title: Inhibition of thrombin generation in human plasma by phospholipid transfer protein.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM180, 10550 North Torrey Pines Rd., La Jolla, CA 92037 USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Deguchi
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Northwest Lipid Metabolism and Diabetes Research Laboratories, Department of Medicine, University of Washington, Seattle, WA 98109 USA.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Wolfbauer
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Northwest Lipid Metabolism and Diabetes Research Laboratories, Department of Medicine, University of Washington, Seattle, WA 98109 USA.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Cheung
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM180, 10550 North Torrey Pines Rd., La Jolla, CA 92037 USA ; Current Address: Department of Biochemistry, College of Medicine and Health Sciences, SQ University, Muscat, Oman.
authors.forename: Yajnavalka
authors.initials: Y
authors.lastname: Banerjee
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM180, 10550 North Torrey Pines Rd., La Jolla, CA 92037 USA.
authors.forename: Darlene J
authors.initials: DJ
authors.lastname: Elias
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM180, 10550 North Torrey Pines Rd., La Jolla, CA 92037 USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Northwest Lipid Metabolism and Diabetes Research Laboratories, Department of Medicine, University of Washington, Seattle, WA 98109 USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Albers
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM180, 10550 North Torrey Pines Rd., La Jolla, CA 92037 USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
keywords: Factor XII; Phospholipid transfer protein; Thrombin generation; Venous thromboembolism