Do asymptomatic clots in children matter?

Thrombosis Research 189 (2020) 24–34

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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

Review Article

Do asymptomatic clots in children matter? b,c,d,⁎

Sophie Jones

a,b,c

, Paul Monagle

, Fiona Newall

a,b,c,d,e

T

a

Department of Paediatrics, The University of Melbourne, Australia Haematology Research Group, Murdoch Children's Research Institute, Melbourne, Australia Department of Clinical Haematology, The Royal Children's Hospital, Melbourne, Australia d Department of Nursing, The University of Melbourne, Australia e Department of Nursing Research, The Royal Children's Hospital, Melbourne, Australia b c

ARTICLE INFO

ABSTRACT

Keywords: Venous thromboembolism Asymptomatic Children Central venous catheter

Asymptomatic venous thrombosis is a common complication among hospitalised paediatric patients. Previous guidelines recommend the treatment of all asymptomatic venous thrombosis, even when the diagnosis is made incidentally or the risk factor is no longer present. Whether clinicians need to treat all asymptomatic thrombosis in children, given the likelihood of long-term sequelae, is unclear and there are significant risks associated with anticoagulation treatment. Asymptomatic thrombosis in children is most frequently associated with central venous catheters (CVCs). The incidence of asymptomatic CVC-related VTE is highest in cohorts of children with cancer, but also reported in neonates, children with congenital heart disease and critically ill children. There is significant variation in reported rates of CVC-related thrombosis among cohorts of children with different underlying diseases and of various ages. As asymptomatic thrombosis is often an incidental finding, rates of asymptomatic VTE in children are most likely underestimated. Evidence about the incidence, characteristics and long-term outcomes associated with asymptomatic thrombosis in children often lacks precision as data is presented collectively with symptomatic thrombosis. This review discusses the current evidence pertaining to the necessity for screening for asymptomatic thrombosis, the risk benefit ratio of treatment and the risk of long-term morbidity. To confidently determine the clinical significance of asymptomatic VTE in children, prospective studies with extended follow up are needed.

1. Introduction Within the literature there exist many reviews about the incidence of venous thromboembolism (VTE) in children, each considering aspects of incidence, diagnosis, risk factors and treatment. None have focused specifically on asymptomatic thrombosis. The incidental diagnosis of an asymptomatic venous thrombotic event (A-VTE) is however, common among hospitalised paediatric patients. By virtue of the diagnosis, asymptomatic VTE are more likely to be secondary, non-occlusive, occur in the upper venous system and be an incidental finding [1–3]. Most paediatric institutions treat all VTE diagnosed due to concerns about the acute and long-term risks associated with thrombosis [4]. The potential acute complications of VTE include extension, pulmonary embolism, loss of venous access or sepsis in children with central venous catheter (CVC)-related VTE, and in neonates with a right-to-left intra-cardiac shunt, paradoxical embolism or stroke [4,5]. Long-term outcomes include recurrence, loss of vascular access and post thrombotic syndrome (PTS) [6,7]. The majority of studies available

⁎

report outcomes for children with symptomatic and asymptomatic VTE together, hence the actual rate of acute and long-term morbidity for children with asymptomatic VTE is indistinguishable from children with symptomatic VTE [1,8]. Without specific outcome data for children with asymptomatic VTE, the risk benefit ratio of exposing sick children to anticoagulant therapy to treat an asymptomatic VTE is unknown. The American College of Chest Physicians (ACCP) guidelines from 2012 recommend that secondary asymptomatic VTE be treated for three months, even when the risk factor is no longer present [4]. The ACCP guidelines also do not advocate for routine screening for asymptomatic VTE [4]. The American Society of Haematology (ASH) guidelines published in 2018 also suggest against routine screening for asymptomatic CVC-related VTE but recommend either treatment or no treatment of an incidentally found asymptomatic CVC-related thrombosis [9]. The ASH Guidelines acknowledge that this is a conditional recommendation based on a low level of certainty in the evidence about the benefits of treatment [9]. This paper focuses on children diagnosed

Corresponding author at: Department of Clinical Haematology, The Royal Children's Hospital Melbourne, 50 Flemington Rd, Parkville, Victoria 3052, Australia. E-mail address: [email protected] (S. Jones).

https://doi.org/10.1016/j.thromres.2020.02.013 Received 23 August 2018; Received in revised form 13 February 2020; Accepted 14 February 2020 Available online 19 February 2020 0049-3848/ © 2020 Elsevier Ltd. All rights reserved.

Thrombosis Research 189 (2020) 24–34

Identification

S. Jones, et al.

Studies idenfied through database searching (n = 285)

Studies idenfied through reference lists (n = 11)

Included

Eligibility

Screening

Duplicate studies removed or case reports or those with adult parcipants (n =212)

Studies assessed for eligibility (n = 84)

Studies removed – full text not available (online), not wri!en in English, not meeng all inclusion criteria (n = 41)

Studies included for evaluaon in the review (n = 43)

Fig. 1. Literature search results and identification of eligible studies.

with an asymptomatic VTE (A-VTE) and discusses the reliability of diagnosis, treatment and outcomes for these children.

majority of A-VTE are CVC-related and CVCs cause different types of thrombus. Three types of CVC-related VTE have been described; thrombus at the catheter tip, fibrin sheath/sleeve and thrombus that adheres to the vessel wall and thrombus causing complete or partial occlusion of the vessel [10,11]. Removal of the CVC can remove any CVC tip thrombosis and the presence of an intraluminal thrombus would not be identified. Both CVC tip and thrombus causing catheter occlusion may be diagnosed as asymptomatic CVC-related VTE if diagnostic screening is performed when a CVC in insitu. Across the studies identified for this review, definitions of thrombosis mostly include these characteristics: presence of echogenic material within the vessel; filling defect; inability to compress and limited or no flow with collateral vessels. Other definitions used in the literature include: constant non-visualisation or sudden cut off of a deep vein; fibrin sheath/band causing luminal narrowing; abnormal Doppler pattern; decreased pulsation amplitude; venous stasis; intraluminal asymptomatic thrombosis defined as inability aspirate CVC and requirement for tPa; thrombus causing haemodynamic instability (threatened occlusion of a major vessel or crossing a heart valve)[8,11–17]. The inconsistencies in the definition of VTE throughout the literature together with the different imaging modalities used contribute to the variation in the incidence of A-VTE reported. Some papers report the differences in the type of VTE diagnosed (i.e. non-occlusive, occlusive, CVC tip or fibrin sheath) but many papers report merely the presence or absence of thrombosis. This limits the inferences and understanding of the severity and extent of both symptomatic and

