Impact of SERPINC1, PROC and PROS1 Mutations on the Thrombotic Phenotype in Children with Venous Thromboembolism: An Observational Multicenter Cohort Study
Authors: Limperger Verena , Kenet Gili , Heller Christine , Kurnik Karin , Knoefler Ralf , Mesters Rolf M , Halimeh Susan , Nowak-Göttl Ulrike 
Published: October 2019

Abstract
Background: Venous thromboembolism [TE] is a multifactorial disease and antithrombin [ATD] -, protein C [PCD] - or protein S [PSD] -deficiency constitutes a major risk factor. The objective of the present study was to i) evaluate the prevalence of ATD, PCD and PSD in a white Israeli-German cohort of children with TE, ii) the underlying gene mutations, and iii) the clinical presentation of ATD, PCD and PCS on symptomatic TE in children.
Methods: In 367 unselected children (0.1-18 years) with TE recruited between July 1996 and December 2013 from Germany & Israel, a comprehensive thrombophilia screening was performed. Along with standardized plasma-based coagulation assays and the use of age-dependent reference values ATD, PCD and PSD were confirmed by family studies and/or molecular diagnosis [gene sequencing & multiplex ligation-dependent probe amplification]. Apart from descriptive analysis non-parametric statistics was performed. To compare the rates of deficiency phenotypes, locations of TE, spontaneous versus provoked TE, presence or absence of a positive family history of TE, Chi-square or Fisher’s exact test was applied.
Results: 6.6% of children were ATD, 6.8% PCD including purpura fulminans (1.4%) and 8.2% patients carried PSD. Mean age at first TE was 13 years (range 0.1 to 18) with no statistically significant difference found between deficiency phenotypes (p=0.32). 38 children were male. 72 of 76 children (95%) showed type 1 deficiency, whereas in 4 cases [ATD] a type 2 deficiency was found (p=0.004). Underlying gene mutations were in the majority of cases missense mutations (SERPINC1: 75%; PROC: 93%; PROS1: 72%), with 24% presence of the Herleen polymorphism (CM951058) in children with PSD. Homozygous genotypes were found in 4 cases [ATD], 6 cases [PCD] and in one PSD carrier [p=0.07]. ATD co-occurred with the factor 5 mutation [F5] at rs6025 in one and the factor 2 susceptibility variant [F2] at rs1799963 in two children. PSD co-occurred with the F5 or the homozygous F2 in one case each. Apart from purpura fulminans which was seen only in neonates with homozygous PCD, thrombotic locations were similarly distributed (p=0.11): multiple veins (n=7), cerebral veins/stroke of venous origin (n=18), deep veins [DVT; n=38], DVT & pulmonary embolism (n=13). The rates of provoked TE were 57% [ATD], 48% [PCD] and 60% in PCD (p=0.06). A positive family history was present in 43% [ATD], 40% [PCD] and 57% [PSD; p=0.41]. After withdrawal of anticoagulation, - performed on an individual basis according to CHEST guidelines (updated according to year of publication) -, recurrence rates were 38% [ATD], 24% [PCD] and 6.6% in carriers of PSD (p=0.017).
Conclusion: Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high risk population

Disclosures
No relevant conflicts of interest to declare.