Cardiovascular risk factors in idiopathic compared to riskassociated venous thromboembolism: A focus on fibrinogen, factor VIII, and high-sensitivity C-reactive protein (hs-CRP)

Summary

There have recently been reports of an increased incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism (VTE) compared to patients with risk-associated VTE. The aim of our study was to evaluate whether elevated clotting factors, which have been linked to chronic subclinical inflammation and arterial thromboembolic disease, have a higher prevalence in idiopathic VTE compared to secondary VTE.Plasma fibrinogen,factor VIII,and high-sensitivity C-reactive protein (hs-CRP) levels were determined in a cohort of sex and age-matched patients with unprovoked VTE (n=101), patients with secondary VTE (n=101), and controls (n=202). Fibrinogen and hs-CRP levels were higher in patients with idiopathic VTE (fibrinogen: median/range: 331/214-524 mg/dl; hs-CRP: median/interquartile range: 1.8/0.8-3.7 mg/l) than in those with risk-associated VTE (299/162-458 mg/dl, p=0.004; 1.5/0.8-2.2 mg/l, p=0.05) and controls (302/185-644 mg/dl, p=0.001; 1.2/0.5-2.2

Keywords

Venous thrombosis - fibrinogen - factor VIII - C-reactive protein

• References

• 1 Sorensen HT, Horvath-Puho E, Pedersen L. et al. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370: 1773-1779.
• 2 Prandoni P, Bilora F, Marchiori A. et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348: 1435-1441.
• 3 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-963.
• 4 Fibrinogen Studies Collaboration. Danesh J, Lewington S, Thompson SG. et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant metaanalysis. JAMA 2005; 294: 1799-1809.
• 5 Mosesson MW, Siebenlist KR, Meh DA. The structure and biological features of fibrinogen and fibrin. Ann NY Acad Sci 2001; 936: 11-30.
• 6 Tracy RP, Bovill EG, Yanez D. et al. Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results form the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1995; 15: 1269-1279.
• 7 Feinbloom D, Bauer KA. Assessment of hemostatic risk factors in predicting arterial thrombotic events. Arterioscler Thromb Vasc Biol 2005; 25: 2043-2053.
• 8 Kawasaki T, Kaida T, Arnout J. et al. A new animal model of thrombophilia confirms that high plasma factor VIII levels are thrombogenic. Thromb Haemost 1999; 81: 306-311.
• 9 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731-738.
• 10 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.
• 11 Rumley A, Lowe GD, Sweetnam PM. et al. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study. Br J Haematol 1999; 105: 110-116.
• 12 Meade TW, Cooper JA, Stirling Y. et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 1994; 88: 601-607.
• 13 Folsom AR, Rosamond WD, Shahar E. et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation 1999; 100: 736-742.
• 14 Koster T, Rosendaal FR, Reitsma PH. et al. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms - the Leiden Thrombophilia Study (LETS). Thromb Haemost 1994; 71: 719-722.
• 15 Kamphuisen PW, Eikenboom JC, Vos HL. et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999; 81: 680-683.
• 16 Van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thromb Haemost 2003; 1: 2677-2678.
• 17 Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ. et al. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ` levels. Blood 2005; 106: 4176-83.
• 18 Koster T, Blann AD, Briet E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
• 19 O`Donnell J, Tuddenham EG, Manning R. et al. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-828.
• 20 Kraaijenhagen RA, in't Anker PS, Koopman MM. et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
• 21 Bloemenkamp KW, Helmerhorst FM, Rosendaal FR. et al. Venous thrombosis, oral contraceptives and high factor VIII levels. Thromb Haemost 1999; 82: 1024-1027.
• 22 Wells PS, Langlois NJ, Webster MA. et al. Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada - is it necessary to define a new upper reference range for VIII?. Thromb Haemost 2005; 93: 842-846.
• 23 Tirado I, Mateo J, Soria JM. et al. The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost 2005; 93: 468-474.
• 24 Danesh J, Wheeler JG, Hirschfield GM. et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387-1397.
• 25 Vormittag R, Vukovich T, Schönauer V. et al. Basal high-sensitivity-C-reactive protein levels in patients with spontaneous venous thromboembolism. Thromb Haemost 2005; 93: 488-493.
• 26 Prandoni P, Ghirarduzzi A, Prins MH. et al. Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis. J Thromb Haemost 2006; 4: 1891-1896.
• 27 Becattini C, Agnelli G, Prandoni P. et al. A prospective study on cardiovascular events after acute pulmonary embolism. Eur Heart J 2005; 77-83.
• 28 Spencer FA, Ginsberg JS, Chong A. et al. The relationship between unprovoked venous thromboembolism, age, and acute myocardial infarction. J Thromb Haemost 2008; 6: 1507-1513.
• 29 Spencer FA, Gore JM, Lessard D. et al. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost 2008; 100: 780-788.
• 30 Kluft C. Effects on haemostasis variables by second and third generation combined oral contraceptives: a review of directly comparative studies. Curr Med Chem 2000; 7: 585-591.
• 31 Pearson TA, Mensah GA, Alexander RW. et al. Centers for Disease Control and Prevention; American Heart Association Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499-451.
• 32 Bova C, Marchiori A, Noto A. et al. Incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism. Thromb Haemost 2006; 96: 132-136.
• 33 Koenig W. Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost 2003; 89: 601-609.
• 34 Danesh J, Collins R, Appleby P. et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: metaanalyses of prospective studies. JAMA 1998; 279: 1477-1482.
• 35 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115-126.
• 36 Saito I, Folsom AR, Brancati FL. et al. Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Ann Intern Med 2000; 133: 81-91.
• 37 Tracy RP, Arnold AM, Ettinger W. et al. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 1776-1783.
• 38 Bank I, van de Poel MH, Coppens M. et al. Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study. Thromb Haemost 2007; 98: 1040-1044.
• 39 Berger M, Moscatelli H, Kulle B. et al. Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism. Thromb Haemost 2008; 99: 905-908.
• 40 Pecheniuk NM, Elias DJ, Deguchi H. et al. Elevated plasma fibronectin levels associated with venous thromboembolism. Thromb Haemost 2008; 100: 224-228.
• 41 Vaya A, Mira Y, Ferrando F. et al. Hyperlipidaemia and venous thromboembolism in patients lacking thrombophilic risk factors. Br J Haematol 2002; 118: 255-259.
• 42 Hainaut P, Jaumotte C, Verhelst D. et al. Hyperhomocysteinemia and venous thromboembolism: a risk factor more prevalent in the elderly and in idiopathic cases. Thromb Res 2002; 106: 121-125.
• 43 Christansen SC, Naess IA, Cannegieter SC. et al. Inflammatory cytokines as risk factors for a first venous thrombosis: a prospective population-based study. PLoS Med 2006; 3: e334.
• 44 Conlan MG, Folsom AR, Finch A. et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70: 380-385.