furthermore, prospective long-term paediatric studies are required with well-defined PTS inclusion criteria, interval duplex ultrasonography, and regular clinical and quality-of-life assessment to provide reliable data on PTS morbidity and overall prognosis. Observational studies are needed to guide treatment choices in children with PTS, as well as to pave the way towards randomised controlled trials, providing a basis for evidence-based guidelines for treatment of paediatric PTS.

Conclusion

The increasing DVT incidence in paediatric admissions implies that childhood PTS prevalence may rise. Although characteristics of high-risk patients have been defined, clear and evidence-based guidelines are required to reduce paediatric DVTs associated with hospital admissions. Where DVT does occur, early recognition and prompt and effective treatment are paramount in reducing PTS risk. Further research is required to deliver robust evidence guiding appropriate treatment strategies for PTS, with validated tools permitting severity scoring to assess efficacy of adopted strategies.

Footnotes

Authors’ contribution

KV researched literature and reviewed articles for inclusion. KV wrote the first draft of the review with support from MQ. All authors reviewed and edited the manuscript and approved the final version.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MQ is grateful for the funding received from the Joint Royal College of Surgeons/Dunhill Medical Trust Fellowship, the Circulation Foundation, the Graham-Dixon Charitable Trust, Mason Medical Research Trust and the Rosetrees Trust.

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