The relevance of coagulation in cardiovascular disease: what do the biomarkers tell us?

Summary

Several haemostatic factors have been associated with incident arterial cardiovascular disease in prospective studies and meta-analyses. Plasma fibrinogen shows a strong and consistent association with risk; however, this may reflect its inflammatory marker status, and causality remains to be proven. The common haemostatic gene polymorphisms for factor II, factor V and the von Willebrand factor: Factor VIII (non-O blood group) show significant associations with coronary heart disease (CHD) risk, consistent with potential causality. Increased D-dimer and t-PA antigen levels are associated with CHD risk, suggesting roles for coagulation activation and endothelial disturbance. There is little evidence for associations with CVD with other haemostatic factors.

Keywords

Arterial thrombosis - epidemiological studies - coagulation factors

• References

• 1 Macfarlane RG. Introduction. Br Med Bull 1977; 33: 183-185.
• 2 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 1095: 1135-1143.
• 3 Lowe GDO. Can haematological tests predict cardiovascular risk ? The 2005 Kettle Lecture. Br J Haematol 2006; 133: 232-250.
• 4 Lowe GDO. Epidemiology of venous thromboembolism: the need for large (including prospective) studies and meta-analyses. J Thromb Haemost 2012; 10: 2186-2188.
• 5 Rosendaal FR. Etiology of venous thrombosis: the need for small original studires. J Thromb Haemst 2012; 10: 2191-2193.
• 6 Jespersen J, Bertina RM, Haverkate F. Laboraory testing in thrombosis – a manual. 2nd edn.. Dordrecht: Kluwer Academic Publishers; 1999
• 7 Willeit P, Thompson A, Aspelund T. et al. Haemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses. PLoS One 2013; 8: e55175.
• 8 Peters SA, Woodward MA, Rumley A. et al. Direct comparisons of three plasma fibrinogen assays wth the von Clauss assay in prediction of cardiovascular disease and all-causes mortality: the Scottish Heart Health Extended Cohort. Br J Haematol 2013; 162: 392-399.
• 9 Lewis MR, Callas PW, Jenny NS. et al. Longitudinal stability of coagulation, fibrinolysis, and inflammation factors in stored plasma samples. Thromb Hae-most 2001; 86: 1495-1500.
• 10 Woodward M. Epidemiology. Study Design and Data Analysis. 2nd ed.. Boca Raton: Chapman and Hall / CRC Press; 1999
• 11 Lowe GD, Rumley A, Sweetnam PM. et al. Fibrin D-dimer, markers of coagulation activation and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 2001; 86: 822-827.
• 12 Stott DJ, Robertson M, Rumley A. et al. Activation of haemostasis and decline in cognitive function in older people. Aretrioscler Thromb Vasc Biol 2010; 30: 605-611.
• 13 Verhovsek M, Douketos J, Yi Q. et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008; 149: 481-490.
• 14 Tosetto A, Iorio A, Marcucci M. et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10: 1019-1025.
• 15 Emerging Risk Factors Collaboration. Kaptoge S, Angelantonio E, Pennells L. et al. C-reactive protein, fibrinogen and cardiovascular disease prediction. N Engl J Med 2012; 367: 1310-1320.
• 16 Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 2006; 113: 2335-2362.
• 17 Woodward M, Tunstall-Pedoe H, Rumley A. et al. Does fibrinogen add to prediction of cardiovascular disease? Results from the Scottish Heart Heart Extended Cohort Study. Br J Haematol 2009; 146: 442-446.
• 18 Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and non-vascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
• 19 Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparioson of C-reactive protein, fibrinogen, homocysteine, lipoprotain (a), and standard cholesterol screening as predictors for peripheral arterial disease. J Am Med Assoc 2001; 285: 2481-2485.
• 20 Tzoulaki I, Murray GD, Lee AJ. et al. Inflammatory, haemostatic and rheological markers for incident peripheral arterial disease: Edinburgh Artery Study. Eur Heart J 2007; 28: 354-362.
• 21 Fibrinogen Studies Collaboration. Associations of plasma fibrinogen levels with established cardiovascular risk factors, inflammatory markers and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies. Am J Epidemiol 2007; 166: 867-879.
• 22 Danesh J, Collins R, Appleby P. et al. Associations of fibrinogen, C-reactive protein, albumin or leucocyte count with coronary heart disease: meta-analyses of prospective studies. J Am Med Assoc 1998; 279: 1477-1482.
