Abstract 34: Elevated Plasma CETP Activity and Hyper-procoagulant R451Q-CETP Mutation Linked to Venous Thrombosis Risk

Abstract

Cholesteryl ester transfer protein (CETP) is an important lipid transfer factor in plasma that enhances prothrombinase activity in purified reaction mixtures. To test the hypothesis that CETP activity is linked to venous thrombosis (VTE), we measured CETP lipid transfer activity in plasmas of 49 male VTE patients (age < 55 yrs old) and matched controls. CETP activity levels were significantly higher for VTE patients than controls (p= 0.0008) (see Figure panel A). Elevated CETP activity (> 90th percentile of controls) was significantly associated with VTE risk (odds ratio= 4.1 (95%CI, 1.4-13)). A subset of patients carrying CETP mutations A373P and R451Q, which were also linked to VTE risk, showed significantly higher plasma CETP activity compared with non-carriers (110 % (105-115 %) vs 80 % (66-92 %) (p=0.0004)). To test the hypothesis that these mutations enhance procoagulant activity of CETP, we made recombinant CETPs in a stable HEK293 cell expression system and measured the procoagulant activity of recombinant wt-CETP, A373P-CETP, and R451Q-CETP that were added to reaction mixtures containing factors Xa, Va, prothrombin and lipids. Quite remarkably, the R451Q-CETP mutant had five-fold higher thrombin generation activity compared to wt-CETP or A373P-CETP (see Figure panel B). In summary, our data show that (1) elevated CETP lipid transfer activity in plasma was associated with the risk of VTE and (2) recombinant R451Q-CETP which is linked to VTE has much higher procoagulant activity than wt-CETP. These clinical and basic findings indicate that the lipid transfer activity of CETP may contribute to risk for thrombosis and that further studies of this hypothesis are merited.