Definition of post-thrombotic syndrome following lower extremity deep venous thrombosis and standardization of outcome measurement in pediatric clinical investigations



    1. Section of Hematology/Oncology/Bone Marrow Transplantation, Department of Pediatrics
    2. Division of Hematology/Oncology, Department of Medicine, Children’s Hospital Colorado, The Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado
    3. CPC Clinical Research, Aurora, CO, USA
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  • L. R. BRANDÃO,

    1. Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada
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    1. Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • S. R. KAHN,

    1. Center for Clinical Epidemiology and Community Studies, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
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    1. Department of Clinical Haematology, Royal Children’s Hospital, University of Melbourne, Melbourne, Vic., Australia
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    1. Department of Pediatric Hematology/Oncology, Hadassah Hebrew-University Hospital, Jerusalem, Israel
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    1. Division of Hematology/Oncology and Stem Cell Transplantation, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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  • A. K. C. CHAN,

    1. Division of Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada
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  • on behalf of the Perinatal and Paediatric Haemostasis Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis

Neil A. Goldenberg, CPC Clinical Research, University of Colorado, 13199 E. Montview Blvd., Suite 200, Aurora, CO 80045, USA.
Tel.: +1 303 724 7028; fax: +1 303 724 0947.


Post-thrombotic syndrome (PTS) is a syndrome of chronic venous insufficiency following deep venous thrombosis (DVT) that affects children as well as adults. PTS may be characterized by physical signs in an affected limb such as edema, dilated superficial collateral veins, stasis dermatitis and/or ulceration, and functional consequences such as limitation in activities due to associated pain. The pathophysiology of PTS involves venous hypertension [1], which may result from persistent thrombotic veno-occlusion, venous valvular reflux due to damage from previous thrombosis, or other causes of impaired venous return. Additionally, inflammation may contribute to venous valvular damage [2]. The estimated frequency of PTS following upper/lower extremity DVT in children is 26%, based on a systematic review involving approximately 20 eligible studies and nearly 1000 patients [3].


The Subcommittee recently identified the development of PTS as ‘an important secondary outcome of interest’ in clinical investigations of pediatric venous thromboembolism (VTE) [4], given the increasing incidence of venous thromboembolism (VTE) in children [5]. Furthermore, for clinical trial endpoints such as PTS that are not discrete events (i.e. hard endpoints, like death and recurrent thrombosis), standardization of definitions and efforts to control measurement variability are particularly needed. In anticipation of an increasing number of pediatric VTE trials to evaluate appropriate duration of anticoagulant therapy, safety/efficacy of new anticoagulants and thrombolytic interventions, pediatric-appropriate PTS outcomes must be defined and standardized.


Recommendations given here are based on presentations and discussions at Perinatal and Paediatric Haemostasis Subcommittee meetings during the 58th and 59th Scientific and Standardization Committee (SSC) Meetings of the International Society on Thrombosis and Haemostasis (ISTH). A Working Group for Paediatric PTS was comprised of N.A. Goldenberg and A.K.C. Chan (co-chairmen), L.R. Brandao, J. Journeycake, S. Revel-Vilk and A. Sharath-kumar. Key source materials included a systematic review of pediatric PTS literature [3], Subcommittee recommendations for pediatric VTE study outcomes in general [4] and SSC recommendations for PTS outcome definitions in particular, among adults [6]. Final recommendations were derived by consensus. A manuscript draft was then developed by the Working Group and circulated to the Subcommittee chairman and S.R. Kahn, and subsequently revised to incorporate their input.

Overview of PTS measures reviewed

Pediatric studies reporting on standardized PTS assessment following lower extremity DVT have used one of the following measures: a pediatric modification of the Villalta score for adult PTS (referred to hereafter as ‘modified Villalta score’) [7–11]; the Manco-Johnson instrument, which combines the basic Clinical-Etiologic-Anatomic-Pathophysiologic (CEAP) classification of chronic venous disease with the Wong-Baker pediatric pain scale [12–14]; and the CEAP alone [15]. These measures have been summarized previously [3], and their components are listed in Tables 1 and 2.

