Download PDF
Thromb Haemost 2019; 119(02): 192-202
DOI: 10.1055/s-0038-1676817
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Apolipoprotein C-III Strongly Correlates with Activated Factor VII–Anti-Thrombin Complex: An Additional Link between Plasma Lipids and Coagulation

Nicola Martinelli
1   Department of Medicine, University of Verona, Verona, Italy
,
Marcello Baroni
2   Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
,
Annalisa Castagna
1   Department of Medicine, University of Verona, Verona, Italy
,
Barbara Lunghi
2   Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
,
Filippo Stefanoni
1   Department of Medicine, University of Verona, Verona, Italy
,
Federica Tosi
1   Department of Medicine, University of Verona, Verona, Italy
,
Jacopo Croce
1   Department of Medicine, University of Verona, Verona, Italy
,
Silvia Udali
1   Department of Medicine, University of Verona, Verona, Italy
,
Barry Woodhams
3   Haemacon Ltd, Bromley, Kent, United Kingdom
,
Domenico Girelli
1   Department of Medicine, University of Verona, Verona, Italy
,
Francesco Bernardi
2   Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
,
Oliviero Olivieri
1   Department of Medicine, University of Verona, Verona, Italy
› Author Affiliations Funding This work was supported by the Cariverona Foundation (project B36J16002570003), Verona, Italy, and by the grants 2010XE5L2R_002 (MIUR) and 1786/2012 Strategic Research Program of Emilia Romagna Region, Italy.
Further Information

Publication History

21 July 2018

06 November 2018

Publication Date:
02 January 2019 (online)

   Permissions and Reprints

Abstract

Activated factor VII–anti-thrombin (FVIIa-AT) complex is a potential biomarker of pro-thrombotic diathesis reflecting FVIIa–tissue factor (TF) interaction and has been associated with mortality in patients with coronary artery disease (CAD). Previous data indicated plasma lipids as predictors of FVIIa-AT variability, and plasma lipoproteins as potential stimulators of the coagulation cascade. Our aim was to evaluate the relationships between FVIIa-AT plasma concentration and a broad apolipoprotein profile (including ApoA-I, ApoB, ApoC-III and ApoE). Within the framework of the observational Verona Heart Study, we selected 666 subjects (131 CAD-free and 535 CAD, 75.4% males, mean age: 61.1 ± 10.9 years) not taking anticoagulant drugs and for whom plasma samples were available for both FVIIa-AT assay and a complete lipid profile. Plasma concentration of FVIIa-AT levels significantly and directly correlated with total and high-density lipoprotein cholesterol, triglycerides, ApoA-I, ApoC-III and ApoE levels. ApoC-III showed the strongest correlation (R = 0.235, p = 7.7 × 10−10), confirmed in all the sub-group analyses (males/females and CAD/CAD-free). Only ApoC-III remained associated with FVIIa-AT plasma concentration, even after adjustment for sex, age, CAD diagnosis, body mass index, renal function, smoking status, lipid-lowering therapies and FVIIa levels. The APOC3 gene locus-tagging polymorphism rs964184, previously linked with cardiovascular risk and plasma lipids by genome-wide association studies, was associated with both ApoC-III and FVIIa-AT plasma concentration. Our results indicate a strong association between ApoC-III and FVIIa-AT levels, thereby suggesting that an increased ApoC-III concentration may identify subjects with a pro-thrombotic diathesis characterized by an enhanced TF-FVIIa interaction and activity.

Keywords

activated factor VII–anti-thrombin complex - APOC3 gene polymorphism - apolipoprotein C-III - coagulation - plasma lipids

Supplementary Material

 