1.1. Search A database search using Medline (Ovid and Web of knowledge) and Cinahl was conducted using the following key search terms in each database: ‘asymptomatic’, ‘venous thrombosis’, ‘thrombosis’, ‘thromboembolism’, ‘paediatric’ or ‘child’, ‘central venous catheter’. Various combinations of the search terms were used to narrow the search to identify articles that were specifically related to this review. The search was restricted to articles, excluding commentaries, case reports, editorials and reviews, published in English between January 1990 and March 2019 and limited to children under the age of eighteen years. Reference lists of retrieved articles were searched and articles not identified in the database search were included. All articles that reported the incidence or outcome of A-VTE were included. Articles that only reported symptomatic VTE were excluded. The search results and application of inclusion and exclusion criteria for studies is depicted in Fig. 1. Table 1 displays 43 studies identified from the search that report the incidence of asymptomatic VTE in children. 2. Definition and diagnosis of Asymptomatic Venous Thromboembolism Clarity around definitions of A-VTE is lacking, especially as the 25

26 Haemophilia & CVC Cancer with CVC PICU with CVC Children with upper extremity VTE PICU with femoral CVC Children with lower extremity VTE Children with cancer & tunnelled CVC PICU with untunnelled CVC Post cardiac surgery with thrombosis

339 305 84 203

Li et al. [12]; USA, prospective cohort study Manlhiot et al. [56]; Canada, retrospective

Bleeding disorder & CVC Children on TPN & CVC

20 114 101 158 134

36 32

Inpatient with CVC Neonates with UVC and PICC Neonates Cancer with CVC Infants with CHD & CVC Neonates

Cost [77]; USA; retrospective & prospective Vegting et al. [78]; Netherlands; retrospective/ prospective Ranta et al. [79]; Finland; retrospective/prospective Albisetti et al. [8]; Switzerland; prospective Faustino et al. [38]; USA; prospective Avila et al. [43]; Canada; retrospective Sol et al. [37]; Netherlands; prospective, observational Avila et al. [44]; Canada; retrospective Schoot et al. [17]; Netherlands, multicentre RCT

90 339 18 124 90 4734

Children with cancer and CVC Children with cancer & CVC Children with cancer & CVC Children with a PICC Children with cancer & CVC Cancer with CVC Cancer with CVC (solid tumours)

Children with cancer & CVC Children with CVC Thalassaemia with CVC Premature infants with UVC

60 186 23 210 287 73 71 214 56 47 42

Children with cancer & CVC Children with cancer & CVC All VTE cases

24 41 100

Journeycake [35]; USA: retrospective Rudd et al. [58]; Norway; RCT Rudd et al. [34]; Norway; prospective Dubois et al. [76]; Canada; prospective Farinasso et al. [59]; Italy: prospective Gupta et al. [20]; USA; retrospective Schiavetti et al. [61]; Italy; cross-sectional, observational Hanslik et al. [1]: Austria; prospective Haumont et al. [45]; Belgium; retrospective Demirel et al. [39]; Turkey; retrospective Oceipa et al. [14]; Poland; prospective Schoeder et al. [42]: USA; RCT van Elteren et al. [41]; Netherlands; retrospective

CHD with CVC Children on TPN with CVC Neonates with CVC PICU with femoral CVC PICU with femoral CVC CHD with CVC Children with cancer & CVC PICU with CVC Children with cancer & CVC All VTE cases

25 32 46 20 50 2474 25 76 77 99

Moore et al. [54]; USA: prospective Dollery et al. [64]; Canada; retrospective Pippus et al. [40]; Canada; prospective Talbott et al. [49]; USA: prospective Krafte-Jacobs et al. [31]; USA; prospective Petäjä et al. [55]; Finland; retrospective Wilimas et al. [62]; USA; prospective Beck et al. [47] Canada; prospective Knofler et al. [60]; Germany; prospective van Ommen et al. [33]; Netherlands; prospective registrya Glaser et al. [63]; USA, prospective Rudd et al. [3]; Norway; prospective van Ommen et al. [74]; Netherlands; prospective registrya Mitchell et al. [2]; North America; open RCT Massicotte et al. [36]; International; RCT Finkelstein et al. [75]; Israel; retrospective Butler-O'Hara et al. [13]; USA; RCT

Population

N

Study & location

Table 1 Studies reporting asymptomatic VTE in children.

(4.8)

(0.5) (3.6)

(1.75) (2.7)

10 (11.9) 232/513 (45)

279 (82.3) 8/305 (2.6)

1 (5) 5 (4.4) 0 81 (51.3) 10/134 (7.5)

n/a 6 (18.75)

5 (5.5) 0 11 (61) 3/124 (2.4) n/a 28 (0.6)

5 2 0 1 2 0 2

3 (5) 6 (3.8) 2 (8.7) 0

3 (12.5) 0 71 (71)

0 8 (2.5) 4 (8.7) 0 9 (18) 15 (0.6) 0 7 (9.2) 9 (11.7) 64 (64.6)

Symptomatic VTE n (%)

28 (33.3) 281/513 (55)

60 (17.7) 11/185 (5.9)

4 (20) 45 (39.5) 16 (15.8) 77 (48.7) 3/42 (7.1)

14/30 (46.6) 4 (12.5)