• 23 Danesh J, Collins R, Peto R. et al. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000; 21: 515-520.
• 24 Lowe GDO. Ancrod in acute ischaemic stroke. Proc Roy Coll Phys Edin 2001; 31 (Suppl. 08) 20-24.
• 25 Hennerici MG, Kay R, Bogousslavsky J. et al. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial. Lancet 2006; 368: 1871-1878.
• 26 Sabater-Lleal M, Huang J, Chasman D. et al. Multiethnic meta-analysis of genome-wide association studies in > 100,000 subjects identifies 23 fibrinogen-associated loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 2013; 128: 1310-1324.
• 27 Machlus KR, Cardenas JC, Church FC. et al. Causal relationship between hyper-fibrinogenemia, thrombosis and resistance to thrombolysis in mice. Blood 2011; 117: 4953-4963.
• 28 Ariens RAS. Fibrin(ogen) and thrombotic disease. J Thromb Haemost 2013; 11 (Suppl. 01) 294-305.
• 29 Kaptoge S, Seshasai SR, Gao P. et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analyses. Eur Heart J. 2013 Epub ahead of print.
• 30 Paterson CC, Smith AE, Yarnell JW. et al. The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: the Caerphilly Study. Atherosclerosis 2010; 209: 551-557.
• 31 Sarwar N, Butterworth AS, Freitag DF. et al. IL6R Genetics Consotium., Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012; 379: 1205-1213.
• 32 CRP CHD Genetics Consortium. Association between C-reactive protein and coronary heart disease: Mendelian randomisation analysis based on individual participant data. Br Med J 2011; 342: d548.
• 33 Lowe G, Woodward M, Hillis G. et al. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes mellitus and cardiovascular disease or risk factors: the ADVANCE Study. Diabetes. 2014 63.
• 34 Yamagishi K, Aleksic N, Hannan PJ. et al. Coagulation factors II, V, IX, X. XI, XII, plasminogen and alpha2antiplasmin and risk of coronary heart disease. J Atheroscler Thromb 2010; 17: 402-409.
• 35 Juul K, Tybjaerg-Hansen A, Schnohr P. et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004; 140: 330-347.
• 36 Weischer M, Juul K, Zacho J. et al. Prothrombin and risk of venous thromboembolism, ischemic heart disease and ischemic cerebrovascular disease in the general population. Atherosclerosis 2010; 208: 480-483.
• 37 Emmerich J, Rosendaal FR, Cattaneo M. et al. Combined effect of factor V Leiden and prothrombin 20120A on the risk of venous thromboembolism. Thromb Haemost 2001; 86: 809-816.
• 38 Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20120A, and methylenetetrafolatereductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J 2003; 146: 948-957.
• 39 Ye Z, Liu EHC, Higgins JPT. et al. Seven haemostatic gene polymorphisms in coronary heart disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006; 367: 651-658.
• 40 Smith A, Patterson C, Yarnell J. et al. Which haemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and stroke ? The Caerphilly Study. Circulation 2005; 112: 3080-3087.
• 41 Van der Bom JG, Bots ML, Haverkate F. et al. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Me 1996; 125: 265-269.
• 42 Empana JP, Canoui-Poitrine F, Luc G. et al. Contribution of novel biomarkers to incident stable angina and acute coronary syndrome: the PRIME Study. Eur Heart J 2008; 29: 1966-1974.
• 43 Ten Cate H. Tissue factor-driven thrombin generation and inflammation in atherosclerosis. Thromb Res 2012; 129 (Suppl. 02) S38-40.
• 44 Smith NL, Huffman JE, Strachan DP. et al. Genetic predictors of fibrin D-dimer levels in healthy adults. Circulation 2011; 123: 1864-1872.
• 45 Meade TW, De Stavola B. Long-term effects of haemostatic variables on fatal coronary heart disease: 30 year results from the first prospective Northwick Park Heart Study (NPHS-1). J Thromb Haemost 2007; 5: 461-471.
• 46 Cooper JA, Miller GJ, Bauer KA. et al. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation 2000; 102: 2816-2822.
• 47 Tzoulaki I, Murray GD, Lee AJ. et al. Relative value of inflammatory, hemostatic and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery Study. Circulation 2007; 115: 2119-2127.
• 48 Zakai NA, Katz R, Jenny NS. et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly; the Cardiovascular Health Study. J Thromb Haemost 2007; 5: 1128-1135.
