Standardization of post-thrombotic syndrome definition and outcome assessment following upper venous system thrombosis in pediatric practice

Authors

  • S. REVEL-VILK,

    1. Department of Pediatric Hematology/Oncology, Hadassah Hebrew-University Hospital, Jerusalem, Israel
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  • L. R. BRANDÃO,

    1. Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Paediatrics, Hospital for Sick Children, Toronto, Canada
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  • J. JOURNEYCAKE,

    1. Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
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  • A. GOLDENBERG,

    1. Division of Hematology/Oncology, Department of Pediatrics, Section of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, the Mountain States Regional Hemophilia and Thrombosis Center, and CPC Clinical Research, Children’s Hospital Colorado, University of Colorado, Aurora, CO, USA
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  • P. MONAGLE,

    1. Department of Clinical Haematology, Royal Children’s Hospital, University of Melbourne, Melbourne, Australia
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  • A. SHARATHKUMAR,

    1. Division of Hematology/Oncology and Stem Cell Transplantation, Ann and Rober H. Lurie Children’s Hospital of Chicago, 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, 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

Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 12, Issue 11, 1948, Article first published online: 10 November 2014

Shoshana Revel-Vilk, Department of Pediatric Hematology/Oncology, Hadassah Hebrew-University Hospital, POB 12000, Jerusalem 91120, Israel.
Tel.: +972 2 6777 408; fax: +972 2 6777 833.
E-mail: shoshanav@hadassah.org.il

Introduction

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 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 [1].

Rationale

The subcommittee recently published the definition of PTS following lower extremity DVT and standardization of outcome measurement in pediatric clinical investigations [2]. The subcommittee further identified the need to separately define PTS following non-cerebral upper venous system thrombotic event (UVSTE), given the mechanical differences (e.g. gravity, weight bearing) between the upper and lower venous systems of the body and the higher rate of UVSTE secondary to central venous catheters (CVCs) [3].

Methods

A Working Group for Pediatric PTS was comprised of S. Revel-Vilk and A. K. C. Chan (co-chairman), L. R. Brandão, J. Journeycake, N. A. Goldenberg and A. Sharathkumar. A systematic review of adult and pediatric upper venous system PTS literature was performed using PubMed, including the following terms: post-thrombosis AND upper extremity; post-thrombotic AND upper extremity; upper extremity thrombosis.

Results

Summary of literature review

Few studies have reported the prevalence and risk factors of PTS after a UVSTE in adults [4–12]. A systemic review of PTS after upper extremity DVT was published in 2006; seven studies were reviewed [5]. Frequency of PTS after a UVSTE ranged from 7% to 46%, with a weighted mean frequency of 15%. As no scale was validated for assessment of PTS post-UVSTE, various definitions were used for PTS. Two studies used a modification of the Villalta PTS scale for lower extremity [4,11]. Residual thrombus after therapy and axillary or subclavian involvement appeared to be associated with increased risk and a CVC-related UVSTE was associated with decreased risk of PTS [5]. In a later study, 32 adults with a primary UVSTE were tested for development of PTS using several scales (i.e. modified Villalta scale, Disability of the Arm, Shoulder and Hand (DASH) score, Visual Analogue Scale (VAS) and arm exercise test); 28% of patients had mild to moderate PTS [6]. The modified Villalta scale and DASH score showed a moderate correlation (r = 0.58, P < 0.001). By contrast, scores for the arm exercise test and VAS did not differ between those with and those without PTS, as defined by the modified Villalta score. A study that followed 55 adult patients with a UVSTE found that scoring for PTS was effective to assess its severity, but did not discriminate PTS from other causes of arm complaints [7]. The scoring used in this study was a non-validated scoring system. Functional disability was greater, and quality of life (QoL) was lower, among patient with PTS, compared with those without PTS [4,8], and when PTS involved the dominant arm [4]. Validation of a standardized scale specific for PTS of the upper extremity was recommended to standardize the diagnosis of this condition and consequently help to establish better management protocols [5]. In addition, it was recommended to study the impact of upper extremity PTS on patients’ QoL, daily symptoms and ability to carry out activities of daily living, particularly if the dominant arm is affected.

In children, most studies of PTS included children with both lower and upper venous system thrombotic events [1], without separately reporting PTS outcomes for the two entities. However, in a recently published study of 69 children with venous thrombotic events, PTS assessed with the modified Villalta scale was found in 4/21 (19%) children after UVSTEs; this was less frequent when compared with the PTS rate after lower extremity DVT (32/49; 65%) [13].

Similar to the adult recommendations, the Working Group concluded that standardization of a PTS tool for UVSTEs in children is needed, with special emphasis on the effects on QoL, daily activities and symptoms. As in the pediatric age group most venous thrombosis events are in the upper venous system, the standardization and the applicability of a PTS scale post-UVSTE is at least as important for this population. While steps have been taken toward establishment of pediatric age-specific norms for contralateral difference in limb circumference (one key feature in UVSTE PTS) [13,14] and validation of one pediatric scale (the Manco-Johnson instrument) [14], the subcommittee concluded from the literature review that both the modified Villalta score and the Manco-Johnson instrument have limitations in UVSTE PTS assessment. These limitations are further discussed below, informing recommendations for standardization of definition and outcome assessment of PTS following a UVSTE in children.

