Procoagulant activities of plasma factor VIIc and factor Xc are positively and independently associated with concentrations of the high-density lipoprotein apolipoprotein, apo A-II

Summary

The pro- and antiatherogenic roles of apolipoproteins B andA-I, respectively, are well-established although the importance of apolipoprotein A-II remains unclear. There is extensive evidence for the involvement of plasma lipoproteins in haemostatic function. However, in-vivo studies of relationships between haemostatic variables and apolipoprotein concentrations are very limited. Plasma fibrinogen, factors VIIc and Xc (FVIIc and FXc, respectively), apolipoproteins (apo) A-I, A-II and B, triglycerides, total, low-density and high-density lipoprotein (HDL) cholesterol, and cholesterol in HDL subfractions 2 and 3 were measured in 186 apparently healthy Caucasian men (aged 26–78 years; body mass index 19.9–37.8 kg/m²).Associations between haemostatic, apolipoprotein,lipid and lipoprotein variables were explored in uni- and multivariable analyses. Fibrinogen did not correlate with any of the lipid-related variables. FVIIc and FXc were significant positive univariate correlates of total cholesterol (correlation coefficients 0.26,p<0.001 and 0.19,p<0.05,respectively) triglycerides (0.37, p<0.001 and 0.36, p<0.001), and apoB (0.21, p<0.01 and 0.17, p<0.05) and apoA-II (0.19, p<0.05 and 0.29, p<0.001). HDL₂ subfraction cholesterol correlated negatively with FVIIc and FXc (-0.20, p<0.01 and –0.22, p<0.01, respectively). In multivariable analysis, only the associations of FVIIc and FXc with total cholesterol, triglycerides and apoA-II remained statistically significant. In conclusion, total cholesterol and triglycerides were the major independent lipid correlates of FVIIc and FXc. The independent and positive associations of apoA-II with FVIIc and FXc suggest a prothrombotic involvement for this apolipoprotein

Keywords

Apolipoproteins - high density lipoprotein - lipids - apoA-II - factor VII - factor X - fibrinogen