20 (22.2) 4 (1.2) 7 (39) 4/37 (10.8) 14 (15.5) 4 (0.08)

16 (5.5) 26 (35.5) 17 (23.9) 19 (8.9) 39 (69.6) 10 (21.2) 3 (7.1)

19 (31.7) 15 (9.5) 6 (26) 11 (5.2)

9 (37.5) 18 (41) 29 (29)

5 (20) 4 (12.5) 7 (15.2) 7 (35) 4 (8) 5 (0.2) 3 (12%) 10/93 (10.7) 2/12 (16) 35 (35.7)

Asymptomatic VTE n (%)

(continued on next page)

Inflammation and CVC dysfunction described as signs of symptomatic DVT 377 clots within central veins - ? no asymptomatic

No VTE-related mortality N = 283 (83.5%) were CVC-related

Nil VTE-related mortality Nil VTE-related mortality 42 screened. No VTE-related mortality, PTS reported

Most children had multiple DVT

Timing of ultrasound not standardised; performed at any time over 10 month study period U/s and venography screening diagnosed via echocardiogram N = 1 died from thrombotic complication associated with protein C deficiency Ultrasound performed median 22 months post CVC removal (1–54) 8/53 (UFH) and 6/37 (placebo). Study closed early due to futility. No mortality. No VTE-related mortality; (signs were thrombocytopenia, sepsis, thalamus bleeding, CVC obstruction)

Follow up assessment diagnosed VTE.

4 (short-term), 7 (long-term); 13 cases of VTE determined not to be clinically significant 312 tunnelled infusion port; 106 tunnelled external catheter; 26 other

Diagnostic screening

N=1 N = 57 CVC related

Venography

2 weekly ultrasound surveillance; symptomatic VTE all r/to IVC, Blinded ultrasounds; no patient treated N = 11 in standard CVC group had VTE Detected on echocardiogram CT performed minimum of 2 months after CVC removal 93 CVCs. One patient had 4 DVT, one patient had 2 DVT Screening only performed in presence of inherited pro-thrombotic risk factors 2 (2%)

Linogram upon removal of CVC

Other

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Key for abbreviations: RCT: randomised controlled trial; PICU: paediatric intensive care unit; CHD: congenital heart disease; UFH: unfractionated heparin; LMWH: low molecular weight heparin; VTE: venous thromboembolism; ALL: acute lymphoblastic leukaemia; PICC: percutaneous inserted central catheter; CVC: central venous catheter; VKA; vitamin K antagonist; INR: international normalised ratio; SVT: superficial venous thrombosis. Note: Not all patients included in studies in Table 1 had VTE, hence ‘n’ value for symptomatic and asymptomatic CVL-related VTE add up to N value for study. a Registries of VTE cases so data only used to report outcomes for A-VTE. Incidence of A-VTE not included in summaries of incidence.

31/146 (21) 189 Jones et al. [11]; Australia; prospective cohort study

PICU with untunnelled CVC

2 (1)

Only intraluminal asymptomatic thrombosis defined as inability aspirate CVC and requirement for tPa Ultrasound performed 5–7 days after CVC insertion or prior to discharge 85 (25.8) 2 (0.6) 330 Stammers et al. [15]; Canada, retrospective

Children with cancer & CVC

Asymptomatic VTE n (%) Study & location

Table 1 (continued)

N

Population

Symptomatic VTE n (%)

Other

S. Jones, et al.

asymptomatic VTE. Venography is reported to be the gold standard modality for the diagnosis of VTE in children, in both the lower and upper venous system [10,12]. In particular, the intra-thoracic vessels and distal vessels of the lower extremities are best visualised using contrast venography [1]. In the secondary analysis of the PARKAA study, which examined the sensitivity of US and venography in the diagnosis of upper system CVC-related VTE, venography demonstrated a sensitivity of 79% in detecting VTE. The majority of VTE not diagnosed by venography were in the jugular veins and were detected by US [7]. The superiority of US over venography in detecting thrombus in the jugular veins was also demonstrated in a study of 16 boys with haemophilia, in which US but not venography identified an internal jugular thrombus [18]. This is not surprising as contrast for venography is usually injected into the arm veins which means it would not be expected to fill the jugular veins unless there was retrograde flow due to extensive blockage [18]. Ultrasound is predominantly used to diagnose VTE in children as it is readily available and non-invasive. US is most sensitive in the examination of neck vessels but less sensitive for imaging the intra thoracic vessels due to the overlying shadows produced by the clavicles, sternum and lung [1,7,10,19,20]. Diagnosis of VTE in the subclavian vessels via US requires assessment of the compressibility of the vessel [21]. The positioning of the clavicle prohibits the compressibility of the subclavian veins in children and thus ultrasound does not provide a complete diagnostic assessment of the vessel patency [20]. Thus, venography is the gold standard for the diagnosis of VTE in the intrathoracic vessels [10]. Where gold standard imaging cannot be feasibly performed in the context of clinical studies, the limitations of the modality need to be acknowledged and definitions of VTE established a priori [22]. The majority of studies in Table 2, that prospectively screened for A-VTE used ultrasound as the primary imaging modality. Echocardiogram is recommended for the diagnosis of intracardiac thrombus but has varying sensitivity in the diagnosis of CVC-related thrombosis [10,23]. Despite this, echocardiogram has been employed as one of the diagnostic modalities options in six studies presented in Table 2. 3. Incidence of asymptomatic VTE in children Literature indicates that infants and children with VTE are exposed to multiple risk factors, many of which are a consequence of their underlying disease. Cancer (and specifically asparaginase therapy), congenital heart disease (CHD), trauma, surgery and systemic lupus erythematosus are the commonly reported underlying disorders present in children diagnosed with VTE [10,24–27]. The presence of a central venous catheter (CVC) is the most significant risk factor for VTE in children [4,28–33]. This has been established from registries of VTE in children from Canada and the Netherlands and confirmed by crosssectional and prospective studies of children with CVC-related VTE [29–33]. Screening for VTE in hospitalised children is not routine clinical practice and thus VTE is mostly diagnosed after the appearance of clinical signs and symptoms [1,34]. There is however, a growing amount of literature that reports both asymptomatic and symptomatic VTE, diagnosed through screening in the context of prospective cohort studies [1,2,35–38]. The majority of these studies focus on the incidence of A-VTE among children with a CVC. Table 1 displays 43 studies that report the incidence of asymptomatic VTE in different cohorts including neonates, children with cancer, CHD, critical illness, bleeding disorders and children requiring TPN. All of these studies report the proportion of CVC-related A-VTE. Summary data for each of the cohorts is presented in Fig. 2 and the prospective data for the different cohorts is briefly described here. 27

