Factor VII and Fibrinogen Levels as Risk Factors for Venous Thrombosis

Summary

The plasma levels of coagulation factor VII and fibrinogen are well known risk factors for arterial thrombosis. We tested the hypothesis that this association also exists for venous thrombosis. Additionally, MspI and Haelll polymorphisms in the factor VII and fibrinogen genes have recently been reported to be associated with the concentration of both proteins in the plasma. However, no conclusion could be drawn with respect to an increase or decrease in thrombosis risk. We undertook a population-based case-control study, in which 199 patients with a first, objectively confirmed episode of deep vein thrombosis, aged less than 70, and without a known malignant disorder were compared to 199 age-and sex-matched healthy controls, to evaluate the clinical importance of these reported findings.

For fibrinogen we found a positive level-related association between the plasma fibrinogen level and thrombotic risk. Subjects with a plasma fibrinogen greater than 5 g/1 had an almost 4-fold increase of thrombosis risk. The frequencies of the different Haelll genotypes were out of balance only for the thrombosis patients, with a deficit of the H1H2 genotype. Possession of an H1H2 genotype was associated with a 40% reduction in thrombosis risk.

For factor VII, neither the plasma level nor the MspI genotypes were related to deep vein thrombosis, although possession of a M2 allele was clearly associated with significantly lower factor VII levels. The frequencies of the Mspl-genotypes were the same for patients and control subjects and, exhibited Hardy-Weinberg equilibrium.

Our results support that plasma fibrinogen, a determinant of arterial thrombosis is also a risk factor for venous thrombosis, while factor VII plasma concentration is unrelated to deep vein thrombosis, which is supported by the data from the DNA analysis of polymorphisms.

• References

• 1 Koster T, Rosendaal FR, van der Meer FJ M, Briet E, Vandenbroucke JP. More objective diagnosis of venous thromboembolism?. Neth J Med 1991; 38: 246-8
• 2 Hirsh J, Hull R, Raskob GE. Epidemiology and pathogenesis of venous thrombosis. J Am Coll Cardiol 1986; 8: 104B-13B
• 3 Marder VJ, Shulman NR. Clinical aspects of congenital factor VII deficiency. Am J of Med 1964; 37: 182-94
• 4 Mariani G, Marzucconi MG. Factor VII congenital deficiency. Haemostasis 1983; 13: 169-77
• 5 Beck EA. Congenital abnormalities of fibrinogen. Clinics in Haematology 1979; 8: 169-81
• 6 Boyer C, Wolf M, Rothschild C, Migaud M, Amiral J, Mannucci PM, Meyer D, Larrieu MJ. An enzyme immunoassay (ELISA) for the quantitation of human factor VII. Thromb Haemost 1986; 56: 250-5
• 7 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-5
• 8 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR S, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease; principal results of the Northwick Part Heart Study. Lancet 1986; ii: 533-7
• 9 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease; the Framingham Study. JAMA 1987; 258: 1183-6
• 10 Meade TW, North WR S. Population based distributions of haemostatic variables. Br Med Bull 1977; 33: 283-8
• 11 Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemiological study on factor VII factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age gender, body-weight, smoking, al eohnl. pill-using and menopause. Thromb Haemost 1985; 54: 475-9
• 12 Thompson S, Martin J, Meade T. Sources of variability in coagulation factor assays. Thromb Ilacmust 1987; 58: 1073-7
• 13 Berg K. Genetics of atherosclerosis. In: Atherosclerosis. Biology and clinical science. Olssuii AG. ed. Edinburgh: Churchill-Livingstone; 1987: 323-37
• 14 Hnmpliiites SE, Look M, Dubowitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1987; i: 1452-5
• 15 Green F, Kelleher C, Wilkes H, Temple A, Meade T, Humphries S. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb 1991; 11: 540-6
• 16 Thomas AE, Green FR, Kelleher CE, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promotor region of the (3 fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65 (05) 487-90
• 17 Humphries SE, Lane A, Dawson S, Green FR. The study of gene-environment interactions that influences thrombosis and fibrinolysis. Genetic variation at the loci for factor VII and plasminogen activator inhibitor-1. Arch Pathol Lab Med 1992; 116: 1322-9
• 18 Meer van der FJ M, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153: 1557-62
• 19 Loeliger EA, van Dyk-Wierda CA, van den Besselaar AM H P, Broekmans AW, Roos J. Anticoagulant control and the risk of bleeding; organizational infrastructure. In: Anticoagulants and myocardial infarction: a reappraisal. Meade TW. ed. Chichester, UK: John Wiley and sons; 1984: 157-62
• 20 Meade TW, Chakrabarty, Haines AP, North WR S, Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J 1979; 1: 153-6
• 21 Schlesselman JJ. Cases-control studies. design, conduct, analysis New York, Oxford: University Press; 1982
• 22 Lowe GD O, Drummond MM, Lorimer AR. et al. Relation between extent of coronary heart disease and blood viscosity. Br Med J 1980; i: 673-4
• 23 Meade TW, Vickers MV, Thompson SG, Seghatchian MJ. The effect of physiological levels of fibrinogen on platelet aggregation. Thromb Res 1985; 38: 527-34
• 24 Scarabin PY, Bara L, Ricard S, Poirier O, Cambou JP, Arveiler D, Luc G, Evans AE, Samama MM, Cambien F. Genetic variation at the (3-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction. The ECTIM Study. Arterioscler Thromb 1993; 13: 886-891
• 25 Green F, Hamsten A, Blomback M, Humphries S. The role of (3-fibrinogen genotype in determining plasma levels in young survivors of myocardial infartion and healthy controls from Sweden. Thromb Haemost 1993; 70: 915-20