  • References

  • 1 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473 (7347): 317-325
    PubMedGoogle Scholar
  • 2 Reiner Ž. Statins in the primary prevention of cardiovascular disease. Nat Rev Cardiol 2013; 10 (08) 453-464
    CrossrefPubMedGoogle Scholar
  • 3 Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol 2017; 14 (07) 401-411
    CrossrefPubMedGoogle Scholar
  • 4 Muller MP, Wang Y, Morrissey JH, Tajkhorshid E. Lipid specificity of the membrane binding domain of coagulation factor X. J Thromb Haemost 2017; 15 (10) 2005-2016
    CrossrefPubMedGoogle Scholar
  • 5 Ke K, Yuan J, Morrissey JH. Tissue factor residues that putatively interact with membrane phospholipids. PLoS One 2014; 9 (02) e88675
    CrossrefPubMedGoogle Scholar
  • 6 Hemker HC, Esnouf MP, Hemker PW, Swart AC, Macfarlane RG. Formation of prothrombin converting activity. Nature 1967; 215 (5098): 248-251
    CrossrefPubMedGoogle Scholar
  • 7 Hoffman CJ, Lawson WE, Miller RH, Hultin MB. Correlation of vitamin K-dependent clotting factors with cholesterol and triglycerides in healthy young adults. Arterioscler Thromb 1994; 14 (11) 1737-1740
    CrossrefPubMedGoogle Scholar
  • 8 Tosi F, Micaglio R, Sandri M. , et al. Increased plasma thrombin potential is associated with stable coronary artery disease: an angiographically-controlled study. Thromb Res 2017; 155: 16-22
    CrossrefPubMedGoogle Scholar
  • 9 Rota S, McWilliam NA, Baglin TP, Byrne CD. Atherogenic lipoproteins support assembly of the prothrombinase complex and thrombin generation: modulation by oxidation and vitamin E. Blood 1998; 91 (02) 508-515
    CrossrefPubMedGoogle Scholar
  • 10 Moyer MP, Tracy RP, Tracy PB, van't Veer C, Sparks CE, Mann KG. Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. Arterioscler Thromb Vasc Biol 1998; 18 (03) 458-465
    CrossrefPubMedGoogle Scholar
  • 11 Morrissey JH. Tissue factor: a key molecule in hemostatic and nonhemostatic systems. Int J Hematol 2004; 79 (02) 103-108
    CrossrefPubMedGoogle Scholar
  • 12 Chen VM, Hogg PJ. Encryption and decryption of tissue factor. J Thromb Haemost 2013; 11 (Suppl. 01) 277-284
    CrossrefPubMedGoogle Scholar
  • 13 Chiu J, Passam F, Butera D, Hogg PJ. Protein disulfide isomerase in thrombosis. Semin Thromb Hemost 2015; 41 (07) 765-773
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Morissey JH. Assay for Measuring FVIIa-Antithrombin Complexes. Oklahoma City, OK: Oklahoma Medical Research Foundation; 2003
    Google Scholar
  • 15 Spiezia L, Rossetto V, Campello E. , et al. Factor VIIa-antithrombin complexes in patients with arterial and venous thrombosis. Thromb Haemost 2010; 103 (06) 1188-1192
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Silveira A, Scanavini D, Boquist S. , et al. Relationships of plasma factor VIIa-antithrombin complexes to manifest and future cardiovascular disease. Thromb Res 2012; 130 (02) 221-225
    CrossrefPubMedGoogle Scholar
  • 17 Martinelli N, Girelli D, Baroni M. , et al. Activated factor VII-antithrombin complex predicts mortality in patients with stable coronary artery disease: a cohort study. J Thromb Haemost 2016; 14 (04) 655-666
    CrossrefPubMedGoogle Scholar
  • 18 Olson NC, Raffield LM, Lange LA. , et al. Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk. J Thromb Haemost 2018; 16 (01) 19-30
    CrossrefPubMedGoogle Scholar
  • 19 Martinelli N, Girelli D, Lunghi B. , et al. Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile. Blood 2010; 116 (25) 5688-5697
    CrossrefPubMedGoogle Scholar
  • 20 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. ; Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130 (06) 461-470
    CrossrefPubMedGoogle Scholar
  • 21 Martinelli N, Olivieri O, Shen GQ. , et al. Additive effect of LRP8/APOER2 R952Q variant to APOE epsilon2/epsilon3/epsilon4 genotype in modulating apolipoprotein E concentration and the risk of myocardial infarction: a case-control study. BMC Med Genet 2009; 10: 41
    PubMedGoogle Scholar
  • 22 Olivieri O, Martinelli N, Girelli D. , et al. Apolipoprotein C-III predicts cardiovascular mortality in severe coronary artery disease and is associated with an enhanced plasma thrombin generation. J Thromb Haemost 2010; 8 (03) 463-471
    CrossrefPubMedGoogle Scholar
  • 23 Olivieri O, Martinelli N, Baroni M. , et al. Factor II activity is similarly increased in patients with elevated apolipoprotein CIII and in carriers of the factor II 20210A allele. J Am Heart Assoc 2013; 2 (06) e000440
    PubMedGoogle Scholar
  • 24 Kathiresan S, Willer CJ, Peloso GM. , et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009; 41 (01) 56-65
    CrossrefPubMedGoogle Scholar
  • 25 Schunkert H, König IR, Kathiresan S. , et al; Cardiogenics; CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011; 43 (04) 333-338
    CrossrefPubMedGoogle Scholar
  • 26 Webb TR, Erdmann J, Stirrups KE. , et al; Wellcome Trust Case Control Consortium; MORGAM Investigators; Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Systematic evaluation of pleiotropy identifies 6 further loci associated with coronary artery disease. J Am Coll Cardiol 2017; 69 (07) 823-836