28

10/50 (20%)

3 (7.1%)

47

42

Schoeder et al. [42]: infants with CHD & CVC

90

124

90

39 (69.6%)

56

Hanslik et al. [1]: CHD with CVC Oceipa et al. [14]; cancer with CVC

19 (8.9%)

214

Dubois et al. [76]; Children with a PICC Farinasso et al. [59]; cancer & CVC Gupta et al. [20]; cancer & CVC Schiavetti et al. [61]; cancer with CVC

14 (15.5%)

4/37 (10.8%)

20 (22.2%)

17 (23.9%)

71

Rudd et al. [34]; cancer & CVC

26 (35.5%)

11 (5.2%)

210

73

6 (26%)

23

Rudd et al. [58]; cancer & CVC

15 (9.5%)

186

Massicotte et al. [36]; Children with CVC Finkelstein et al. [75]; Thalassaemia & CVC Butler-O'Hara et al. [13]; Premature infants with UVC

19 (31.7%)

60

Mitchell et al. [2]; cancer & CVC

18 (41%)

41

10 (10.7%) of 93 CVCs

76

9 (37.5%)

3 (12%)

25

24

4 (8%)

50

Glaser et al. [63]; cancer & CVC Rudd et al. [3]; cancer & CVC

7 (35%)

20

2/12 (16%)

7 (15.2%)

46

77

5 (20%)

A-VTE

25

N

Knofler et al. [60]; cancer & CVC

Moore et al. [54]; CHD with CVC Pippus et al. [40]; neonates with CVC Talbott et al. [49]; PICU with femoral CVC Krafte-Jacobs et al. [31]; PICU with femoral CVC Wilimas et al. [62]; cancer & CVC Beck et al. [47]; PICU with CVC

Study & population

N = 2 VTE treated with UFH 10 units/kg/h; not specified if A-VTE

All VTE treated with LMWH for 1 month Not stated

All VTE treated with LMWH for 3–4 months

Not stated

Not stated

Not stated

n/a

A-VTE not treated.

No

Not stated

Not stated

Not stated

Not stated

Not stated

N = 3 received no treatment; N = 7 received LMWH or UFH Not stated

Not stated

Not stated

No

Not stated

Not stated

Treatment

Table 2 Prospective studies with data on screening, treatment and follow up of A-VTE.

Serial ultrasound until CVC removal

Ultrasound, venography and echocardiogram screening within 1 week of CVC removal. Ultrasound performed median 22 months post CVC removal (1–54)

Ultrasound performed once, prior to CVC removal

Pre-operative ultrasound prior to CVC insertion

Serial ultrasound and venous angiography for the life of the PICC Spiral CT and ultrasound

Ultrasound performed at 1, 3 and 6 months after enrolment. Ultrasound and/or MRI at study entry (median time of 37 months post CVC removal)

Blinded ultrasound at inclusion and then 3–5 months later Ultrasound, bilateral venography or Echocardiography, MRI of head and upper body 28 days to 3 months post chemotherapy induction. Venogram 30 days after CVC insertion or at CVC removal. Ultrasound if venography not possible. Echocardiogram every 6 months; diagnosis of AVTE confirmed by ultrasound Echocardiogram at study entry and serial surveillance whilst catheter insitu and then 1–2 weeks after removal.

Venography immediately prior to port removal

Ultrasounds screening, confirmed with venography

Blinded ultrasounds within 48 h, 3–5 days and 7–10 days after insertion Ultrasound performed within 72 h of insertion, weekly and after removal of CVC CT performed minimum of 2 months after CVC removal. Ultrasound at 2, 4, 6 or 7 days after insertion then weekly.

Two weekly ultrasound surveillance

Linogram upon removal of CVC

Imaging modality

No follow up

One month. Resolution of VTE demonstrated for all but one child. No follow up

All patients had resolution of VTE at end of treatment.

No follow up

No follow up

6 months study period and reimaging. PTS assessment at study entry (median time of 37 months post CVC removal) No follow up

Mean of 37 months. PTS/ resolution not reported. Repeat imaging demonstrated resolution in 13 patients median of 49 days after diagnosis.

No

No

Assessed for PTS at 1–39 months of port insertion. 3–5 months for resolution.

n/a

Median time of CT was 32.5 months after CVC removal. Patients with VTE had follow up ultrasound 1 month later

n/a

Failed recanalization in 2 patients, 4 weeks and 17 months later. n/a

n/a

Follow up (PTS/resolution)

No mortality.

Not stated

Not stated

Not stated

Not stated

Not stated

Not stated

Not stated

Not stated if any VTErelated deaths. N = 15 lost to follow up at one year. No VTE-related mortality.

Not stated

No VTE-related mortality.

N = 2 but unclear if VTE related. Not stated

Not stated

Not stated

No VTE-related mortality

Not stated

Not stated

Not stated

Not stated

Not stated

Mortality

(continued on next page)

Timing of ultrasound not standardised; performed at any time over 10 month study period Resolution of VTE not reported specifically for A-VTE. VTE defined as venous stasis (n = 12), venous thrombosis (n = 4), VTE defined as “definite” and “probable”

PICC removed when VTE diagnosed.

Follow up assessment diagnosed VTE.

