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

Figure 1.

The development of PTS from DVT.

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.

References

Goldenberg

Donadini

Kahn

et al.

Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica 2010; 95: 1952–1959.

Wittens

Davies

Bækgaard

et al.

Editor’s choice – management of chronic venous disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2015; 49: 678–737.

Sandoval

Sheehan

Stonerock

et al.

Incidence, risk factors, and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk. J Vasc Surg 2008; 47: 837–843.

Boulet

Grosse

Thornburg

et al.

Trends in venous thromboembolism-related hospitalizations, 1994–2009. Pediatrics 2012; 130: e812–e820.

Nobuhara

et al.

Determination of risk factors for deep venous thrombosis in hospitalized children. J Pediatr Surg 2008; 43: 1095–1099.

Andrew

David

Adams

et al.

Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83: 1251–1257.

Chan

AKC

Monagle

. Updates in thrombosis in pediatrics: where are we after 20 years? Hematol Am Soc Hematol Educ Program 2012; 2012: 439–443.

Raffini

Huang

Y-S

et al.

Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124: 1001–1008.

Stein

Kayali

Olson

. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr 2004; 145: 563–565.

10.

Setty

O’Brien

Kerlin

. Pediatric venous thromboembolism in the United States: a tertiary care complication of chronic diseases. Pediatr Blood Cancer 2012; 59: 258–264.

11.

Wright

Watts

. Venous thromboembolism in pediatric patients: epidemiologic data from a pediatric tertiary care center in Alabama. J Pediatr Hematol Oncol 2011; 33: 261–264.

12.

Van Arendonk

Schneider

Haider

et al.

Venous thromboembolism after trauma: when do children become adults?

JAMA Surg 2013; 148: 1123–1130.

13.

Sharathkumar

Mahajerin

Heidt

et al.

Risk-prediction tool for identifying hospitalized children with a predisposition for development of venous thromboembolism: Peds-Clot clinical Decision Rule. J Thromb Haemost 2012; 10: 1326–1334.

14.

Kumar

Rodriguez

Matsumoto

JMS

et al.

Prevalence and risk factors for post thrombotic syndrome after deep vein thrombosis in children: a cohort study. Thromb Res 2015; 135: 347–351.

15.

Van Ommen

Heijboer

Büller

et al.

Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001; 139: 676–681.

16.

Gaballah

Shi

Kukreja

et al.

Endovascular Thrombolysis in the management of iliofemoral thrombosis in children: a multi-institutional experience. J Vasc Interv Radiol 2016; 27: 524–530.

17.

Ishola

Kirk

Guffey

et al.

Risk factors and co-morbidities in adolescent thromboembolism are different than those in younger children. Thromb Res 2016; 141: 178–182.

18.

Raffini

Raybagkar

Cahill

et al.

May-Thurner syndrome (iliac vein compression) and thrombosis in adolescents. Pediatr Blood Cancer 2006; 47: 834–838.

19.

Takemoto

Sohi

Desai

et al.

Hospital-associated venous thromboembolism in children: incidence and clinical characteristics. J Pediatr 2014; 164: 332–338.

20.

Junker

Koch

H-G

Auberger

et al.

Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol 1999; 19: 2568–2572.

21.

National Institute for Health and Care Excellence. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. NICE Guideline 2015. CG144.

22.

Baglin

Gray

Greaves

et al.

Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149: 209–220.

23.

Kahn

Ginsberg

. The post-thrombotic syndrome: current knowledge, controversies, and directions for future research. Blood Rev 2002; 16: 155–165.

24.

De Wolf

MAF

Wittens

CHA

Kahn

. Incidence and risk factors of the post-thrombotic syndrome. Phlebology 2012; 27: 85–94.

25.

Reich-Schupke

Altmeyer

Stücker

. What do we know of post-thrombotic syndrome? Current status of post-thrombotic syndrome in adults. J Dtsch Dermatol Ges 2010; 8: 81–87.

26.

Spentzouris

Scriven

et al.

Pediatric venous thromboembolism in relation to adults. J Vasc Surg 2012; 55: 1785–1793.

27.

Boulden

Crary

et al.

Determination of pediatric norms for assessment of upper venous system post-thrombotic syndrome. J Thromb Haemost 2007; 5: 1077–1079.

28.

Revel-Vilk

Brandão

Journeycake

et al.

Standardization of post-thrombotic syndrome definition and outcome assessment following upper venous system thrombosis in pediatric practice. J Thromb Haemost 2012; 10: 2182–2185.

29.

Goldenberg

Pounder

et al.

Validation of upper extremity post-thrombotic syndrome outcome measurement in children. J Pediatr 2010; 157: 852–855.

30.

Sirachainan

Chuansumrit

Angchaisuksiri

et al.

Venous thromboembolism in Thai children. Pediatr Hematol Oncol 2007; 24: 245–256.

31.

Athale

Nagel

et al.

Thromboembolism in children with lymphoma. Thromb Res 2008; 122: 459–465.