Table 1.  Components of standardized outcome measures for PTS utilizing the modified Villalta score
  1. *Reported by patient, parent, caregiver or proxy. Greater than 3% increase in mid-calf circumference in the affected extremity compared with the contralateral side.

 Pain or abnormal use1
 Increased limb circumference1
 Change in skin color1
 Pitting edema1
 Venous collaterals on skin1
 Pigmentation of skin1
 Tenderness on palpation of deep veins1
 Varicosities1 moderate; 2 severe
 Head swelling1 moderate; 2 severe
Total score
 Mild post-thrombotic syndrome1–3
 Moderate post-thrombotic syndrome4–8
 Severe post-thrombotic syndrome≥ 9
Table 2.  Components of standardized outcome measures for PTS utilizing the Manco-Johnson instrument
  1. *Greater than 1 cm increase in mid-calf or mid-thigh circumference in the affected extremity compared with the contralateral extremity [13, 14].

 Dilated superficial collateral veins1
 Venous stasis dermatitis1
 Venous stasis ulcers1
 Chronic lower-extremity pain
  limiting aerobic activities1
  limiting activities of daily living1
  at rest1
Post-thrombotic syndrome absent0
Any post-thrombotic syndrome present≥ 1
Physically and functionally significant PTSSigns ≥ 1 and symptoms ≥ 1


While the Working Group concurred with the adult PTS recommendation that both the presence and clinical significance of PTS following lower extremity DVT be evaluated using objective (i.e. signs) and subjective (i.e. symptoms) criteria, it recognized limitations in the degree to which subjective criteria can be reliably assessed in pediatrics, particularly among young children. This value is reflected by the fact that neither the modified Villalta scale nor the Manco-Johnson instrument extensively assesses PTS symptoms when compared with the original (i.e. adult) Villalta scale. The Working group also agreed with the adult PTS recommendation that, to minimize confounding by acute thrombotic veno-occlusion, definitive diagnosis of PTS be deferred until at least 6 months following the acute DVT event. However, the Working Group further advocated for a time point of 6 months post-event as constituting ‘possible PTS’ and 12 or more months as indicating ‘definitive PTS’. This recommendation was based on the observation that, although data on natural history of PTS in children are limited, in a cohort study published by Goldenberg et al. employing annual PTS assessment, all cases of PTS at 2 years following presentation of acute DVT had been noted at 1 year post-event [12]. Given the lack of published validation data to date on test-retest reliability of pediatric PTS assessment, the Working group also recommended that a diagnosis of ‘definitive PTS’ in children presently be restricted by concordance on two independent PTS evaluations performed at least 3 months apart.

When considering the modified Villalta scale and the Manco-Johnson instrument, both strengths and weaknesses (summarized in Table 3) were identified for each measure and the published evidence for its validation and/or application. Based upon this assessment, the Working Group found insufficient justification to advocate the use of one measure over the other. Hence, the Working Group recommended that the definition of pediatric PTS (i.e. irrespective of clinical significance) employ the criteria displayed in Tables 1 and 2 for either the modified Villalta score or the Manco-Johnson instrument. The Working Group further recommended that a new entity termed clinically-important PTS in children be defined using the Manco-Johnson instrument, as summarized in Tables 1 and 2 and previously reported as ‘physically and functionally significant PTS’ [13,14]. Alternatively, although clinically-important PTS has not yet been defined in published work using the modified Villata score, evidence of pain using this measure and/or a score of > 3 could be used to define clinical significance. Lastly, the Working Group advised that, whenever feasible, forthcoming research should use both pediatric PTS measures in order to cross-validate PTS findings, better understand strengths and limitations of each measure, and potentially lead to the development of a harmonized measure adopting the most informative and reproducible components of the modified Villalta scale and Manco-Johnson instrument.

