The factor V Leiden (FVL, rs6025) and the prothrombin gene mutation (PGM, rs1799963) are responsible for the majority of inherited thrombophilic states in Caucasians. FVL and PGM mutations are single nucleotide base changes from guanine to adenine, which occur at position 1691 (G1691A) and at position 20210 (G20210A), respectively. The result of these mutations promotes a hypercoagulative state, predisposing affected individuals to venous thromboembolism. The FVL mutation causes an amino acid substitution of arginine for glutamine in the gene product, which alters the ability of activated protein C to cleave activated factor V and VIII, resulting in a prothrombotic state.
Similarly, the PGM leads to increased serum levels of prothrombin, the penultimate product of the coagulation cascade. The risk of venous thromboembolism is dependent on zygosity and may result in recurrent thrombotic events, especially considering that many affected individuals are young. Therefore, genetic testing is necessary to determine the presence of FVL or PGM and establish zygosity. Genotyping also helps guide clinical therapeutic decisions and provides critical information for other family members who may be at risk of harboring these mutations.