32.

Goldenberg

Durham

et al.

A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children. Blood 2007; 110: 45–53.

33.

Kuhle

Spavor

Massicotte

et al.

Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost 2008; 6: 589–594.

34.

Sharathkumar

Pipe

. Post-thrombotic syndrome in children: a single center experience. J Pediatr Hematol Oncol 2008; 30: 261–266.

35.

Kuhle

Koloshuk

Marzinotto

et al.

A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res 2003; 111: 227–233.

36.

Lee

ACW

et al.

Symptomatic venous thromboembolism in Hong Kong Chinese children. Hong Kong Med J 2003; 9: 259–262.

37.

Nguyen

Laberge

et al.

Spontaneous deep vein thrombosis in childhood and adolescence. J Pediatr Surg 1986; 21: 640–643.

38.

Kreuz

Stoll

Junker

et al.

Familial elevated factor VIII in children with symptomatic venous thrombosis and post-thrombotic syndrome: results of a multicenter study. Arterioscler Thromb Vasc Biol 2006; 26: 1901–1906.

39.

Newall

Wallace

Crock

et al.

Venous thromboembolic disease: a single-centre case series study. J Paediatr Child Health 2006; 42: 803–807.

40.

Schobess

Düring

Bidlingmaier

et al.

Long-term safety and efficacy data on childhood venous thrombosis treated with a low molecular weight heparin: an open-label pilot study of once-daily versus twice-daily enoxaparin administration. Haematologica 2006; 91: 1701–1704.

41.

Goldenberg

Knapp-Clevenger

Manco-Johnson

. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. N Engl J Med 2004; 351: 1081–1088.

42.

Van Ommen

Heijboer

Van Den Dool

et al.

Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost 2003; 1: 2516–2522.

43.

Gurgey

Aslan

. Outcome of noncatheter-related thrombosis in children: influence of underlying or coexisting factors. J Pediatr Hematol Oncol 2001; 23: 159–164.

44.

Häusler

Hübner

et al.

Long term complications of inferior vena cava thrombosis. Arch Dis Child 2001; 85: 228–233.

45.

Monagle

Adams

Mahoney

et al.

Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000; 47: 763–766.

46.

Revel-Vilk

Menahem

et al.

Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors is associated with a history of obstruction. Pediatr Blood Cancer 2010; 55: 153–156.

47.

Goldenberg

Brandao

Journeycake

et al.

Definition of post-thrombotic syndrome following lower extremity deep venous thrombosis and standardization of outcome measurement in pediatric clinical investigations. J Thromb Haemost 2012; 10: 477–480.

48.

Male

Julian

Massicotte

et al.

Significant association with location of central venous line placement and risk of venous thrombosis in children. Thromb Haemost 2005; 94: 516–521.

49.

Avila

Duan

Cipolla

et al.

Postthrombotic syndrome following upper extremity deep vein thrombosis in children. Blood 2014; 124: 1166–1173.

50.

Kahn

. How I treat postthrombotic syndrome. Blood 2009; 114: 4624–4631.

51.

Kahn

. Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome. J Thromb Haemost 2009; 7: 884–888.

52.

Eklöf

Rutherford

Bergan

et al.

Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–1252.

53.

Kumar

Rodriguez

Matsumoto

JMS

et al.

Development and initial validation of a questionnaire to diagnose the presence and severity of post-thrombotic syndrome in children. Pediatr Blood Cancer 2012; 58: 643–644.

54.

Manco-Johnson

Knapp-Clevenger

Miller

BI HT

. Post-thrombotic syndrome (PTS) in children: validation of a new pediatric outcome instrument and results in a comprehensive cohort of children with extremity deep vein thrombosis (DVT). Blood 2003; 102: 553A–553A.

55.

Raffini

Davenport

et al.

Comparison of 3 postthrombotic syndrome assessment scales demonstrates significant variability in children and adolescents with deep vein thrombosis. J Pediatr Hematol Oncol 2015; 37: 611–615.

56.

Prandoni

Kahn

. Post-thrombotic syndrome: prevalence, prognostication and need for progress. Br J Haematol 2009; 145: 286–295.

57.

Creary

Heiny

Croop

et al.

Clinical course of postthrombotic syndrome in children with history of venous thromboembolism. Blood Coagul Fibrinolysis 2012; 23: 39–44.

58.

Manlhiot

Brandão

Schwartz

et al.

Management and outcomes of patients with occlusive thrombosis after pediatric cardiac surgery. J Pediatr 2016; 169: 146–153.

59.

Polen

Weintraub

Stoffer

et al.

Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors: a prospective cohort study. Pediatr Blood Cancer 2015; 62: 285–290.

60.

Luceri

Tala

Weismann

et al.

Prevalence of post-thrombotic syndrome after cardiac catheterization. Pediatr Blood Cancer 2015; 62: 1222–1227.

61.

Kumar

Rodriguez

Matsumoto

JMS

et al.

