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Dear Sir,

High levels of fibrinogen have been associated with an increased risk of arterial thrombosis [1]. The importance of hyperfibrinogenemia in the pathogenesis of deep venous thrombosis is, however, not yet unequivocally established. In a recent review, Koenig postulated several possible mechanisms explaining an increased risk of venous thrombosis associated with increased fibrinogen levels [2]. Increased levels of fibrinogen may lead to increased thrombus size, the formation of tight and rigid network structures and impaired fibrinolysis due to interference with the binding of plasminogen to its receptor [2].

High levels of fibrinogen were associated with an increased risk of deep venous thrombosis in 1994, in the first 199 patients and control subjects of the Leiden Thrombophilia Study (LETS) [3]. Individuals with a fibrinogen level >4 g L−1 had a more than 2-fold increased risk of venous thrombosis compared with those with lower levels, and beyond a fibrinogen level of 5 g L−1 an even stronger association was demonstrated. A major difficulty in the interpretation of the causal nature of this association is that levels are dependent on so many other factors, since fibrinogen is an acute-phase reactant. When truly causal, genetic variants contributing to elevated levels of fibrinogen should also be associated with an increased risk of venous thrombosis. More recently, it was shown that several fibrinogen genotypes contribute to the variation in fibrinogen levels, but were themselves not strongly associated with an increased risk of venous thrombosis [4].

We re-analyzed the association between fibrinogen levels and the risk of deep venous thrombosis in the total group of patients and control subjects of the LETS (n = 948). By stratification into subgroups, we tried to identify subgroups of hyperfibrinogenemic individuals in whom the risk of venous thrombosis was increased.

In total, 474 consecutive patients with a first deep venous thrombosis and 474 age- and sex-matched control subjects were included in this study. The fibrinogen concentration was measured according to the method of Clauss using Dade® thrombin (Baxter, Miami, FL, USA). Fibrinogen levels were expressed in g L−1.

The mean age of patients was 45.1 years (range 14–69) and of control subjects 44.7 years (range 14–72). Of the total study population, 42.6% (n = 404) were men.

Fibrinogen levels were increased in the total group of patients compared with control subjects [mean difference 0.18 g L−1, 95% confidence interval (CI) 0.08, 0.28]. In control subjects, fibrinogen levels were similar in men and women (mean difference 0.05 g L−1, 95% CI −0.07, 0.17) but were positively associated with age, i.e. individuals aged > 45 years had higher fibrinogen levels compared with individuals aged <45 years (mean difference 0.20, 95% CI 0.08, 0.32).

Table 1 shows the risk of venous thrombosis associated with increased levels of fibrinogen, stratified by sex and age. The risk of thrombosis was increased in the patient group up to a 2.8-fold increased risk for individuals with fibrinogen levels above the 95th percentile (4.49 g L−1), compared with individuals with fibrinogen levels below the 95th percentile [odds ratio (OR) 2.8, 95% CI 1.7, 4.6]. There was no difference in risk for men and women with high fibrinogen levels. Stratification by age showed that the risk of venous thrombosis associated with hyperfibrinogenemia was mainly increased in older individuals. In individuals younger than 45 years, even fibrinogen levels beyond the 95th percentile, i.e. 4.49 g L−1, were not associated with an increased risk of venous thrombosis. In older individuals an excess thrombotic risk became apparent for fibrinogen levels >3 g L−1. Further stratification in finer age groups revealed the same trend.

Table 1.  Risk of venous thrombosis associated with fibrinogen levels
Dichotomization at different cut-off points* (fibrinogen level in g L−1)All (n = 948)Men (n = 404)Women (n = 544)Age < 45 (n = 473)Age > 45 (n = 475)
  • *

    Fibrinogen levels were dichotomized at the 95th, 90th, 75th, 50th, and 25th percentile measured in the control subjects (n = 474).

95th percentile (4.49)2.8 (1.7–4.6)2.7 (1.3–5.8)2.8 (1.4–5.6)1.5 (0.7–3.3)4.2 (2.1–8.3)
90th percentile (4.11)2.1 (1.4–3.1)2.1 (1.2–3.8)2.1 (1.3–3.5)1.4 (0.7–2.5)2.8 (1.7–4.6)
75th percentile (3.62)1.6 (1.2–2.1)1.7 (1.1–2.6)1.5 (1.1–2.2)1.2 (0.8–1.8)2.0 (1.4–3.0)
50th percentile (3.17)1.4 (1.1–1.8)1.1 (0.8–1.7)1.6 (1.1–2.2)1.1 (0.7–1.5)1.8 (1.3–2.6)
25th percentile (2.81)1.2 (0.9–1.6)1.2 (0.8–1.8)1.1 (0.7–1.7)1.1 (0.7–1.6)1.3 (0.8–2.0)

Adjustment for age, oral contraceptives, high levels of factors (F) II, VIII, IX and XI, which have been described as associated with an increased risk of venous thrombosis, the prothrombin 20210A mutation and the FV Leiden mutation, resulted in lower risk estimates associated with high fibrinogen levels in all subgroups. In the group of individuals older than 45 years, again the risk of thrombosis associated with high levels of fibrinogen was highest (OR 1.8, 95% CI 1.0, 3.5). Further adjustment for C-reactive protein levels resulted in a thrombotic risk associated with high levels of fibrinogen of 1.5 (OR 1.5, 95% CI 0.8, 3.0) in the group of individuals older than 45 years.

There are several possible explanations for the increased risk of venous thrombosis associated with high levels of fibrinogen. First, since fibrinogen is an acute-phase reactant, it could be a post hoc phenomenon. Second, high levels of fibrinogen could truly be a cause of venous thrombosis. However, the increased risk could only be demonstrated in the elderly, therefore these explanations are not likely. Clearly, young individuals have not yet accumulated age-associated risk factors as much as the elderly. Therefore, a third possibility is that high levels of fibrinogen associated with an increased risk of venous thrombosis in the elderly are merely a reflection of other age-related risk factors for venous thrombosis in these individuals. Although adjustment for several known thrombotic risk factors did not result in a complete disappearance of the increased thrombotic risk of venous thrombosis in this group, this explanation is the most likely.

These results may explain the differences in earlier reports of the risk of venous thrombosis associated with high levels of fibrinogen, i.e. the age of the study populations differed. In an analysis of the joint effect of oral contraceptive use and the levels of procoagulant factors, we could not demonstrate an increased risk of venous thrombosis associated with high fibrinogen levels in premenopausal women aged ≤49 years [5]. The results of the current analysis show that the risk of venous thrombosis is not increased in young individuals; neither in young men nor in young women.

References

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  2. References
  • 1
    Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998; 279: 147782.
  • 2
    Koenig W. Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost 2003; 89: 6019.
  • 3
    Koster T, Rosendaal FR, Reitsma PH, Van Der Velden PA, Briët E, Vandenbroucke JP. 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: 71922.
  • 4
    Renner W, Cichocki L, Forjanics A, Koppel H, Gasser R, Pilger E. G-455A polymorphism of the fibrinogen beta gene and deep vein thrombosis. Eur J Clin Invest 2002; 32: 7558.
  • 5
    Van Hylckama Vlieg A, Rosendaal FR. Interaction between oral contraceptives and coagulation factor levels in deep venous thrombosis. J Thromb Haemost 2003; 1: 218690.