CO086 | CLINICAL AND GENETIC CHARACTERIZATION OF A NEW FAMILY CARRYING THE “FACTOR VIII PADUA” F8 DUPLICATION

Abstract

Background and aims. Elevated factor VIII (FVIII) levels represent a strong risk factor for venous thromboembolism (VTE), yet the underlying genetic determinants remain incompletely defined.Aims. To report a clinical case of recurrent VTE associated with a partial F8 gene duplication and to describe the thrombotic phenotype within the family through pedigree analysis.Methods. Clinical history and pedigree were collected from the proband and relatives. FVIII clotting activity and FVIII antigen were measured using routine assays. F8 copy number variation was assessed by multiplex ligation-dependent probe amplification (MLPA). Whole-blood thrombin generation (WB-TG) was performed in available subjects under basal conditions and after addition of 20 nM thrombomodulin (TM), measuring lag time, endogenous thrombin potential (ETP), peak thrombin, and TM-mediated inhibition. Platelet-poor plasma (PPP)-TG was assessed in parallel.Results. The proband (II-2, female, 50 years) experienced recurrent deep vein thrombosis, with the first onset at 17 years during oral contraceptive use. The pedigree (Figure 1-A) revealed additional thrombotic manifestations among first-degree relatives, including VTE in the mother (I-2, female, 82 years) and in a male sibling (II-7, 60 years), both in the absence of major transient risk factors. Another carrier (II-3, female, 42 years) developed superficial vein thrombosis in the context of COVID-19 infection, whereas one tested relative (II-6, female, 56 years) had no history of thrombotic events. Standard thrombophilia screening was negative in all tested individuals. However, markedly elevated FVIII levels were consistently observed in all carriers, with FVIII:C ranging from 457% to 498% and FVIII:Ag from 465% to 550%, while the non-carrier relative showed substantially lower levels (FVIII:C 201%, FVIII:Ag 175%). MLPA and further genetic characterization confirmed the duplication of the proximal portion of the F8 gene (promoter, exon 1, and a large part of intron 1, identified as “Factor VIII Padua”) in all affected subjects (Figure 1-B), whereas one unaffected tested relative (II-6, female, 56 years) had no history of VTE, lower FVIII levels, and wild type MLPA. At the time of evaluation, most affected individuals were receiving anticoagulant therapy (edoxaban 60 mg or rivaroxaban 10 mg), with the exception of one carrier (II-3). WB-TG demonstrated a hypercoagulable profile in all tested carriers, with minimal TM-mediated inhibition in the only carrier not receiving anticoagulant therapy (II-3; ETP ratio 0.92) (Figure 1-C). In contrast, PPP-TG showed a hypercoagulable phenotype only in the untreated carrier (II-3) (Figure 1-D). Notably, the PPP-TG ETP ratio was increased in three carriers (0.80, 0.88, and 0.78), further supporting reduced TM sensitivity in plasma.Conclusions. This report adds a new thrombophilic family carrying the “Factor VIII Padua” (F8 duplication) variant to the limited number of families described to date. The combination of extreme FVIII elevation, MLPA confirmation, and thrombin generation evidence supports a consistent FVIII-driven prothrombotic phenotype.