13 cases of VTE determined not to be clinically significant

Screening only performed in presence of inherited prothrombotic risk factors.

Thrombus defined as absent, partial or occlusive.

Linogram likely to only identify vascular occlusion.

Other

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No VTE-related mortality PTS assessed and repeat imaging at two year follow up and reported for A-VTE

Nine studies reported the incidence of A-VTE either in a cohort of neonates or a sub-group of neonates within in larger sample of children [13,33,39–45]. Only two of these studies identified A-VTE through prospective screening [13,40]. An RCT, comparing the rate of VTE between long-term and short-term use of umbilical vein catheters, had a rate of VTE of 5% among 210 infants, with no significant difference in the rate of thrombi between groups. All VTE were asymptomatic and diagnosed via serial echocardiography. The RCT reported only “clinically significant” VTE as defined as a thrombus causing haemodynamic instability (threatened occlusion of a major vessel or crossing a heart valve) or posing a significant threat to the neonate, as determined by the cardiologist. None of the neonates diagnosed with VTE received anticoagulation therapy [13]. The reliability of the incidence of asymptomatic CVC-related VTE in this RCT is limited as echocardiography is not the optimal method for diagnosing VTE in children or neonates and the characterisation of clinically significant thrombi was reliant on a subjective opinion [10,46]. Ultrasound screening at two weekly intervals in a Canadian study reported an incidence of A-VTE of 15.2% in 46 neonates with CVCs [40]. This small study is the only cohort study of neonates that used prospective screening and reliable radiological imaging to determine the rate of A-VTE. 3.2. Critically ill children Seven studies prospectively screened for the incidence of A-VTE in critically ill children in paediatric intensive care units (PICU) [12,31,37,38,47–49]. A recent study specifically examined the incidence of asymptomatic and symptomatic CVC-related VTE in a cohort of 134 children with femoral CVCs in PICU [37]. Ten children developed symptomatic CVC-related VTE (7.5%), whilst only 3 children of 52 children screened (7.1%) were identified to have asymptomatic CVCrelated VTE [37]. The rate of asymptomatic CVC-related VTE reported by Sol et al. [37] is low compared to previous studies of asymptomatic CVC-related VTE in critically ill children, which report rates of VTE of between 15.8% and 35% [1,38,49]. Two possible explanations for their lower rate of asymptomatic CVC-related VTE exist. Firstly, the timing of the imaging, performed after the CVC was removed, compared to other studies which perform imaging whilst the CVC is in place [1,12,38,42,47,49]. Secondly, less than 40% of the cohort were screened for asymptomatic CVC-related VTE, thus the smaller sample size and low rate of screening may have resulted in CVC-related VTE being missed [37]. An older study of CVC-related VTE in critically ill children reported an incidence of asymptomatic femoral CVC-related VTE of 35% in a cohort of 20 children [49]. Talbott et al. prospectively followed children only with femoral CVCs but was limited by its small sample size [49]. Comparatively, another prospective study by Beck et al. of 76 children in PICU with CVCs, reported a rate of 10.1% of asymptomatic CVC-related VTE [47]. Faustino et al. reported an incidence of asymptomatic CVC-related VTE of 15.8% in a cohort of 101 children in PICU [38]. There was a high percentage of children with subclavian CVCs in the Faustino study. Ultrasound was the only imaging modality used and ultrasound has limited sensitivity to detect VTE in the subclavian veins (SCV), especially in younger children, thus the incidence of asymptomatic CVCrelated VTE may have been underestimated [21,38]. An additional study conducted by Faustino and colleagues [12,38], again prospectively screened children in PICU with untunnelled CVCs, for CVCrelated VTE. As well as determining the reliability of point of care ultrasound, this study reports an incidence of A-VTE of 33%. The consultative ultrasounds (performed by medical sonographers) diagnosed 38 CVC-related VTE, whilst the point-of-care ultrasounds performed by critical care physicians only diagnosed 17 CVC-related VTE. CVC

One patient with A-VTE treated; 31/146 (21%) 189 Jones et al. [11]; PICU with untunnelled CVC

Li et al. [12]; PICU with untunnelled CVC

84

28 (33.3%)

Not treated

Point-of-care ultrasound and consultative ultrasound performed within 24 h of CVC insertion. Ultrasound performed 5–7 days after CVC insertion or prior to discharge

Not stated.

Ultrasound performed earlier if signs of VTE, infection, CVC removal, death. Repeat ultrasound performed within 24 h of CVC removal. Not stated for patients who had screening A-VTE not treated 11/185 (5.9%) 305

3.1. Neonates

No follow up

Median follow up 2.1 years No VTE-related mortality No treatment of A-VTE 3/42 (7.1%)

16 (15.8%) 101

134

Sol et al. [37]; PICU with femoral CVC Schoot et al. [17]; cancer & CVC

45 (39.5%) 114

A-VTE not treated (only symptomatic) One patient with A-VTE treated

Ultrasound at enrolment, on day of CVC removal or day 28 or day of discharge from PICU and if VTE suspected. Ultrasound screening performed within 72 h of CVC removal Screening ultrasound performed 6 months after enrolment

PTS reported. One patient with AVTE seen for follow up. No follow up

Nil VTE-related mortality

Not reported

Not stated

PTS assessed but time of follow up not reported. PTS assessed median of 3.5 years after CVC placement. No follow up Not stated 4 (20%) 20

Ranta et al. [79]; haemophilia & CVC Albisetti et al. [8]; cancer with CVC Faustino et al. [38]; PICU with CVC

4 (12.5) 32

Only symptomatic VTE treated.

Ultrasound at study commencement and then annually. Ultrasound also performed if CVC occluded. MRI performed after CVC malfunction and after CVC removal MRV performed a median of 3.5 years after CVC.

