Several inherited prothrombotic risk factors have been identified so far. Among them, the
factor V (
FV) Leiden mutation causes a reduced ability of activated
protein C to inactivate activated FV and is the most frequent genetic predisposing factor for
venous thromboembolism. However, the high prevalence of
FV Leiden (up to 15%) in the Caucasian population suggests that this mutation might confer an evolutionary survival advantage. Indeed, there is mounting evidence about the role of
FV Leiden in modulating the clinical phenotype of some physiological and pathological conditions, including
hemophilia. The existing literature on the interaction between
FV Leiden and
hemophilia-related
factor VIII or IX mutations is analyzed in this review focusing on the clinical effects and possible pathogenic mechanisms. In summary, current evidence suggests that this prothrombotic mutation may compensate for the low
factor VIII or IX levels, resulting in more efficient
thrombin generation and ensuing attenuation of clinical symptoms. On the other hand, the association of this prothrombotic mutation with other acquired or inherited thrombophilic factors might overcome the congenital
bleeding tendency in hemophiliacs, thereby increasing the risk of thrombotic complications.