• 49 Folsom AR, Wu KK, Rosamond WD. et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102-1108.
• 50 Junker R, Heinrich J, Schulte H. et al. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol 1997; 17: 1539-1544.
• 51 Lowe GD, Rumley A, McMahon A. et al. for the West of Scotland Coronary Prevention Study Group. Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heart disease. Arterioscler Thromb Vasc Biol 2004; 24: 1529-1534.
• 52 Folsom A, Rosamond W, Shahar E. et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. Circulation 1999; 100: 736-742.
• 53 Rudnicka AR, Mt-Isa S, Meade TW. Associations of plasma fibrinogen and factor VII clotting activity with coronary heart disease and stroke: prospective cohort study from the screening phase of the Thrombosis Prevention Trial. J Thromb Haemost 2006; 4: 2405-10.
• 54 Meade TW, Stirling Y. The Northwick Park Heart Studies: contrasts between the two Factor VII assays used. J Thromb Haemost 2012; 10: 482-484.
• 55 Bongers TN, de Maat MP, van Goor ML. et al. High von Willebrand factor levels increase the risk of first ischaemic stroke: influence of ADAMTS13. inflammation, and genetic variability. Stroke 2006; 37: 2672-2677.
• 56 Wannamethee SG, Whincup PH, Lennon L. et al. Fibrin D-dimer, tissue-type plasminogen activator, von Willebrand factor and risk of incident stroke in older men. Stroke 2012; 43: 1206-1211.
• 57 Rumley A, Lowe GDO, Sweetnam PM. et al. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Study. Br J Haematol. 1999; 105: 110-116.
• 58 Meade TW, Mellows S, Brozovic M. et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; ii: 533-537.
• 59 Meade TW, Cooper JC, Stirling Y. et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol. 1994; 88: 601-607.
• 60 Jenkins PV, Rawley O, Smith OP. et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157: 653-663.
• 61 Sramek A, Kriek MD, Rosendaal FR. Decreased mortality of ischaemic heart disease among carriers of haemophilia. Lancet 2003; 362: 351-354.
• 62 Tuinenburg A, Mauser-Bunschoten EP, Verhaar MC. et al. Cardiovascular disease in patients with hemophilia. J Thromb Haemost 2009; 7: 247-254.
• 63 Sanders YV, Eikelboom J, de Wee EM. et al. Reduced prevalence of aretrial thrombosis in von Willebrand disease. J Thromb Haemost 2013; 11: 845-854.
• 64 Sramek A, Reiber JHC, Gerrits WBJ. et al. Decreased coagulability has no clinically relevant effect on atherogenesis. Observations in individuals with a hereditary bleeding tendency. Circulation 2001; 104: 762-767.
• 65 Wu O, Bayoumi N, Vickers MA. et al. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 62-69.
• 66 Dentali F, Sironi AP, Ageno W. et al. Non-O blood type is the commonest genetic risk factor for VTE: results from a meta-analysis of the literature. Semin Thromb Haemost 2012; 38: 535-548.
• 67 Dentali F, Sironi AP, Ageno W. et al. ABO blood group and vascular disease: an update. Semin Thromb Haemost 2014; 40: 49-59.
• 68 Van Loon JE, Karousi M, Leebeck FW. et al. Von Willebrand factor plasma levels, genetic variations and coronary heart disease in an older population?. J Thromb Haemost 2012; 10: 1262-1269.
• 69 Van Schie MC, Wieberdink RE, Koudstaal PJ. et al. Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study. J Thromb Haemost 2012; 10: 550-556.
• 70 Rumley A, Lowe G, Stott D. et al. Coagulation activation markers are associated with cardiovascular events and death in the elderly at risk: PROSPER study cohort. J Thromb Haemost. 2009 Suppl 2. Abstract OC-WE-033.
• 71 Algra TB, van de Graaf Y, Helmerhorst F. et al. Procoagulant factors and the risk of myocardial infarction in young women. Eur J Haematol 2006; 77: 67-73.
• 72 Doggen CJ, Rosendaal FR, Meijers JC. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men : opposite and synergistic effects of factors XI and XII. Blood 2006; 108: 4045-4051.
• 73 Berliner JI, Rybicki AC, Kaplan RC. et al. Elevated levels of Factor XI are associated with cardiovascular disease in women. Thromb Res 2002; 107: 55-60.