Not stated

PTS assessed a median of 27 months after CVC insertion. 3 year study but no evaluation of resolution or PTS. 14/30 (46%)

Cost [77]; bleeding disorder & CVC Vegting et al. [78]; children on TPN & CVC

36

Not stated

Ultrasound and venography at 24 month intervals

Mortality Follow up (PTS/resolution) Imaging modality Treatment A-VTE N Study & population

Table 2 (continued)

No VTE related mortality

Other

VTE defined as complete occlusion of vessel CVC insitu in 37% at time of MRV

S. Jones, et al.

29

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Fig. 2. Prospective studies reporting incidence of A-VTE after screening. Total number of studies in review n = 43. Incidence refers to the reported incidence of asymptomatic VTE only, as specified by each study within the sub-groups. *Other cohorts: bleeding/haematological disorder, TPN dependent, all VTE, children with CVC. CHD: congenital heart disease; CVC: central venous catheter; TPN: total parental nutrition.

heavily on the use of CVCs and together with the tumour itself and treatments such as L-asparaginase, there is a high risk of thrombosis in this population [17]. Fifteen studies were identified to report A-VTE in children with cancer; 13 of these studies were prospective designs and all studies included the incidence of CVC-related VTE. The prospective studies that screened for A-VTE in children with cancer report incidences of between 5.9% and 69% [2,3,8,17,34,58–60]. The largest sample size was a recent RCT of 305 children, comparing the efficacy of ethanol locks to standard heparin locks in preventing CVC-associated bloodstream infections [17]. The incidence of A-VTE was determined via ultrasound screening performed at study completion. Of the 185 children screened, 5.9% had A-VTE. This rate of A-VTE is possibly underestimated as only 60% of the cohort had a screening ultrasound performed. Furthermore, 16 patients in the study diagnosed with a CVC-associated blood stream infection did not have an ultrasound performed, despite this being prescribed in the protocol, and two patients were diagnosed with non-CVC related VTE but did not have ultrasound evaluation of the vessel in which their CVC was placed [17]. The variance in the rate of asymptomatic VTE across the 13 studies that screened for A-VTE is influenced by many factors. The timing of diagnostic imaging and whether the CVC had been removed at the time of imaging can impact the likelihood of A-VTE being present. In a study by Wilimas et al. [62], CTs were performed a minimum of two months after CVC removal (maximum time was 10 years). More recently, Ociepa et al.'s study of children with malignancy and an untunnelled CVC, performing ultrasound screening for 37 children a median of 22 months after CVC removal [14]. Schiavetti's observational study of 42 children with solid tumours performed screening ultrasounds at any time prior to CVC removal across the 10 month study period [61]. These three studies report incidences of A-VTE of 12%, 10.8% and 7.1%, respectively [14,61,62]. These rates of A-VTE are lower than those reported by studies that perform screening with the CVC insitu. Reported incidences of A-VTE from the PAARKA study, Farinasso et al., Rudd et al., Glaser et al. who all performed diagnostic imaging whilst the CVC was insitu (and whilst the children were undergoing treatment), vary from 31.7% to 69.6% [2,21,58,63]. Albisetti et al. investigated the rate of VTE in children with cancer and a port-a-cath and reported no significant difference in the rate of thrombosis between children with a port-a-cath insitu and those who had their port-a-cath removed (45% vs 36%, p = 0.42). However, the difference in the rate of A-VTE between these two subgroups was not reported [8].

placement into the SCV was associated with discordance between the point-of-care and consultant ultrasound (odds ratio 4.0, 95% confidence interval 1.15 to 13.94), supporting previous evidence of the limited sensitivity of ultrasound to detect VTE in the SCV [12]. A recent study excluded children with CVCs in the SCV and performed ultrasounds within one week of CVC insertion for a cohort of 189 children with untunnelled jugular and femoral CVCs in PICU [11]. The rate of A-VTE was 21%. Similar to previous studies there was a higher incidence of A-VTE for children with femoral CVCs (33% versus 18.6% for children with jugular CVCs). The multitude of factors that contribute to the risk of thrombosis in children in PICU has been well described. Femoral CVCs are more commonly utilised in children in urgent need of venous access and the children are more likely to have significant acuity of illness [50]. States of sepsis, hypotension and shock exacerbate the low flow state through the femoral veins and can contribute to a higher risk of thrombosis. 3.3. Congenital heart disease Children with CHD represent a significant proportion of children diagnosed with VTE [1,51–53]. Five studies described in Table 1 have specifically investigated A-VTE in neonates and children with CHD [1,42,54–56]. Three studies of children with CHD screened for A-VTE. Rates of A-VTE reported in these studies ranged from 15.5% to 22% (all CVC-related) [1,42,54]. The early study by Moore et al. only used linogram to diagnose CVC-related thrombosis and thus it is likely that the extent of the thrombosis was underestimated and that other CVC-related thrombosis may have been missed [54,57]. All children in Hanslik et al.'s study, known as the KIDCAT study, had their CVC's placed into the upper venous system [1]. The rate of asymptomatic CVC-related thrombosis was 22% yet it should be highlighted firstly that the KIDCAT study performed venography, venous ultrasound and echocardiography for all patients and secondly, the KIDCAT study included children with CVCs placed into the subclavian vein. The gold standard for imaging of the subclavian vein is venography and thus by including venography as an imaging modality, the KIDCAT study was able to enrol children with subclavian CVCs and presents a reliable measure of A-VTE [21]. 3.4. Cancer Another population for whom A-VTE has been extensively investigated is children with cancer. Modern oncology treatments rely 30

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4. Routine screening for asymptomatic VTE

their PICU admission [11]. Importantly, none of the 174 children who received some form of follow up two years after CVC insertion had any thrombus extension or embolisation despite not receiving treatment for the A-VTE [11]. The evidence to date presents variation in the rate of resolution of A-VTE and that resolution (either partial or complete) may be independent of treatment in certain cohorts of children, such as neonates and those with asymptomatic CVC-related VTE. The strength of this evidence is limited as the rate of A-VTE reported in each study is likely to be underestimated. However, overall, the data indicates that the level of risk of recurrence or poor resolution from not treating A-VTE is low.

