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Activated Protein C Resistance and Factor V Leiden Mutation Are Independent Risk Factors for Venous Thromboembolism

Francesco Rodeghiero, MD; and Alberto Tosetto, MD
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From S. Bortolo Hospital, Vicenza, Italy.

Ann Intern Med. 1999;130(8):643-650. doi:10.7326/0003-4819-130-8-199904200-00004
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Background: Resistance to activated protein C due to the factor V R506Q (Leiden) mutation is the most common clotting abnormality in patients with venous thromboembolism.

Objective: To evaluate the risk for venous thromboembolism associated with the factor V Leiden mutation or with resistance to activated protein C in the general population.

Design: Cross-sectional survey.

Setting: General community of Vicenza, Italy.

Patients: A population-based sample of 15 109 white persons 18 to 65 years of age who were randomly selected from the census list.

Measurements: Sequential validated approach based on participants' reports and Doppler ultrasonography. Resistance to activated protein C was investigated in all participants; 2134 participants with resistance to activated protein C were screened for the factor V Leiden mutation.

Results: Carriers of the factor V Leiden mutation had a relative risk of 3.3 (95% CI, 1.7 to 6.1) for venous thromboembolism before 65 years of age. The fraction of cases attributable to the factor V Leiden mutation was 6.6%. By 65 years of age, 5.7% of carriers of the mutation had had venous thromboembolism, mostly after surgery. Participants with a reduced response to activated protein C were at higher risk even if they did not carry the mutation (odds ratio, 1.7 [CI, 1.0 to 2.7]); the attributable risk for venous thromboembolism was 5.1%.

Conclusions: The factor V Leiden mutation and resistance to activated protein C are important, independent risk factors for venous thromboembolism. Screening strategies for the factor V Leiden mutation in patients undergoing surgery or experiencing major trauma cannot be recommended, but phenotypic evaluation of resistance to activated protein C should be encouraged in patients with venous thromboembolism.


Grahic Jump Location
Probability of remaining free of thrombosis and age at thrombosis in participants with the factor V Leiden mutation and normal controls.
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