Health-related quality of life in children and young adults with post-thrombotic syndrome: results from a cross-sectional study. Pediatr Blood Cancer 2014; 61: 546–551.

62.

Prandoni

. Healthcare burden associated with the post-thrombotic syndrome and potential impact of the new oral anticoagulants. Eur J Haematol 2012; 88: 185–194.

63.

Geerts

Bergqvist

Pineo

et al.

Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 381S–453S.

64.

Alikhan

Bedenis

Cohen

. Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane database Syst Rev 2014; 5: CD003747–CD003747.

65.

Mahajerin

Webber

Morris

et al.

Development and implementation results of a Venous Thromboembolism Prophylaxis Guideline in a tertiary care pediatric hospital. Hosp Pediatr 2015; 5: 630–636.

66.

Yen

Van Arendonk

Streiff

et al.

Risk factors for venous thromboembolism in pediatric trauma patients and validation of a novel scoring system: the risk of clots in kids with trauma score. Pediatr Crit Care Med 2016; 17: 391–399.

67.

Sabharwal

Zhao

Passanante

. Venous thromboembolism in children: details of 46 cases based on a follow-up survey of POSNA members. J Pediatr Orthop 2013; 33: 768–774.

68.

Monagle

Chan

AKC

Goldenberg

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. Chest 2012; 141: e737S–e801S.

69.

Michieli

et al.

FondaKIDS II: long-term follow-up data of children receiving fondaparinux for treatment of venous thromboembolic events. Thromb Res 2014; 134: 643–647.

70.

Goldenberg

Branchford

Wang

et al.

Percutaneous mechanical and pharmacomechanical thrombolysis for occlusive deep vein thrombosis of the proximal limb in adolescent subjects: findings from an institution-based prospective inception cohort study of pediatric venous thromboembolism. J Vasc Interv Radiol 2011; 22: 121–132.

71.

Williams

. Thrombolysis in children. Br J Haematol 2010; 148): 26–36.

72.

Haig

Enden

Grøtta

et al.

Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Haematol 2016; 3: e64–e71.

73.

Kearon

Akl

Ornelas

et al.

Antithrombotic therapy for VTE disease. Chest 2016; 149: 315–352.

74.

Greene

Goldenberg

. Deep vein thrombosis: thrombolysis in the pediatric population. Semin Intervent Radiol 2012; 29: 36–43.

75.

Kolbach

Sandbrink

MWC

Hamulyak

et al.

Non-pharmaceutical measures for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev 2004; (1): CD004174–CD004174.

76.

Kearon

Akl

Comerota

et al.

Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e419S–e494S.

77.

Kahn

Shapiro

Wells

et al.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014; 383: 880–888.

78.

Lattimer

Azzam

Kalodiki

et al.

Compression stockings significantly improve hemodynamic performance in post-thrombotic syndrome irrespective of class or length. J Vasc Surg 2013; 58: 158–165.

79.

Biss

Kahr

WHA

Brandão

et al.

The use of elastic compression stockings for post-thrombotic syndrome in a child. Pediatr Blood Cancer 2009; 53: 462–463.

80.

Kahn

Shapiro

Ginsberg

. Compression stockings to prevent post-thrombotic syndrome – authors’ reply. Lancet 2014; 384: 130–131.

81.

O’Donnell

McRae

Kahn

et al.

Evaluation of a venous-return assist device to treat severe post-thrombotic syndrome (VENOPTS). A randomized controlled trial. Thromb Haemost 2008; 99: 623–629.

82.

Ginsberg

Magier

Mackinnon

et al.

Intermittent compression units for severe post-phlebitic syndrome: a randomized crossover study. CMAJ 1999; 160: 1303–1306.

83.

Padberg

Johnston

Sisto

. Structured exercise improves calf muscle pump function in chronic venous insufficiency: a randomized trial. J Vasc Surg 2004; 39: 79–87.

84.

Kahn

Shrier

Shapiro

et al.

Six-month exercise training program to treat post-thrombotic syndrome: a randomized controlled two-centre trial. CMAJ 2011; 183: 37–44.

85.

Pittler

Ernst

. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev 2012; 11: CD003230–CD003230.

86.

Baldwin

Moore

Rudarakanchana

et al.

Post-thrombotic syndrome: a clinical review. J Thromb Haemost 2013; 11: 795–805.

87.

Delis

Bjarnason

Wennberg

et al.

Successful iliac vein and inferior vena cava stenting ameliorates venous claudication and improves venous outflow, calf muscle pump function, and clinical status in post-thrombotic syndrome. Ann Surg 2007; 245: 130–139.

88.

Frazer

Ing

. Stenting of stenotic or occluded iliofemoral veins, superior and inferior vena cavae in children with congenital heart disease: acute results and intermediate follow up. Catheter Cardiovasc Interv 2009; 73: 181–188.

89.

Barnes

Newall

Monagle

. Post-thrombotic syndrome. Arch Dis Child 2002; 86: 212–214.