PB0554 - Molecular, laboratory and clinical characteristics of inherited antithrombin deficiency: a large, single centre cohort study from the United Kingdom.

Background: Inherited antithrombin (AT) deficiency is an autosomal dominant thrombophilia resulting from variants in SERPINC1. It is associated with a high risk of venous thromboembolism (VTE).

Aims: To describe a large patient cohort with AT deficiency.

Methods: A single centre registry of 109 patients (40 male: 69 female). Patient consent was obtained to perform PCR-mediated Sanger sequencing for all SERPINC1 exons. Multiplex ligation-dependent probe amplification was used for copy number analysis to detect large deletions or duplications. AT activity and antigen levels were measured using established assays (Hyphen Biophen, France).

Results: We identified 43 causative variants in SERPINC1 gene including 14 novel. The most frequent variant (n=11) was AT Northwick Park (p.Arg425Cys). The variant types were: missense (66%), deletions (19% -one whole gene deletion), splice site (6%), duplications (2%), nonsense (1%), insertions (1%), unidentifiable (1%). Amongst all patients, 42% had Type 1 AT defects, 37% Type 2 and 21% were unclassified. Among Type 2 defects, 18% were heparin binding site (HBS), 15% reactive site (RS), and 3% pleiotropic (T2PE). Three unrelated patients had homozygous HBS defects for AT Budapest 3 (p.Leu131Phe). Two compound heterozygous variants (p.Asn450His and p.Arg457Thr) were identified in one family; consistent with Type 1 defect. FVL mutation was detected in 6 /77 (8%), of which five (83%) had VTE; PT20210 was detected in one case (1%). Table 1 describes the clinical characteristics of this cohort. The median age of VTE in all AT defects was < 50 years. There was a higher rate of VTE recurrence in those with Type 1 defects in comparison to Type 2 (57% vs 25%, d.f=1, χ2=5.2, p=0.02)

Conclusion(s): We demonstrate a high heterogeneity of SERPINC1 defects in the UK population with a predominance of Type 1. Approximately half of this cohort had no clear family history of VTE and/or AT deficiency.