Rationale: It is unclear whether elevated plasma fibrinogen is associated with both deep venous thrombosis (DVT) and its complication, pulmonary embolism (PE), and whether elevated fibrinogen is a direct cause of these disorders.
Objectives: We tested the hypotheses that elevated plasma fibrinogen is associated with increased risk of DVT alone, with any PE, and with PE in combination with DVT.
Methods: We studied 77,608 individuals from the Danish general population, of whom 1,679 were diagnosed with DVT alone, 1,119 with any PE, and 272 with both PE and DVT. To test a potential causal relationship using a Mendelian randomization approach, we genotyped for FGB (rs1800790; rs4220) encoding fibrinogen β chain.
Measurements and main results: Increasing plasma fibrinogen quintiles were associated with increased risk of PE in combination with DVT (P-trend < 0.0001): multivariable adjusted odds ratio was 2.1 (95% confidence interval [CI], 1.2-3.8) in individuals with fibrinogen levels greater than or equal to 4.6 g/L (fifth quintile) versus less than or equal to 3.0 g/L (first quintile). Corresponding odds ratios were 1.7 (95% CI, 1.3-2.3) for any PE (P-trend < 0.0001) and 1.9 (95% CI, 1.0-3.6) for PE in those with DVT (P-trend = 0.003). There was, however, no association after multivariable adjustment between plasma fibrinogen quintiles and risk of DVT alone (P-trend = 0.4). Fibrinogen-increasing alleles were associated with a 7% lifelong increase in plasma fibrinogen levels; however, these genetic variants were not associated with risk of PE or DVT.
Conclusions: Elevated plasma fibrinogen levels are associated with increased risk of PE in combination with DVT but not with DVT alone. Elevated fibrinogen levels per se may not be causally associated with PE or DVT. Limitations include imprecise definitions of PE and DVT.