Due to the variance in reported incidence of A-VTE in children, questions have been raised as to the role of ultrasound screening to assist in early detection [4,21,56,64]. Screening for A-VTE is currently not routine practice in most paediatric centres and whether this relates to feasibility, cost or uncertainty about the utility is unknown. Prompt commencement of anticoagulation following the diagnosis of VTE has been demonstrated to reduce the risk of poor outcomes (PTS, recurrence, extension) in one study, however this has not been explored prospectively [65]. However, to our knowledge, no study to date has attempted to determine if early detection of A-VTE through screening and treatment with anticoagulation correlates to a reduction in the incidence and severity of acute complications or long-term sequelae (such as PTS) in children, compared to the outcomes achieved when no routine screening is conducted.

5.2. Post thrombotic syndrome Since the publication of a consensus statement from the Perinatal and Pediatric Haemostasis Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) in 2012, recommending studies delineate between PTS from CVC-related and non-CVC related VTE, PTS has been more commonly reported as an outcome after CVC-related VTE in paediatric studies [68]. Importantly, some studies of CVC-related VTE in children reporting PTS as an outcome have also reported the incidence of PTS after asymptomatic CVC-related VTE. Studies exploring PTS after asymptomatic CVC-related VTE have been conducted mostly in cohorts of children with cancer. Two studies have evaluated the incidence of PTS in children with CHD post cardiac catheterisation, one recent study followed a cohort of critically ill children with asymptomatic CVC-related thrombosis and two retrospective studies have reported the incidence of PTS following VTE in the upper and lower extremities [37,43,44,52,69]. A retrospective study conducted in Canada reported the incidence of PTS in 158 children with upper extremity VTE, of whom 48% were asymptomatic [43]. In this study, CVC-related VTE was reported and accounted for 100% of VTE for the neonatal group (n = 25) and 92% for the non-neonatal group; 12% of neonates and 50% of non-neonates were symptomatic. The highest incidence of PTS in the Avila study was reported among children with primary, symptomatic upper extremity VTE (idiopathic) [43]. Only four neonates with CVC-related VTE developed mild PTS, as classified by the Modified Villalta Scale (MVS), whilst nearly half of the non-neonatal group developed mild PTS. Two children in the non-neonatal group developed moderate PTS. A sub-analysis of the PARKAA study assessed PTS in a cohort of 13 children with asymptomatic CVC-related thrombosis [70]. Seven out of 13 children (54%) demonstrated signs of PTS when assessed using the MVS at a mean time of 7.3 years after CVC placement, only one child was diagnosed with moderate PTS [70]. A study by Kuhle et al. [70] compared the incidence of PTS to a non-selected group of cancer survivors who had not been screened for asymptomatic CVC-related VTE; the incidence of PTS in this cohort was 24% (n = 10). Similar to the PARKAA group, one child was diagnosed to have moderate PTS. Polen et al. prospectively assessed 158 children with cancer for PTS but retrospectively collected data about CVC-related VTE [71]. The rate of A-VTE for this cohort is unclear and no imaging was performed at the time of the PTS assessments. The MVS identified PTS in 52 children (34%) and the MJI diagnosed 46 (30.5%) children with PTS. CVC occlusion, CVC-related VTE and the insertion of more than two CVC were associated with PTS diagnosis [71]. Both the study by Sol et al. and Jones et al. reported the incidence of PTS in children diagnosed with asymptomatic CVC-related VTE in PICU [11,37]. Similarities between the two studies include the median age of the cohorts (1 year and 1.8 years, respectively), follow up period and timing of assessment of PTS (mean of 2.2 years and median of 2.1 years, respectively) and the conduct of both PTS assessment and diagnostic imaging at follow up. Only one child diagnosed with A-VTE during their PICU admission was seen for follow up in the Sol et al. study; there was no evidence of residual thrombus or PTS [37]. A further six children

5. Treatment and long-term outcomes of A-VTE Table 2 displays 31 studies that have utilised screening to diagnose A-VTE; nineteen of these studies performed some follow up after VTE diagnosis. Eleven studies reported outcomes for children with A-VTE, separate to the outcomes for all children with VTE but only two studies performed follow up and assessed long-term outcomes specifically for children with A-VTE [11,37]. 5.1. Residual and recurrent VTE Decisions about the treatment of A-VTE are informed by the risk of recurrence and/or residual thrombosis that may then affect a child's long-term quality of life. As presented in Table 2, a limited number of studies have reported rates of resolution or recurrence among children with A-VTE, as distinct from the outcomes for all cases of VTE. The length of follow up to determine resolution varied considerably, ranging from one month to 12 years. Among a cohort of 32 neonates, 25 with VTE received treatment with low molecular weight heparin and seven were observed without treatment. Four of the 32 neonates had A-VTE, diagnosed as a chance finding [41,66]. At follow up, within three months of VTE diagnosis, 68% of the neonates treated had complete resolution of the VTE and a further 24% had partial resolution. Of the seven neonates that did not receive treatment, six had full resolution and one neonate had partial resolution, two months after diagnosis [41]. However, like many studies reporting follow up data for children with VTE, outcomes for the children with A-VTE (treated or not) are not specified. Two prospective studies conducted in Norway, reported that many asymptomatic CVC-related VTE are transient [3,58]. The rates of transient thrombosis reported by the two Rudd studies are 22% (4 of 18) and 62.6% (10 of 16), all of which had resolved by the time of follow up imaging five to six months later. None of the patients identified in the two studies by Rudd [3,34]received treatment for their asymptomatic CVC-related thrombosis. A German retrospective and prospective study of 29 children with inferior vena cava thrombosis related to a CVC, reports outcomes a median of 10 years after diagnosis of VTE [67]. Six of seven patients with “limited” thrombosis (extending to right atrium, pararenal or intrahepatic region only) had spontaneous and complete resolution of thrombus observed, despite none of these patients receiving anticoagulation therapy. Conversely, only four of 21 patients with extensive thrombosis (extending at least two caval segments) demonstrated IVC patency, despite surgical thrombectomy or thrombolysis. The study by Jones et al. [11] assessed the long-term outcomes of AVTE. Among the cohort of 189 children recruited from PICU with untunnelled CVCs, 120 were followed up two years later and had repeat imaging [11]. Sixteen children had residual thrombus at follow up, however only three of these children had evidence of A-VTE during 31