Table 3.  Strengths and weaknesses of the modified Villalta score (MVS) and Manco-Johnson instrument (MJI) and published evidence for their validation and application following lower extremity DVT in children
  1. IRR, inter-rater reliability; PTS, post-thrombotic syndrome; HR-QoL, health-related quality of life.

Feasible for clinical useYesYes
Internal validity (norms, IRR) publishedNoYes
Reports graded severity of PTSYesNo
Reports functional limitation (i.e. clinical significance)NoYes
External validity vs. HR-QoL publishedNoNo
Use in cohorts published from differing institutionsYesNo
Training material (e.g. video, assessment) implementedNoYes
Translation into multiple languages validatedNoNo


A systematic review of the pediatric DVT literature recently revealed marked variability in the definition, measurement and reporting (and consequently, observed frequency) of PTS [3]. The present recommendations represent an effort to improve standardization in the definition, measurement and reporting of PTS following lower extremity DVT in pediatric clinical investigations, whether prospective cohort studies or interventional clinical trials. As with the general VTE outcome recommendations of the Subcommittee, these recommendations are influenced by values and preferences of the Working Group members and their collective pediatric patient/parent clinical experiences. We acknowledge that each of the members, having been called upon by the Subcommittee for his/her expertise in the pediatric PTS field, has been a past contributor to, or is actively involved in, clinical research in the area; nevertheless, the Subcommittee has striven to minimize bias by means of the geographical and intellectual diversity of the Working Group’s membership, and via the process outlined above in the Methods for development of its recommendations.

In addition to the recommendations for definition and standardization of pediatric PTS, several priorities were identified for future work in the field. First, the modified Villalta score and Manco-Johnson instrument should both be administered in clinical investigations whenever feasible, in order to assess their concordance and comparative reliability, as well as identify advantages and disadvantages of each. If warranted, this could lead to the development of a unified measure that adopts optimal features of each system. Second, as noted previously, further validation efforts must be pursued on a multicenter basis, also evaluating sensitivity to change in signs/symptoms, and incorporating quality of life (QOL) measures. Third, although study design and analytic methodology were not in the purview of the Working Group (and are the subject of a separate effort by the Subcommittee), and although costly in time and resources, we nevertheless recommend that future pediatric multicenter clinical trials of DVT treatment and prophylaxis incorporate assessment of inter-rater reliability in PTS determination, via the utilization of two appropriately trained, independent, mutually-blinded PTS examiners in a subset of enrolled patients, in order to establish validity of PTS outcome determination in the pediatric clinical trial setting. Fourth, training in the use of the modified Villalta score and Manco-Johnson instrument must be made broadly and readily available, in order to facilitate standardization in practise, as well as to determine their acceptability and external validity. To this end, a training video developed by Dr Neil Goldenberg on the administration of the Manco-Johnson instrument is accessible via the internet at the Kids-DOTT clinical trial website ( Although we are not aware of a training video for the modified Villalta score, a training video for the original Villalta score has been developed by Dr Susan Kahn and is available via the internet at

Recommendations for standardization of PTS definitions and outcomes measures following upper extremity DVT are also needed, and should strive to address the clinical significance of ‘loss of venous access’, in addition to conventional signs and symptoms assessed by existing measures. Furthermore, post-thrombotic sequelae beyond the classic ‘syndrome’ defined for limb DVT are of great importance in other common forms of VTE in children (e.g. portal hypertension following portal vein thrombosis), and should be addressed. Such recommendations are the objective of future efforts by the Working Group.


N.A. Goldenberg and J. Journeycake are each funded in part by career development awards from the National Institutes of Health, and National Heart, Lung, and Blood Institute. S.R. Kahn is a recipient of a National Research Scholar Award from the Fonds de la Recherche en Santé du Quebec (FRSQ).

Disclosure of Conflict of Interests

The authors state that they have no conflict of interest.