    PubMedGoogle Scholar
  • 27 Greenow K, Pearce NJ, Ramji DP. The key role of apolipoprotein E in atherosclerosis. J Mol Med (Berl) 2005; 83 (05) 329-342
    PubMedGoogle Scholar
  • 28 Fallaize R, Carvalho-Wells AL, Tierney AC. , et al. APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the metabolic syndrome. Sci Rep 2017; 7 (01) 6274
    CrossrefPubMedGoogle Scholar
  • 29 Olivieri O, Martinelli N, Bassi A. , et al. ApoE epsilon2/epsilon3/epsilon4 polymorphism, ApoC-III/ApoE ratio and metabolic syndrome. Clin Exp Med 2007; 7 (04) 164-172
    CrossrefPubMedGoogle Scholar
  • 30 Wyler von Ballmoos MC, Haring B, Sacks FM. The risk of cardiovascular events with increased apolipoprotein CIII: a systematic review and meta-analysis. J Clin Lipidol 2015; 9 (04) 498-510
    CrossrefPubMedGoogle Scholar
  • 31 Pechlaner R, Tsimikas S, Yin X. , et al. Very-low-density lipoprotein-associated apolipoproteins predict cardiovascular events and are lowered by inhibition of APOC-III. J Am Coll Cardiol 2017; 69 (07) 789-800
    PubMedGoogle Scholar
  • 32 Sacks FM. The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia. Curr Opin Lipidol 2015; 26 (01) 56-63
    CrossrefPubMedGoogle Scholar
  • 33 Crosby J, Peloso GM, Auer PL. , et al; TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014; 371 (01) 22-31
    CrossrefPubMedGoogle Scholar
  • 34 Gaudet D, Alexander VJ, Baker BF. , et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015; 373 (05) 438-447
    CrossrefPubMedGoogle Scholar
  • 35 Jensen MK, Aroner SA, Mukamal KJ. , et al. High-density lipoprotein subspecies defined by presence of apolipoprotein C-III and incident coronary heart disease in four cohorts. Circulation 2018; 137 (13) 1364-1373
    CrossrefPubMedGoogle Scholar
  • 36 Morton AM, Koch M, Mendivil CO. , et al. Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk. JCI Insight 2018; 3 (04) 98045
    CrossrefPubMedGoogle Scholar
  • 37 Kjalke M, Silveira A, Hamsten A, Hedner U, Ezban M. Plasma lipoproteins enhance tissue factor-independent factor VII activation. Arterioscler Thromb Vasc Biol 2000; 20 (07) 1835-1841
    CrossrefPubMedGoogle Scholar
  • 38 Silveira A, Carlo A, Adam M. , et al. VIIaAT complexes, procoagulant phospholipids, and thrombin generation during postprandial lipemia. Int J Lab Hematol 2018; 40 (03) 251-257
    CrossrefPubMedGoogle Scholar
  • 39 Archer WR, Desroches S, Lamarche B. , et al. Variations in plasma apolipoprotein C-III levels are strong correlates of the triglyceride response to a high-monounsaturated fatty acid diet and a high-carbohydrate diet. Metabolism 2005; 54 (10) 1390-1397
    CrossrefPubMedGoogle Scholar
  • 40 Parra EJ, Mazurek A, Gignoux CR. , et al. Admixture mapping in two Mexican samples identifies significant associations of locus ancestry with triglyceride levels in the BUD13/ZNF259/APOA5 region and fine mapping points to rs964184 as the main driver of the association signal. PLoS One 2017; 12 (02) e0172880
    CrossrefPubMedGoogle Scholar
  • 41 Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet 2017; 18 (06) 331-344
    PubMedGoogle Scholar
  • 42 Reilly MP, Li M, He J. , et al; Myocardial Infarction Genetics Consortium; Wellcome Trust Case Control Consortium. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 2011; 377 (9763): 383-392
    CrossrefPubMedGoogle Scholar
  • 43 Howson JMM, Zhao W, Barnes DR. , et al; CARDIoGRAMplusC4D; EPIC-CVD. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet 2017; 49 (07) 1113-1119
    CrossrefPubMedGoogle Scholar
  • 44 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117 (01) 93-102
    CrossrefPubMedGoogle Scholar
  • 45 Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol 2017; 4 (02) e83-e93
    PubMedGoogle Scholar
  • 46 Cardin AD, Jackson RL, Johnson JD. Effects of human plasma apolipoproteins C-I, C-II and C-III on the phase-transition of sonicated vesicles of dipalmitoylphosphatidylcholine. FEBS Lett 1982; 141 (02) 193-197
    CrossrefPubMedGoogle Scholar
  • 47 Hanson CL, Ilag LL, Malo J, Hatters DM, Howlett GJ, Robinson CV. Phospholipid complexation and association with apolipoprotein C-II: insights from mass spectrometry. Biophys J 2003; 85 (06) 3802-3812
    CrossrefPubMedGoogle Scholar
  • 48 Hathcock JJ, Rusinova E, Gentry RD, Andree H, Nemerson Y. Phospholipid regulates the activation of factor X by tissue factor/factor VIIa (TF/VIIa) via substrate and product interactions. Biochemistry 2005; 44 (22) 8187-8197
    CrossrefPubMedGoogle Scholar
  • 49 Mariani G, Conard J, Bernardi F. , et al. Oral contraceptives highlight the genotype-specific association between serum phospholipids and activated factor VII. Arterioscler Thromb Vasc Biol 1999; 19 (08) 2024-2028
    CrossrefPubMedGoogle Scholar
  • 50 Morrissey JH, Davis-Harrison RL, Tavoosi N. , et al. Protein-phospholipid interactions in blood clotting. Thromb Res 2010; 125 (Suppl. 01) S23-S25
    CrossrefPubMedGoogle Scholar