Points for consideration

The Working Group concluded that the current definition of PTS as a syndrome characterized by various combinations of swelling, dilated collateral venous circulation, skin changes relating to venous stasis and pain/discomfort is most fitting for lower extremity PTS. However, the syndrome must be defined more broadly to account for the spectrum of post-thrombotic sequelae observed following DVT in other vascular territories, such as the cerebral sinovenous system (e.g. loss of visual acuity, chronic headache), renal veins (e.g. chronic hypertension), portal venous system (e.g. gastroesophageal variceal bleeding) and upper venous system. With specific regard to the upper venous system (the purview of this report), the Working Group identified several differences between the lower extremities and the upper venous system that may affect the scoring of a PTS scale post-UVSTE. First, the physical and functional findings may differ in their presence/severity. As there is no weight bearing on the upper extremities, the physical findings of UVSTE PTS are expected to be less severe compared with lower extremity PTS. The functional findings in the upper extremities may consist less of pain, and manifest more with impairment in gross or fine motor functions. Second, in children most UVSTEs are secondary to CVCs. Development of a CVC-related thrombosis can effect catheter patency and result both in catheter removal and in loss of venous patency for future venous access; the latter feature is not scored in the current PTS scales. Third, the current PTS scales capture signs and symptoms principally related to the extremity, with assessment simply made of presence/absence of superior vena cava syndrome. Therefore, dilated superficial collateral veins and venous eczema of the neck is likely to go un-scored when absent in the upper extremities. In addition, the Working Group addressed the issue of existence of PTS after CVC use in children, without history of overt DVT. Although by definition, PTS cannot be diagnosed without an antecedent venous thrombosis, the Working Group recognized the importance of vessel injury secondary to the use of CVCs, and of CVC-related asymptomatic thrombosis. Indeed, physical and functional findings similar to those reported in PTS have been reported secondary to the use of CVCs [14–17].

Recommendations

  • 1 PTS scales comprehensively assessing post-thrombotic outcomes following a UVSTE, especially in the research setting, should include physical, functional and QoL domains (Table 1).
  • 2 Neck and head findings should be included in the post-UVSTE PTS scale. The same physical and functional items scored in the upper extremities should be scored in the head/neck (with the exception of contralateral difference in circumferences, which is not applicable).
  • 3 Loss of venous access should be part of the post-UVSTE PTS scale. Loss of venous access could be defined in two ways: by residual complete occlusion or atresia of a vessel (e.g. subclavian vein) on appropriate radiological imaging, or via surgical report documenting inability to insert a subsequent CVC through the vein. The Working Group recognized that inclusion of the latter in the PTS score might cause reporting bias as only those needing a CVC for the long term, with repeated CVC insertion attempts, could be scored. In order to minimize the report bias the subcommittee suggests reporting separately PTS for CVC-related DVT and non-CVC-related DVT.
  • 4 A scripted questionnaire should be employed to standardize the assessment of limitations in age-appropriate activities involving the upper extremity, head and neck. The development of such a questionnaire would benefit from collaboration between pediatric thrombosis experts and occupational therapists/physiotherapists who more routinely assess upper extremity functional limitations.
  • 5 As suggested for lower extremity PTS, QoL measurements should be part of the assessment of PTS [2]. It is likely that a pediatric venous-specific QoL tool will need to be developed and validated for this purpose.
  • 6 Because PTS signs and symptoms have been reported in patients with CVCs in the absence of overt DVT history, and in order to better appreciate the long-term consequences of CVCs, PTS occurring after CVC-related DVT should be reported separately from PTS after CVC use (in the absence of overt DVT history).
Table 1.   Physical, functional and QoL domains in PTS assessment following UVSTE
DomainItems to be assessed
  1. QoL, quality of life; PTS, post-thrombotic syndrome; UVSTE, upper venous system thrombotic event.

PhysicalSwelling, increased limb circumference, changes in skin color, collaterals, tenderness on palpation, varicosities, ulceration, head swelling
FunctionalPain at rest, pain limiting activities, limitation in activities (not associated with pain), loss of venous access
QoLPediatric quality of life measurements, pediatric venous-specific quality of life

The present recommendations represent an effort to improve standardization in the definition, measurement and reporting of UVSTE PTS in children (Table 2). Other recommendations related to standardization of pediatric PTS, including additional validation efforts in children and the timing of assessments, were discussed in a previous Working Group communication on PTS following DVT of the lower extremities [2]. These efforts will be critical to achieving the recommended incorporation of PTS as a reliable endpoint in future interventional clinical trials of antithrombotic therapies in children [18].

Table 2.   Strengths and weaknesses of the modified Villalta score (MVS) and Manco-Johnson instrument (MJI) for assessment of PTS post-UVSTE scale
CharacteristicMVSMJI
  1. PTS, post-thrombotic syndrome; UVSTE, upper venous system thrombotic event.

Assessment of normal pediatric upper venous systemYesYes
Validation of PTS instrument for upper venous systemNoYes
Assessment of physical findingsYesYes
Assessment of painYesYes
Assessment of loss of venous accessNoNo
Assessment of age-appropriate limitation in activitiesNoNo
Assessment of quality of lifeNoNo

Disclosure of Conflict of Interests

The authors state that they have no conflict of interest.

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