Plasma cholesteryl ester transfer protein and blood coagulability

 

 Buy Article Permissions and Reprints

Summary

Dyslipoproteinemia involving low levels of high density lipoprotein (HDL) is linked to venous thrombosis in young male adults and to recurrence of venous thrombosis in patients who have experienced a previous unprovoked venous thrombosis episode. Plasma cholesteryl ester transfer protein (CETP) modulates HDL metabolism and some lipoproteins can affect blood coagulation reactions with either procoagulant or anticoagulant effects. Hence, we evaluated relationships between the mass of CETP and blood coagulability in plasma samples from 39 normal healthy adults. For clotting initiated by dilute tissue factor or factor XIa,clotting times significantly correlated with CETP antigen levels. Thus,coagulation initiated by either the extrinsic or intrinsic coagulation pathway is positively correlated with CETP plasma levels. When added to plasma, a recombinant CETP preparation dose-dependently shortened factor Xa-1-stage clotting times, showing that it augmented procoagulant activity in plasma. In reaction mixtures containing purified factors Xa and Va and prothrombin, the recombinant CETP preparation dose-dependently increased prothrombin activation, suggesting it specifically enhances prothrombinase activity. Thus, our data highlight a previously unknown positive relationship between CETP plasma levels and blood coagulability that might relate to risks for thrombotic events.

• References

• 1 García de Frutos P. Mechanisms of thrombophilia. Thromb Haemost 2007; 98: 485-487.
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 Medina P, Navarro S, Estellés A. et al. Polymorphisms in the endothelial protein C receptor gene and thrombophilia. Thromb Haemost 2007; 98: 564-569.
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Vayá A, Falcó C, Simó M. et al. Influence of lipids and obesity on haemorheological parameters in patients with deep vein thrombosis. Thromb Haemost 2007; 98: 621-626.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Tsai AW, Cushman M, Rosamond WD. et al. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162: 1182-1189.
  CrossrefPubMedGoogle Scholar
• 5 Kawasaki T, Kambayashi J, Ariyoshi H. et al. Hypercholesterolemia as a risk factor for deep-vein thrombosis. Thromb Res 1997; 88: 67-73.
  CrossrefPubMedGoogle Scholar
• 6 Lippi G, Brocco G, Manzato F. et al. Relationship between venous thromboembolism and lipid or lipoprotein disorders. Thromb Res 1999; 95: 353-354.
  CrossrefPubMedGoogle Scholar
• 7 Gonzalez-Ordonez AJ, Fernandez-Carreira JM, Fernandez-Alvarez CR. et al. The concentrations of soluble vascular cell adhesion molecule-1 and lipids are independently associated with venous thromboembolism. Haematologica 2003; 88: 1035-1043.
  PubMedGoogle Scholar
• 8 Deguchi H, Pecheniuk NM, Elias DJ. et al. Highdensity lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men. Circulation 2005; 112: 893-899.
  CrossrefPubMedGoogle Scholar
• 9 Eichinger S, Pecheniuk N. M, Hron G. et al. High density lipoprotein and the risk of recurrent venous thromboembolism. Circulation 2007; 115: 1609-1614.
  CrossrefPubMedGoogle Scholar
• 10 Pecheniuk NM, Deguchi H, Elias DJ. et al. Cholesteryl ester transfer protein genotypes associated with venous thrombosis and dyslipoproteinemia in males. J Thromb Haemost 2006; 4: 2080-2082.
  CrossrefPubMedGoogle Scholar
• 11 Griffin JH, Fernandez JA, Deguchi H. Plasma lipoproteins, hemostasis and thrombosis. Thromb Haemost 2001; 86: 386-394.
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Griffin JH, Kojima K, Banka CL. et al. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. J Clin Invest 1999; 103: 219-227.
  CrossrefPubMedGoogle Scholar
• 13 Mineo C, Deguchi H, Griffin JH. et al. Endothelial and antithrombotic actions of HDL. Circ Res 2006; 98: 1352-1364.
  CrossrefPubMedGoogle Scholar
• 14 Barter PJ, Brewer Jr HB, Chapman MJ. et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 160-167.
  CrossrefPubMedGoogle Scholar
• 15 Deguchi H, Fernandez JA, Hackeng TM. et al. Cardiolipin is a normal component of human plasma lipoproteins. Proc Natl Acad Sci U S A 2000; 97: 1743-1748.
  CrossrefPubMedGoogle Scholar
• 16 Kyrle PA, Weltermann A, Minar E. et al. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004; 350: 2558-2563.
  CrossrefPubMedGoogle Scholar
• 17 White RH, Dager WE, Zhou H. et al. Racial and gender differences in the incidence of recurrent venous thromboembolism. Thromb Haemost 2006; 96: 267-273.
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Jackson CM. Models for reaction mechanisms in haemostasis – contributions from the study of prothrombin activation. Thromb Haemost 2007; 98: 24-35.
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 Qiu X, Mistry A, Ammirati MJ. et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol 2007; 14: 106-113.
  CrossrefPubMedGoogle Scholar
• 20 de Grooth GJ, Kuivenhoven JA, Stalenhoef AF. et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation 2002; 105: 2159-2165.
  CrossrefPubMedGoogle Scholar
• 21 Clark RW, Sutfin TA, Ruggeri RB. et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 2004; 24: 490-497.
  CrossrefPubMedGoogle Scholar
• 22 Brousseau ME, Schaefer EJ, Wolfe ML. et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004; 350: 1505-1515.
  CrossrefPubMedGoogle Scholar
• 23 Tall AR. CETP inhibitors to increase HDL cholesterol levels. N Engl J Med 2007; 356: 1364-1366.
  CrossrefPubMedGoogle Scholar
• 24 Kastelein JJ, van Leuven SI, Burgess L. et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007; 356: 1620-1630.
  CrossrefPubMedGoogle Scholar
• 25 Nissen SE, Tardif JC, Nicholls SJ. et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007; 356: 1304-1316.
  CrossrefPubMedGoogle Scholar
• 26 Pearson H. When good cholesterol turns bad. Nature 2006; 444: 794-795.
  PubMedGoogle Scholar
• 27 Clark RW, Ruggeri RB, Cunningham D. et al. Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action. J Lipid Res 2006; 47: 537-552.
  CrossrefPubMedGoogle Scholar