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.
METHODS: The in vitro effects of PLTP on blood coagulation reactions and the correlations between plasma PLTP activity levels and VTE were studied.
RESULTS: Recombinant (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.
CONCLUSION: These 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.