Despite the essential
anticoagulant function of
antithrombin and the high risk of
thrombosis associated with its deficiency, the prevalence of
antithrombin deficiency among patients with
venous thromboembolism (VTE) is very low. However, increasing evidence suggests that
antithrombin deficiency may be underestimated. The analysis of SERPINC1, the gene encoding
antithrombin, in 1,304 consecutive Chinese VTE patients and 1,334 healthy controls revealed a hotspot involving residues 294 and 295 that severely increases the risk of VTE. We detected the c.883G>A (p.Val295Met) (rs201381904) mutation in 11 patients and just one control (OR = 13.6; 95% CI: 1.7-107.1); c.881G>T (p.Arg294Leu) (rs587776397) in six patients but no controls; and c.880C>T (p.Arg294Cys) (rs747142328) in two patients but no controls. In addition, c.881G>A (p.Arg294His) (rs587776397) was identified in one control. These mutations were absent in a Caucasian cohort. Carriers of these mutations had normal
antithrombin levels and
anticoagulant activity, consistent with results obtained in a recombinant model. However, mutation carriers had a significantly increased endogenous
thrombin potential. Our results suggest the existence in the Chinese population of a hotspot in SERPINC1 that significantly increases the risk of VTE by impairing the
anticoagulant capacity of the
hemostatic system. This effect is not revealed by current
antigen or in vitro functional
antithrombin assays.