• References

• 1 Alessi M-C, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008; 99: 995-1000.
• 2 Rosenson RS, Lowe GD. Effects of lipids and lipoproteins on thrombosis and rheology. Atherosclerosis 1998; 140: 271-280.
• 3 Rota S. et al. Atherogenic lipoproteins support assembly of the prothrombinase complex and thrombin generation: modulation by oxidation and vitamin E. Blood 1998; 91: 508-515.
• 4 Griffin JH. et al. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. J Clin Invest 1999; 103: 219-227.
• 5 Nofer JR. et al. HDL and arteriosclerosis: beyond reverse cholesterol transport. Atherosclerosis 2002; 161: 1-16.
• 6 Carson SD. Plasma high density lipoproteins inhibit the activation of coagulation factor X by factor VII and tissue factor. FEBS Lett 1981; 132: 37-40.
• 7 Lesnik P. et al. Anticoagulant activity of tissue factor pathway inhibitor in human plasma is prudentially associated with dense subspecies of LDL and HDL and with Lp(a). Arterioscler Thromb Vasc Biol 1993; 13: 1066-1075.
• 8 Schultz JR. et al. Protein composition determines the antiatherogenic properties of HDL in transgenic mice. Nature 1993; 365: 762-764.
• 9 Walldius G. et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001; 358: 2026-2033.
• 10 Blanco-Vaca F. et al. Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein. J Lipid Res 2001; 42: 1727-1739.
• 11 Tailleux A. et al. Apolipoprotein A-II, HDL metabolism and atherosclerosis. Atherosclerosis 2002; 164: 1-13.
• 12 Carson SD. Tissue factor (coagulation factor III) inhibition by apolipoprotein A-II. J Biol Chem 1987; 262: 718-721.
• 13 Epand RM. et al. HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity. Arterioscler Thromb 1994; 14: 1775-1783.
• 14 Ettelaie C. et al. Comparison of the inhibitory effects of ApoB100 and tissue factor pathway inhibitor on tissue factor and the influence of lipoprotein oxidation. Arterioscler Thromb Vasc Biol 1999; 19: 1784-1790.
• 15 Godsland IF. et al. Associations of smoking, alcohol and physical activity with risk factors for coronary heart disease and diabetes in the first follow-up cohort of the HDDRISC Study (HDDRISC-1). J Intern Med 1998; 244: 33-41.
• 16 Godsland IF. et al. Plasma total homocysteine concentrations are unrelated to insulin sensitivity and components of the metabolic syndrome in healthy men. J Clin Endocrinol Metab 2001; 86: 719-723.
• 17 Warnick GR, Albers JJ. A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high density lipoprotein cholesterol. J Lipid Res 1978; 19: 65-76.
• 18 Gidez LI. et al. Separation and quantitation of subclasses of human plasma high density lipoproteins by a simple precipitation procedure. J Lipid Res 1982; 23: 1206-1223.
• 19 Kalaria VG. et al. Gender-related differences in thrombogenic factors predicting recurrent cardiac events in patients after acute myocardial infarction. The THROMBO Investigators. Am J Cardiol 2000; 85: 1401-1408.
• 20 Brunner EJ. et al. Gender and employment grade differences in blood cholesterol, apolipoproteins and haemostatic factors in the Whitehall II study. Atherosclerosis 1993; 102: 195-207.
• 21 Cooper JA. et al. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation 2000; 102: 2816-2822.
• 22 Hansen JB. et al. Serum lipids and regulation of tissue factor-induced coagulation in middle-aged men. Thromb Res 2001; 102: 3-13.
• 23 Ribas V. et al. Human apolipoprotein A-II enrichment displaces paraoxonase from HDL and impairs its antioxidant properties: a new mechanism linking HDL protein composition and antiatherogenic potential. Circ Res 2004; 95: 789-797.
• 24 Castellani LW. et al. Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles. J Clin Invest 1997; 100: 464-474.
• 25 Mackness MI. et al. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis 1993; 104: 129-135.
• 26 Lesnik P. et al. Tissue factor pathway inhibitor activity associated with LDL is inactivated by cell- and copper-mediated oxidation. Arterioscler Thromb Vasc Biol 1995; 15: 1121-1130.
• 27 Godsland IF. et al. Hemostatic risk factors and insulin sensitivity, regional body fat distribution and the metabolic syndrome. J Clin Endocrinol Metab 2005; 90: 190-197.
• 28 Castellani LW. et al. Studies with apolipoprotein A-II transgenic mice indicate a role for HDLs in adiposity and insulin resistance. Diabetes 2001; 50: 643-651.
• 29 Weng W, Breslow JL. Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility. Proc Natl Acad Sci USA 1996; 93: 14788-14794.
• 30 Escolà-Gil JC. et al. Overexpression of human apolipoprotein A-II in transgenic mice does not increase their susceptibility to insulin resistance and obesity. Diabetologia 2002; 45: 600-601.
• 31 Martín-Campos JM. et al. Apolipoprotein A-II, genetic variation on chromosome 1q21-q24, and disease susceptibility. Curr Opin Lipidol 2004; 15: 247-253.
• 32 Sauvaget D. et al. In vitro transcriptional induction of the human apolipoproteinA-II gene by glucose. Diabetes 2004; 53: 672-678.
• 33 Boucher J. et al. Apolipoprotein A-II regulates HDL stability and affects hepatic lipase association and activity. J Lipid Res 2004; 45: 849-858.
• 34 Boisfer E. et al. Overexpression of human apolipoprotein A-II in mice induces hypertriglyceridemia due to defective very low density lipoprotein hydrolysis. J Biol Chem 1999; 274: 11564-11572.
• 35 Constantino M. et al. Increased activity of vitamin K-dependent clotting factors in human hyperlipoproteinaemia - association with cholesterol and triglyceride levels. Thromb Haemost 1977; 31: 465-474.
• 36 Kjalke M. et al. Plasma lipoproteins enhance tissue factor-independent factor VII activation. Arterioscler Thromb Vasc Biol 2000; 20: 1835-1841.
• 37 Silveira A. et al. In vivo demonstration in humans that large postprandial triglyceride-rich lipoproteins activate coagulation factor VII through the intrinsic coagulation pathway. Arterioscler Thromb Vasc Biol 1996; 16: 1333-1339.
• 38 van ’t Hooft FM. et al. Human evidence that the apolipoprotein A-II gene is implicated in visceral fat accumulation and metabolism of triglyceride-rich lipoproteins. Circulation 2001; 104: 1223-1228.
• 39 Delgado-Lista J. et al. An apolipoprotein A-II polymorphism (-265T/C, rs5082) regulates postprandial response to a saturated fat overload in healthy men. J Nutr 2007; 137: 2024-2028.
• 40 Saigo M. et al. Plasma level of triglyceride-rich lipoprotein remnants is closely associated with the activation of coagulation factor VII in patients with myocardial infarction. Thromb Res 2000; 100: 9-17.
• 41 Wielders SJ. et al. Factor Xa-driven thrombin generation in plasma: dependency on the aminophospholipid density of membranes and inhibition by phospholipid-binding proteins. Thromb Haemost 2007; 98: 1056-1062.
• 42 Kalopissis AD. et al. Apolipoprotein A-II: beyond genetic associations with lipid disorders and insulin resistance. Curr Opin Lipidol 2003; 14: 165-172.
• 43 Chinetti G. et al. PPA R-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nature Med 2001; 07: 53-58.
• 44 Vu-Dac N. et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest 1995; 96: 741-750.
• 45 Eggerman TL. et al. Differential tissue-specific expression of human apoA-I and apoA-II. J Lipid Res 1991; 32: 821-828.
• 46 Perlemuter G. et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FA SEB J 2002; 16: 185-194.
• 47 Petit JM. et al. Apolipoprotein-AII Concentrations are Associated With Liver Steatosis in Patients With Chronic Hepatitis C Dig Dis Sci. 2007; 52: 3431-3434.
• 48 Rodríguez-Iñigo E. et al. Expression of factor VII in the liver of patients with liver disease: correlations with the disease severity and impairment in the hemostasis. Blood Coagul Fibrinolysis 2001; 12: 193-199.
• 49 Humphries SE. et al. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscler Thromb 1994; 14: 193-198.
• 50 Constantino M. et al. Increased activity of vitamin K dependent clotting factors in human hyperlipoproteinaemia. Association with cholesterol and triglyceride levels. Thromb Haemost 1977; 38: 465-474.
• 51 Simpson HCR. et al. Hypertriglyceridaemia and hypercoagulability. Lancet 1983; i: 786-789.
• 52 Xu N. et al. Association of vitamin K-dependent coagulation proteins and C4b binding protein with trig lyceride-rich lipoproteins of human plasma. Arterioscler Thromb Vasc Biol 1998; 18: 33-39.
• 53 Hoffman CJ. et al. Correlation of vitamin K-dependent clotting factors with cholesterol and triglycerides in healthy young adults. Arterioscler Thromb 1994; 14: 1737-1740.
• 54 Lee AJ. et al. Plasma fibrinogen and coronary risk factors: the Scottish Heart and Health Study. J Clin Epidemiol 1990; 43: 913-919.
• 55 Koenig W. et al. Association between rheology and components of lipoproteins in human blood: results from the MONICA-Project Augsburg. Circulation 1992; 85: 2197-2204.
• 56 Cremer P. et al. Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 1994; 24: 444-453.