Post-Thrombotic Syndrome Affecting the Upper Venous System in Children: Validation of Outcome Measurement and Application in a Single-Institutional Prospective Inception Cohort Study.
Authors: Goldenberg Neil A , Pounder Elizabeth , Knapp-Clevenger R. , Manco-Johnson Marilyn J. 
Published: October 2019

Abstract
Abstract 2979
Poster Board II-952

BACKGROUND AND OBJECTIVES:
Post-thrombotic syndrome (PTS) is an important long-term sequela of deep venous thrombosis (DVT) in children, which may involve the upper or lower venous systems (UVS, LVS). The understanding of pediatric PTS has been limited by variability in outcome measurement, and prospective data are particularly lacking for DVT involving the UVS. Validation data have been published for the performance of a pediatric PTS outcome measure (the Manco-Johnson instrument; Figure 1) in the LVS (Goldenberg et al., Blood 2007).
The aims of the present work were to: (1) investigate validity of the Manco-Johnson instrument in the UVS in children, via a cross-sectional derivation cohort/validation cohort design; and (2) preliminarily determine the cumulative incidence of PTS in a prospective inception cohort study of children with DVT affecting the UVS.

METHODS AND RESULTS:

Validation study:
All parameters of the Manco-Johnson instrument were assessed in a derivation cohort (n=78) consisting of healthy children aged 12 months to 21 years who were without personal or first-degree family history of thromboembolism before age 55 years, grouped by age as follows: preschool (12 mo – <6 y; n=30); school age (6 - <13 y, n=28); adolescent (13 – 21 y, n=20). Inter-rater reliability in each parameter of the instrument was evaluated in a mixed validation cohort (n=41) of healthy children and patients with history of DVT affecting the UVS. In the derivation cohort, the upper limit of normal values for contralateral difference in upper limb circumference was 1.0 cm for mid-forearm and mid-upper arm measurements, as calculated by the non-parametric method of Tukey. In addition, dilated superficial collateral veins, venous stasis dermatitis, venous stasis ulcers, and chronic pain of the upper limb, chest or neck that limits activities of daily living or aerobic exercise were all absent among these healthy children. Inter-rater reliability, measured as percent agreement, exceeded 95% for all parameters when applied in the validation cohort by mutually-blinded dual examiners trained in the use of the instrument.

Prospective inception cohort study:
Inclusion criteria consisted of radiologically confirmed DVT of the subclavian vein, brachiocephalic vein, and/or superior vena cava (SVC), and study enrollment between March 2006 and July 2009. All children underwent comprehensive thrombophilia testing and were managed with anticoagulation in accordance with ACCP pediatric guidelines, for a minimum duration of 3 months. In some cases, acute thrombolytic therapy was instituted based upon clinical decisions. Children were evaluated for PTS using the Manco-Johnson instrument at 3-6 months, 12 months, and annually thereafter in long-term follow-up. Repeat imaging was performed at minimum at 3-6 months post-diagnosis, and if persistent, again at 1 year. Prevalence of PTS was analyzed based upon findings at latest follow-up (minimum 1 year post-diagnosis). Individual patient data on diagnostic findings, treatment, thrombus resolution, and PTS outcome are given in Table 1. Among 13 subjects meeting eligibility criteria, median age at DVT diagnosis was 16 years (range: 2 - 21 years). The SVC was involved in one child. Clinical predisposition consisted of central venous catheterization in approximately 50% of cases and an underlying anatomic vascular abnormality (thoracic outlet syndrome, Paget-Schroetter syndrome) in an additional 23%. Thrombophilia at presentation consisted of elevated factor VIII in 70% and antiphospholipid antibodies in nearly 50%. Thrombolysis was employed in the 2 children with anatomic defects and one with catastrophic antiphospholipid antibody syndrome. DVT persisted following a 3-6 course of anticoagulant therapy in 50% of evaluable patients. The cumulative incidence of PTS at 1-2 years among 7 evaluable patients was 29%, and involved both physical findings and functional impairment (i.e., chronic pain limitation) in each case.

CONCLUSIONS:
The present findings demonstrate the validity of the Manco-Johnson instrument for pediatric PTS outcome measurement involving the UVS. Using this instrument, PTS appears to be common in children with DVT affecting the UVS, and functionally significant. Broader use of the Manco-Johnson instrument for PTS outcome assessment in prospective studies and clinical trials of pediatric DVT is warranted.

Disclosures:
Off Label Use: The presentation refers to the use of anticoagulants as a drug class in general in the treatment of venous thromboembolism (VTE) in children. Despite their use in the standard care for pediatric VTE, all anticoagulants remain off-label for this indication in children.