Abstract
BackgroundPlasma phospholipid transfer protein (PLTP) transfers lipids between donors and acceptors (e.g., from HDL to VLDL) and modulates lipoprotein composition, size, and levels. No study has reported an assessment of the effects of PLTP on blood clotting reactions, such as reflected in thrombin generation assays, or on the association of venous thrombosis (VTE) risk with PLTP activity.MethodsThe in vitro effects of PLTP on blood coagulation reactions and the correlations between plasma PLTP activity levels and VTE were studied.ResultsRecombinant (r) PLTP concentration-dependently inhibited plasma thrombin generation and factor XII-dependent kallikrein generation when sulfatide was used to stimulate factor XII autoactivation in plasma. However, rPLTP did not inhibit thrombin generation in plasma induced by factor XIa or tissue factor, implicating an effect of PLTP on contact activation reactions. In purified systems, rPLTP inhibited factor XII autoactivation stimulated by sulfatide in the presence of VLDL. In surface plasmon resonance studies, purified factor XII bound to immobilized rPLTP, implying that rPLTP inhibits factor XII-dependent contact activation by binding factor XII in the presence of lipoproteins. Analysis of plasmas from 40 male patients with unprovoked VTE and 40 matched controls indicated that low PLTP lipid transfer activity (≤25th percentile) was associated with an increased risk of VTE after adjustment for body mass index, plasma lipids, and two known thrombophilic genetic risk factors.ConclusionThese data imply that PLTP may be an antithrombotic plasma protein by inhibiting generation of prothrombotic factor XIIa in the presence of VLDL. This newly discovered anticoagulant activity of PLTP merits further clinical and biochemical studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12959-015-0054-0) contains supplementary material, which is available to authorized users.
Highlights
Plasma phospholipid transfer protein (PLTP) transfers lipids between donors and acceptors and modulates lipoprotein composition, size, and levels
Effects of rPLTP on sulfatide-induced plasma thrombin generation When added to plasma in increasing amounts, rPLTP markedly reduced the total amount of thrombin generation and prolonged the lag time for thrombin generation in plasma activated by sulfatides (Fig. 1a)
RPLTP had no effect or only a very slight effect on factor XIainduced or tissue factor-induced thrombin generation in plasma (Figs. 1b and c). This suggests that rPLTP significantly inhibits the factor XII-dependent contact activation reactions but not the intrinsic or extrinsic coagulation pathways activated by factor XIa or tissue factor
Summary
Plasma phospholipid transfer protein (PLTP) transfers lipids between donors and acceptors (e.g., from HDL to VLDL) and modulates lipoprotein composition, size, and levels. No study has reported an assessment of the effects of PLTP on blood clotting reactions, such as reflected in thrombin generation assays, or on the association of venous thrombosis (VTE) risk with PLTP activity. The blood coagulation system is triggered by either the intrinsic or extrinsic pathway and involves sequential enzymatic activations of serine protease zymogens enhanced by non-enzymatic cofactors, factors Va and VIIIa, resulting in generation of thrombin [1, 2]. The lipid transfer protein, cholesteryl ester transfer protein (CETP), which carries and transfers lipids to modulate plasma lipoprotein levels, can exert procoagulant activity by enhancing prothrombinase activity in purified systems [18]. Molecular mechanisms for CETP procoagulant activity remain unclear, we hypothesized that other lipid transfer proteins can affect blood coagulation
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