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were identified to have mild PTS despite four of these children having no evidence of VTE at either the screening or follow up [37]. Clinically significant PTS was identified in 1.6% (n = 2) of children in the Jones et al. study (2019); one of whom had A-VTE and the other had symptomatic VTE. A further 10 children (8.7%) had mild PTS. Anticoagulation treatment was not given to children with A-VTE in either of these studies [11,37]. Given the increased incidence of PTS in the Avila and the PARKAA studies, despite all children receiving therapeutic anticoagulation, it appears that anticoagulant therapy may not be protective against PTS in all children with A-VTE.

VTE, screening time frame and population, the evidence to support routine screening for A-VTE is low. Diagnosis of A-VTE in children is mired by the variation in diagnostic modalities used and the sensitivity and subjectivity of these modalities. A-VTE is often an incidental finding and thus rates of A-VTE in children are most likely underestimated. Presently, evidence would suggest that routine clinical screening is unwarranted given the low rate of long-term morbidity associated with A-VTE, even in populations of children who were not treated. The level of evidence to support the decision to treat or not treat AVTE continues to be hindered by an absence of reporting of the incidence of asymptomatic thrombosis as separate from all thrombosis. In addition to current position papers from the ISTH, a position paper that provides additional recommendations for the reporting and definition of VTE in children will go a long way to ensure that despite small sample sizes and heterogeneous populations, data generated from individual prospective studies can be interpreted collectively [22]. Given the risks of anticoagulation in unwell children, not treating appears to be the safer option when the risk of long-term morbidity is extremely low, but again the evidence to support this is hindered by a lack of robust data of the long-term outcomes for such children. There are no studies that have assessed standard anticoagulation treatment for children with A-VTE compared to children with who did not receive treatment and measured long-term outcomes, such as PTS. In the absence of robust evidence clinicians must incorporate patient preference and consider individual risks when deciding on treatment for A-VTE [9]. Literature suggests that the difference in thrombotic burden between asymptomatic and symptomatic VTE in children is the driver of differences in rates of complications and predictor of poorer long-term outcomes, such as residual thrombus, recurrence and PTS. However, again the level of evidence is relatively low as there is huge variation in the length of follow up and rates of residual thrombus or resolution reported to date. The other factors that are likely to contribute to an increased risk of long-term morbidity need to be considered and prospectively evaluated in longitudinal studies. These include age, severity and complications of underlying disease or illness, location and extent of thrombus [73]. The design of future prospective studies of A-VTE is important in enabling better understanding of their natural history. Future prospective studies need to:

5.3. Mortality from asymptomatic thrombosis Two recent studies of asymptomatic CVC-related VTE have reported rates of non-VTE related mortality of three per 100 patients and 2.9% in a cohort of 101 children [38,50,72]. Neither of these studies performed standardised follow up and thus mortality was only identified during the study period (hospital admission). Two prospective studies of 134 and 189 children in PICU with CVC's followed the cohorts for a median of two years [11,37]. In the study by Sol et al. [37], only children diagnosed with symptomatic or asymptomatic CVC-related VTE were followed (n = 52), however the authors report a mortality of 22.4% (n = 30) in the whole cohort. In the Jones et al. (2019) study the mortality rate was and 7.4% [11]. No children died of thromboembolic complications or as a complication of anticoagulation therapy and all deaths occurred during or shortly after PICU admission in both of these studies [11,37]. Similarly, the paired studies by Avila et al. report no deaths related to thromboembolic complications among cohorts of 158 children with upper extremity VTE and 339 with lower extremity VTE [43,44]. The proportion of A-VTE was 39% and 17.8%, respectively [43,44]. In contrast, the Canadian registry of children with symptomatic VTE demonstrated that children with CVC-related VTE had an overall mortality of 23% across a median period of two years [32]. The majority of children died of their underlying disease however 3.7% (n = 9) of the cohort died as a direct result of their CVC-related VTE which had caused massive pulmonary embolism (n = 7) or obstructive intra-cardiac thrombosis (n = 2). The findings from recent studies of critically ill children with A-VTE, specifically the absent rate of VTE associated-morbidity also raises the question as to whether the risk of mortality, from A-VTE in children is fundamentally different to the risk for children with symptomatic VTE [11,38,43,44]. The minimal thrombotic burden of A-VTE, generally related to a CVC and in the upper venous system, seems distinctly different to the weighty thrombotic burden of symptomatic VTE in the lower venous system. Differences in thrombotic burden and the associated risk of morbidity and mortality between locations of A-VTE and symptomatology suggest that not all thrombotic events require the same treatment principles [73].

- Have a well-defined and homogenous sample - Have well defined and consistent screening and surveillance procedures - Enable outcome comparison between children who received treatment and those who did not - Follow children for an extended period to determine the incidence of PTS and clot resolution - Evaluate the quality of life impact of long-term morbidity (PTS) associated with VTE in children and adolescents.

6. Discussion

References

Evidence from the literature, suggests that rates of A-VTE are much lower in retrospective studies that rely purely on the reporting of incidental findings, compared to prospective studies that screen for VTE. Furthermore, rates of A-VTE seem lower when screening is performed after CVC removal, but this has not been evaluated systematically in homogenous populations. Differences in VTE incidence can be attributed to variance in clinical setting, age group, diagnostic modality and the timing of radiographic testing. With the majority of A-VTE being CVC-related, the variance in incidence of A-VTE may also relate to CVC location. Overall, the incidence of A-VTE in children remains unclear as this particular complication is often reported together with symptomatic VTE. As studies of A-VTE in children are so varied in the definition of

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