Abstract Number: OC 12.3
Meeting: ISTH 2020 Congress
Background: Antithrombin deficiency (AD) is a severe autosomal dominant thrombophilia. The natural history and genotype-phenotype correlation of AD in children is unclear.
Aims: To elaborate the clinical presentation of congenital AD in children and evaluate its correlation to specific mutations in SERPINC1.
Methods: In 2017, a prospective pediatric-database and DNA-biorepository for congenital AD was established at Nationwide Children’s Hospital (NCH). During the pilot/feasibility phase the database was opened at 4 tertiary-care hospitals in Canada and the US. Approval from research-ethics-board was obtained at each participating hospital. Written consent/assent was obtained from guardians/subjects who met eligibility criteria. Clinical data was entered into a REDCap database. Participating centers had the option of shipping whole-blood to NCH, where DNA extraction and SERPINC1 sequencing were performed. Standard statistical methods were used to summarize parameters. Probability of VTE-free survival was assessed using the Kaplan-Meier method.
Results: 43 participants (25 female) from 31 unique kindreds have been enrolled. Median age (range) at enrollment was 14.8 (1-21) years, median AT activity was 0.52 (0.24-0.87) IU/ml, and median AT antigen level (n=20) was 0.41 (0.12-1.1) IU/ml. 19 (44%) participants have a history of venous thrombo-embolism (VTE). Median age at VTE diagnosis was 12.4 (0.1-19.2) years. Thrombotic locations included leg veins (n=13), cerebral veins (n=5) and pulmonary embolism (n=5). 9 (47%) VTE events were unprovoked. SERPINC1 sequencing has been completed for 30 participants and 21 unique mutations have been identified, including 7 novel variants. Probability of 5-year VTE-free survival (95% CI) for carriers of missense mutations [91.7% (81.3-100)] is significantly higher than carriers of null mutations [60% (33.2-100)]; p< 0.0001 (Figure 1)]. Molecular modeling of novel variants is currently underway.
Conclusions: This is the first pediatric study to document a more severe thrombotic phenotype in carriers of null mutations in SERPINC1, when compared to carriers of missense mutations; underscoring the clinical utility of genetic-testing.
[Figure 1: Probability of VTE free survival in children with congenital antithrombin deficiency]
To cite this abstract in AMA style:
Kumar R, Bakeer N, Al Mughairy A, Dawson J, Stanek J, Dunn A, Chan A, Male C, Forman-Kay J, Williams S. Impact of SERPINC1 Mutation on Thrombotic Phenotype in Children with Congenital Antithrombin Deficiency – First Analysis of the International Society on Thrombosis and Hemostasis (ISTH) Pediatric AT Database and Biorepository [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/impact-of-serpinc1-mutation-on-thrombotic-phenotype-in-children-with-congenital-antithrombin-deficiency-first-analysis-of-the-international-society-on-thrombosis-and-hemostasis-isth-pediatric-at-d/. Accessed March 21, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/impact-of-serpinc1-mutation-on-thrombotic-phenotype-in-children-with-congenital-antithrombin-deficiency-first-analysis-of-the-international-society-on-thrombosis-and-hemostasis-isth-pediatric-at-d/