• 74 Merlo C, Wullemin WA, Redondo M. et al. Elevated levels of plasma prekallik-rein, high molecular weight kininogen and factor XI in coronary heart disease. Atherosclerosis 2002; 161: 261-267.
• 75 Santamaria A, Martinez-Rubio A, Mateo J. et al. Homozygosity of the T allele of the 46C-T polymorphism in the F12 gene is a risk factor for acute coronary artery disease in the Spanish population. Haematologica 2004; 89: 878-894.
• 76 Santamaria A, Mateo J, Tirado I. et al. Homozygosity of the T allele of the 46C-T polymorphism in the F12 gene is a risk factor foie ischemic stroke in the Spanish population. Stroke 2004; 35: 1975-1799.
• 77 Tang W, Schweinbacher C, Lopez L. et al. Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease. Am J Hum Genet 2012; 81: 152-162.
• 78 Voko Z, Bereczky Z, Katona E. et al. Factor XIII Val 34 Leu protects against caoronary artery disease. A meta-analysis. Thromb Haemost 2007; 97: 458-463.
• 79 Wells PS, Anderson JL, Scarvelis DK. et al. Factor XIII Val 34 Leu variant is protective against venous thromboembolism: a HuGE review and meta-analysis. Am J Epidemiol 2006; 164: 101-109.
• 80 Soare AM, Popa C. Deficiencies of protein C, S and antithrombin and activated protein C resistance – their involvement in the occurrence of arterial thrombosis. J Med Life 2010; 3: 412-415.
• 81 Lowe GDO. Fibrin D-dimer and cardiovascular risk. Semin Vasc Med 2005; 5: 387-398.
• 82 Kleinegris MC, ten Cate H, ten Cate-Hoek AJ. D-dimer as a marker for cardiovascular + arterial thrombotic events in patients with peripheral arterial disease. A systematic review. Thromb Haemost 2013; 110: 233-243.
• 83 McCallum PK, Rudnicka A, Rumley A. et al. Low-intensity warfarin reduces thrombin generation and fibrin turnover, but not low-grade inflammation, in men at risk of myocardial infarction. Br J Haematol 2004; 127: 448-450.
• 84 Miller GJ, Ireland H, Cooper J. et al. Relationship between markers of activated coagulation, their correlation with inflammation, and their association with risk for coronary heart disease (NPHS II). J Thromb Haemost 2008; 6: 259-268.
• 85 Siegerink B, Govers-Riemslag JW, Rosendaal FR. et al. Intrinsic coagulation activation and the risk of arterial thrombosis in young women: results from the Risk of Arterial Thrombosis in relation to Oral contraceptives (RATIO) case-control study. Circulation 2010; 122: 1854-1861.
• 86 Govers-Riemslag JW, Smid M, Cooper JA. et al. The plasma kallikrein-kinin system and risk of cardiovascular disease in men. J Thromb Haemost 2007; 5: 1896-1903.
• 87 Lowe GDO, Danesh J, Lewington S. et al. Tissue plasminogen activator antigen and coronary heart disease: prospective study and meta-analysis. Eur Heart J 2004; 25: 252-259.
• 88 Meade TW, Ruddock V, Stirling Y. et al. Fibrinolytic activity, clotting factors and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-1079.
• 89 Meade TW, Cooper JA, Miller GJ. Platelet counts and aggregation measures in the incidence of ischaemic heart disease (IHD). Thromb Haemost 1997; 78: 926-929.
• 90 Lowe GDO, Rumley A, Norrie J. et al on behalf of the West of Scotland Coronary Prevention Group. Blood rheology, cardiovascular risk factors, and cardiovascular disease: the West of Scotland Coronary Prevention Study. Thromb Haemost 2000; 84: 553-558.
• 91 Elwood PC, Beswick A, Pickering J. et al. Platelet tests in the prediction of myocardial infarction and ischaemic stroke: evidence from the Caerphilly Prospective Study. Br J Haematol 2001; 113: 514-520.
• 92 Van der Bom JG, Heckbert SR, Lumley T. et al. Platelet count and the risk for thrombosis and death in the elderly. J Thromb Haemost 2009; 7: 399-405.
• 93 Chu SG, Becker RC, Berger PB. et al. Mean platelet volume as a predictor of cardiovascular risk: a meta-analysis. J Thromb Haemost. 2001 5. (Suppl 2): Abstract AS-TH-033.