Fibrinogen plasma levels as a marker of thrombin activation: New insights on the role of fibrinogen as a cardiovascular risk factor

Fibrinogen has recently emerged as a major risk factor for atherothrombosis. However, the pathophysiologic mechanism linking high fibrinogen concentration to cardiovascular disease is unclear. In this study 136 subjects (75 males, 61 females, age 51.7 ± 14.4 years, mean ± standard deviation, range 17-82) were tested for total and HDL-cholesterol, total triglycerides, apolipoprotein AI, apolipoprotein B, fibrinogen, prothrombin fragment and D-dimer. Moreover, 5 subjects who had hyperfibrinogenemia (range 450 to 950 mg/dl) for at least 6 months by repeated measurements, were treated with a short 7-day course of heparin 12,500 U/day subcutaneously. The effect of heparin on all the above mentioned parameters was observed at the end of treatment and after 7 days of wash-out. Simple regression analysis detected a positive correlation between fibrinogen and age, prothrombin fragment and D-dimer, and a negative correlation between fibrinogen and HDL-cholesterol and apolipoprotein AI. A direct correlation between age and both prothrombin fragment and D-dimer was also demonstrated. Multivariate analysis showed a persistent correlation between fibrinogen and prothrombin fragment, D-dimer and age, that was not influenced by sex, smoking habit and body mass index. In the 5 hyperfibrinogenemic subjects, heparin administration significantly reduced fibrinogen (625.4 ± 211.1 vs 455.2 ± 112.3 mg/dl, p <0.03), prothrombin fragment (0.97 ± 0.1 vs 0.63 ± 0.2 mM, p <0.002) and D-dimer (336 ± 101.8 vs 275.2 ± 78.5 ng/ml, p <0.03). All these parameters returned to baseline after 7 days of wash-out (fibrinogen 632.5 ± 198.2 mg/dl, prothrombin fragment 0.96 ± 0.2 nM, D-dimer 325.8 ± 98.65 ng/ml). These data indicate that fibrinogen plasma levels are strongly correlated to parameters of thrombin activation in plasma and suggest that high fibrinogen plasma levels might be a risk marker for cardiovascular disease because expression of an existing thrombophilia.